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Gastric cancer: a comprehensive review of current and future treatment strategies

Affiliations.

1 Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R, HWCRC 732, Detroit, MI, 48201, USA.
2 Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R, HWCRC 732, Detroit, MI, 48201, USA. [email protected].
PMID: 32894370
PMCID: PMC7680370
DOI: 10.1007/s10555-020-09925-3

Gastric cancer remains a major unmet clinical problem with over 1 million new cases worldwide. It is the fourth most commonly occurring cancer in men and the seventh most commonly occurring cancer in women. A major fraction of gastric cancer has been linked to variety of pathogenic infections including but not limited to Helicobacter pylori (H. pylori) or Epstein Barr virus (EBV). Strategies are being pursued to prevent gastric cancer development such as H. pylori eradication, which has helped to prevent significant proportion of gastric cancer. Today, treatments have helped to manage this disease and the 5-year survival for stage IA and IB tumors treated with surgery are between 60 and 80%. However, patients with stage III tumors undergoing surgery have a dismal 5-year survival rate between 18 and 50% depending on the dataset. These figures indicate the need for more effective molecularly driven treatment strategies. This review discusses the molecular profile of gastric tumors, the success, and challenges with available therapeutic targets along with newer biomarkers and emerging targets.

Keywords: Autophagy; Gastric adenocarcinoma; Gastric cancer; Non coding RNAs; Novel targets; Piwi RNA; lncRNA.

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Conflict of interests: The authors have no conflict to declare.

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Published: 27 May 2023

Gastric cancer treatment: recent progress and future perspectives

Wen-Long Guan 1 , 2 na1 ,
Ye He 1 , 2 na1 &
Rui-Hua Xu 1 , 2

Journal of Hematology & Oncology volume 16 , Article number: 57 ( 2023 ) Cite this article

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Gastric cancer (GC) is one of the most common malignancies worldwide. Most patients are diagnosed at advanced stages due to the subtle symptoms of earlier disease and the low rate of regular screening. Systemic therapies for GC, including chemotherapy, targeted therapy and immunotherapy, have evolved significantly in the past few years. For resectable GC, perioperative chemotherapy has become the standard treatment. Ongoing investigations are exploring the potential benefits of targeted therapy or immunotherapy in the perioperative or adjuvant setting. For metastatic disease, there have been notable advancements in immunotherapy and biomarker-directed therapies recently. Classification based on molecular biomarkers, such as programmed cell death ligand 1 (PD-L1), microsatellite instability (MSI), and human epidermal growth factor receptor 2 (HER2), provides an opportunity to differentiate patients who may benefit from immunotherapy or targeted therapy. Molecular diagnostic techniques have facilitated the characterization of GC genetic profiles and the identification of new potential molecular targets. This review systematically summarizes the main research progress in systemic treatment for GC, discusses current individualized strategies and presents future perspectives.

Gastric cancer (GC) is the fifth most common malignant tumor and the fourth leading cause of cancer-associated death worldwide [ 1 , 2 ]. The incidence varies geographically across the globe, with the highest incidence in Eastern Asia (Japan and Mongolia) and Eastern Europe, whereas incidence rates in Northern Europe and Northern America are generally low, comparable to African regions [ 2 ]. Notably, the incidence of gastric cancer among young adults (aged < 50 years) in recent years has been progressively rising in both low-risk and high-risk countries. Aside from Helicobacter Pylori infection, the occurrence of GC has been linked to genetic risk factors as well as lifestyle factors, such as alcohol consumption and smoking [ 3 , 4 , 5 , 6 ].

Despite the high incidence of GC, most patients are unfortunately diagnosed at advanced stages with dismal prognoses due to the lack of distinguishing clinical indications [ 7 , 8 ]. Systemic chemotherapy is the mainstay treatment for metastatic GC (mGC), with a median overall survival (OS) of ~ 12 months for patients treated with conventional chemotherapy [ 9 ]. Intratumoral and intertumoral heterogeneity are the prominent features of GC that partly contribute to its poor prognosis. However, histological classifications alone are insufficient to effectively stratify patients for individualized treatment and improve patients’ clinical outcomes [ 10 ]. Therefore, cutting-edge diagnostic techniques and drugs are of fundamental importance for better characterizing molecular profiles and identifying potential novel therapeutic targets for GC patients [ 11 , 12 , 13 ].

Trastuzumab, a monoclonal antibody targeting Human Epidermal Receptor 2 (HER2), was the first approved targeted therapy for GC. However, after the ToGA study, progress in the development of treatments for gastric cancer stalled for nearly a decade [ 14 ]. Emerging advances in immunotherapy, particularly in anti-HER2 therapy, and various biomarker-directed therapies in GC have recently broken this trend. For example, anti-programmed cell death 1 (PD-1) antibodies have demonstrated impressive efficacy and prolonged survival in untreated MSI-H/dMMR mGC patients [ 15 ]. Substantial breakthroughs in the treatment of gastric cancer have been achieved with novel anti-HER2 therapeutic agents, such as T-DXd and disitamab vedotin (RC48) [ 16 ]. In addition, in light of the success of immunotherapy and targeted therapy as first-line treatments for advanced gastric cancer, ongoing research is investigating their potential to advance the treatment of patients with locally advanced stage GC.

The treatment landscape of gastric cancer has evolved significantly in the past few years, with the emergence of new immunotherapy and targeted therapies for patients at various stages of the disease (Fig. 1 ). In this review, we systematically summarize the pivotal clinical trials in GC treatment and provide an update on the management of localized and metastatic gastric cancer. We also discuss the developments in immunotherapy and targeted therapy and highlight current individualized treatments and future perspectives.

Updated immunotherapy and targeted therapy for gastric cancer. This algorithm provides guidance for selecting currently available immunotherapy and targeted therapy based on different biomarkers

Management for localized GC

Radical surgery is the primary treatment for resectable gastric cancer. Several therapeutic approaches have been established to lower the risk of recurrence and improve long-term survival, including perioperative chemotherapy, adjuvant chemotherapy, and adjuvant chemoradiotherapy (Table 1 ). They are listed as the recommended treatments for resectable localized GC in current guidelines[ 5 , 17 , 18 ]. Further, the addition of targeted therapy and/or immune checkpoint inhibitors (ICIs) is currently being studied in the neoadjuvant/adjuvant setting.

Perioperative chemotherapy

Perioperative chemotherapy has become the standard treatment for resectable localized GC. Several clinical trials have demonstrated that perioperative chemotherapy could improve the prognosis of patients with resectable GC compared to surgery alone.

The MAGIC trial marked a significant advancement in the field of perioperative chemotherapy for resectable GC. In this phase 3 study, 503 patients were enrolled with resectable gastric, gastroesophageal junction (GEJ), or lower esophageal adenocarcinoma. Patients in the experimental group received three preoperative and three postoperative cycles of epirubicin, cisplatin, and fluorouracil (ECF) [ 19 ]. The results showed that the perioperative ECF regimen could decrease tumor stage and significantly improve progression-free survival (PFS, HR 0.66; 95% CI 0.53–0.81, P < 0.001) and overall survival (OS, HR 0.75; 95% CI 0.60–0.93, P = 0.009). Another phase III trial conducted in 28 French centers compared radical surgery with or without perioperative cisplatin and fluorouracil (CF) chemotherapy and showed that perioperative chemotherapy led to a higher 5-year overall survival rate versus surgery alone (38% versus 24%, respectively; HR 0.69; 95% CI 0.50–0.95, P = 0.02) [ 20 ]. Recently, the randomized phase II/III FLOT4-AIO study compared perioperative FLOT regimen (fluorouracil, leucovorin, oxaliplatin, and docetaxel) with previous standard ECF/ECX (epirubicin, cisplatin, and fluorouracil/capecitabine) regimen in gastric or GEJ cancer patients who had cT2 or higher and nodal positive (cN +) disease [ 21 ]. The results suggested that the FLOT regimen could improve overall survival (50 months versus 35 months), confirming the role of the FLOT regimen as the new standard perioperative treatment for resectable gastric cancer [ 5 , 18 ].

Since most of the clinical trials mentioned above were conducted in western countries, these perioperative regimens (ECF, CF, and FLOT) are less frequently used in Asia. In the phase III PRODIGY trial, 530 Korean patients with cT2-3N + or cT4N any gastric or GEJ cancer were randomly randomized to the neoadjuvant or adjuvant group. Patients in the neoadjuvant arm underwent preoperative DOS (docetaxel, oxaliplatin, and S-1) followed by surgery and S-1 adjuvant chemotherapy, while those in the adjuvant arm received upfront radical surgery followed by S-1 chemotherapy [ 22 ]. The perioperative chemotherapy group had significantly higher rates of R0 resection and pathological complete response (pCR) (95% and 10.4%, respectively). Moreover, PFS was improved in the perioperative arm compared to the adjuvant arm (HR 0.70; 95% CI 0.52–0.95; P = 0.023). The major criticism of this study was that the adjuvant S-1 monotherapy was insufficient for stage III patients, considering another phase III study had demonstrated the superiority of docetaxel plus S-1 to S-1 for 3-year relapse-free survival (RFS) in stage III gastric cancer [ 23 ]. Recently, the phase III RESOLVE trial conducted in China investigated the role of perioperative S-1 plus oxaliplatin (SOX) chemotherapy versus upfront surgery followed by adjuvant chemotherapy [ 24 ]. This study recruited over 1,000 patients with cT4aN + or cT4bN any gastric or GEJ adenocarcinoma, of whom over 60% had gastric cancer. Patients in the intervention group received perioperative SOX (three preoperative cycles and five postoperative cycles followed by three cycles of S-1 monotherapy). The two adjuvant groups received surgery followed by SOX or CAPOX (capecitabine and oxaliplatin) chemotherapy. These results suggested that the perioperative SOX chemotherapy could improve the 3-year disease-free survival (DFS) rate compared to adjuvant CAPOX therapy (59.4% vs. 51.1%, respectively, P = 0.028).

Based on the evidence shown above, perioperative chemotherapy has become the standard treatment in many countries. The FLOT regimen is the most commonly used in Western countries according to the evidence from the FLOT4-AIO study[ 21 ], while the SOX regimen is more recommended in China, based on the results of the RESOLVE study[ 24 ]. However, perioperative chemotherapy is less recommended in Japan, since evidence of the superiority of neoadjuvant chemotherapy is still lacking among Japanese patients[ 25 ].

Adjuvant chemotherapy

Adjuvant chemotherapy is recommended for patients who undergo primary surgery and have stage II or stage III disease due to improvement in survival demonstrated by several clinical trials, particularly in Asian patients. The multi-center phase III CLASSIC trial undertaken in South Korea, China, and Taiwan compared upfront D2 surgery followed by CAPOX adjuvant chemotherapy versus D2 gastrectomy alone in patients with stage II-IIIB gastric cancer [ 26 , 27 ]. Adjuvant CAPOX chemotherapy significantly improved both 5-year DFS (68% vs. 53%; HR 0.58; 95% CI, 0.47 to 0.72; P < 0.0001) and OS (78% vs. 69%; HR 0.66; 95% CI, 0.51 to 0.85; P = 0.0015) compared with surgery alone. Another similar phase III ACTS-GC trial from Japan randomly assigned 1,059 stage II or III GC patients to undergo D2 surgery followed by S-1 monotherapy or D2 surgery alone and showed that adjuvant S-1 monotherapy for one year led to a better 3-year OS than surgery alone (80.1% vs. 70.1%; HR 0.68; 95% CI, 0.52 to 0.87; P = 0.003). The survival benefit persisted after five years of follow-up [ 28 ]. Moreover, the phase III JACCRO GC-07 trial investigated the superiority of adjuvant docetaxel plus S-1 over S-1 monotherapy for pathological stage III gastric cancer [ 23 ]. The addition of docetaxel to S-1 after surgery showed a better 3-year RFS (66% vs. 50%; HR 0.632; 99.99% CI, 0.400 to 0.998; P < 0.001) in the second interim analysis, and the study was terminated as recommended by the independent data and safety monitoring committee. The RESOLVE trial also investigated the non-inferiority of adjuvant SOX chemotherapy compared with the CAPOX regimen. The 3-year DFS was statistically comparable between the two groups (56.5% vs. 51.1%; HR 0.86; 95% CI, 0.68 to 1.07; P = 0.17) [ 24 ]. Based on the results of the phase III trials presented above, several cytotoxic regimens could be used as adjuvant treatments for stage II-III GC after radical surgery, including S-1, CAPOX, SOX, and DS. The choice of regimens depends on many factors, including the pathological staging, patient performance status, and toxicity profile. In general, S-1 monotherapy is more recommended for stage II disease or for patients with poor performance status. Combination therapies such as CAPOX, SOX, or DS are often recommended for pathological stage III disease[ 17 , 25 ].

GC with microsatellite instability-high (MSI-H) or mismatch-repair deficiency (dMMR) is a distinct subtype [ 11 ]. Recently, an individual-patient-data meta-analysis including data from four large phase III studies (CLASSIC, ARTIST, MAGIC, and ITACA-S trial) explored the role of adjuvant chemotherapy in the MSI-H subtype [ 29 ]. It showed that for resectable MSI-H/dMMR GC patients, the prognosis of patients who received surgery alone was better than those who underwent surgery followed by adjuvant chemotherapy, even though the sample size of MSI-H/dMMR in this meta-analysis was very modest (N = 121). Based on this result, adjuvant chemotherapy is not recommended for resectable MSI-H/dMMR GC patients in the latest ESMO guideline [ 5 ]. Additionally, the updated CSCO guidelines suggest that either observation or adjuvant chemotherapy could be considered after a thorough discussion with the patients regarding the possible risks and benefits [ 17 ].

Adjuvant chemoradiotherapy

Unlike chemotherapy, the role of radiotherapy for resectable GC in the adjuvant setting is controversial. Adjuvant chemoradiotherapy (CRT) was once adopted in North America, according to the results of the phase III INT-0116 trial [ 30 ]. In this study, 556 patients with resectable GC or GEJ adenocarcinoma were randomly assigned to the upfront surgery plus adjuvant CRT group or the surgery group. Patients in the experimental arm received adjuvant fluorouracil chemotherapy plus 4500 cGy of radiation (5 × 5). Overall, CRT did prolong the OS compared to surgery alone (36 vs. 27 months, respectively; P = 0.005). However, most patients in this study received D0 or D1 lymphadenectomy and only 10% had D2 lymphadenectomy. The extent of dissection might affect the outcome of the surgery-only group. The phase III ARTIST trial from Korea evaluated the role of postoperative CRT based on the D2 dissection backbone [ 31 ]. Four hundred fifty-eight patients who received D2 lymphadenectomy and R0 resection were enrolled and randomly assigned to the adjuvant chemotherapy arm (capecitabine plus cisplatin, XP) or the adjuvant CRT arm (XP-XRT-XP). Unfortunately, the addition of radiotherapy postoperatively did not improve their DFS ( P = 0.0862). However, in the subgroup analysis, DFS was significantly prolonged in the CRT arm in the patients with lymph node-positive (N +) disease (3-year DFS rate: 77.5% vs.72.3%, HR 0.69, 95% CI 0.474–0.995, P = 0.0365). Based on these findings, the subsequent ARTIST II trial further explored the role of adjuvant CRT in patients with lymph node-positive GC [ 32 ]. Five hundred forty-six patients after D2 dissection were randomly assigned to adjuvant S-1, adjuvant SOX, and adjuvant SOX plus radiotherapy (SOXRT) in a 1:1:1 ratio. However, there was no significant difference in DFS between the adjuvant SOX and SOXRT treatments (3-year DFS rate: 72.8% vs.74.3%; HR 0.97, 95% CI 0.66–1.42, P = 0.879). Therefore, according to current results from these clinical trials, adjuvant CRT is not recommended in patients who received D2 lymphadenectomy and R0 resection.

Novel perioperative therapies

Perioperative targeted therapy.

Anti-HER2 and anti-vascular endothelial growth factor (VEGF) therapies have been recommended as the standard treatments for advanced GC in the first- and second-line setting, respectively. However, the role of targeted therapy in the perioperative or adjuvant setting is still unclear and is currently under investigation.

Anti-HER2 therapy

According to the ToGA study, adding trastuzumab to chemotherapy improved the OS in patients with metastatic HER2-positive GC [ 14 ]. However, the role of anti-HER2 therapy in resectable GC was unclear. In the multicenter phase II HER-FLOT study, patients with HER2-positive esophagogastric adenocarcinoma received perioperative FLOT chemotherapy for four cycles preoperatively and four cycles postoperatively, followed by 9 cycles of trastuzumab monotherapy [ 33 ]. The pCR rate was 21.4%, and the median DFS was 42.5 months. The phase II randomized PETRARCA study investigated the efficacy of adding trastuzumab and pertuzumab to perioperative FLOT chemotherapy in patients with ≥ cT2 or cN + resectable GC [ 34 ]. The pCR rate was significantly improved with trastuzumab and pertuzumab (35% vs. 12%, P = 0.02), and the R0 resection rate and surgical morbidity were comparable between both groups. However, adding targeted therapy to perioperative chemotherapy did not improve DFS or OS and caused more severe adverse events (≥ grade 3), especially diarrhea (41% vs. 5%) and leukopenia (23% vs. 13%). Based on these results, the trial did not proceed to phase III. Another phase II NEOHX study recruited 36 HER2-positive GC patients who received perioperative CAPOX plus trastuzumab treatment, followed by 12 cycles of trastuzumab maintenance therapy [ 35 ]. The pCR rate, 18-month DFS rate, and 5-year OS rate were 9.6%, 71%, and 58%, respectively. The randomized phase II INNOVATION trial assigned patients to 3 groups: perioperative chemotherapy, chemotherapy plus trastuzumab, and chemotherapy plus trastuzumab and pertuzumab [ 36 ]. According to the investigators' choice, the chemotherapy could be FLOT, CAPOX, FOLFOX, or XP. The primary endpoint was major pathological response (MPR) rate, and the result is pending. In general, adding anti-HER2 therapy to chemotherapy showed certain efficacy in the perioperative setting, but the associated survival benefit should be further investigated in a larger randomized trial.

Anti-VEGF therapy

As for anti-VEGF therapy, the randomized, open-label, phase II/III ST03 trial recruited 1,063 resectable esophagogastric adenocarcinoma patients and randomly assigned them to perioperative chemotherapy (ECX) group or perioperative chemotherapy plus bevacizumab group [ 37 ]. The result showed that adding bevacizumab did not improve the 3-year OS (48.1% vs. 50.3% for chemotherapy alone; HR 1.08; 95% CI, 0.91 to 1.29; P = 0.36). Besides, adding bevacizumab was associated with higher rates of postoperative anastomotic leak (24% vs. 10%). Ramucirumab, a VEGF receptor 2 inhibitor, has become one of the standard choices in the second-line treatment of GC [ 5 , 17 , 18 ]. The RAMSES/FLOT7 evaluated the efficacy of adding ramucirumab to perioperative FLOT for resectable GC [ 38 ]. The R0 resection rate in the intervention group was improved compared to the chemotherapy group (96% vs. 82%, P = 0.0093). The median DFS was prolonged in the FLOT plus ramucirumab group (32 months vs. 21 months), while the OS was similar in both groups (46 months vs. 45 months).

Perioperative immunotherapy

Based on several phase III clinical trials, programmed death 1 (PD-1) inhibitors were approved for first- and third-line treatment of unresectable/metastatic GC in different countries [ 5 , 17 , 18 ]. However, the role of ICI in resectable GC remains unclear and is being investigated in various clinical trials. In the randomized phase II DANTE trial, patients with resectable GC were assigned to the experimental arm with the PD-L1 inhibitor atezolizumab plus FLOT chemotherapy and the control arm with standard FLOT chemotherapy [ 39 ]. The R0 resection rate, surgical morbidity and mortality were comparable in both groups. Atezolizumab combined with chemotherapy was associated with tumor downstage and pathological regression, which were more pronounced in patients with a higher PD-L1 combined positive score (CPS).

Several single-arm phase II clinical trials explored the efficacy of perioperative ICIs combined with different treatments (chemotherapy, targeted therapy, or radiotherapy) in resectable GC [ 40 , 41 , 42 , 43 , 44 ]. The pCR rates ranged from 10 to 41%. In the phase III ATTRACTION-5 trial (NCT03006705), the use of nivolumab in the adjuvant setting was investigated. Patients who have undergone D2 surgery will receive either S-1 for one year or CAPOX for six months, with nivolumab added to the adjuvant therapy in the intervention arm. The primary endpoint of the study is relapse-free survival (RFS). The result was announced recently. Unfortunately, the addition of nivolumab did not extend the RFS compared with adjuvant chemotherapy alone. Additionally, the role of pembrolizumab in combination with perioperative chemotherapy for resectable GC is being examined in the phase III clinical trial, KEYNOTE-585 [ 45 ]. The chemotherapy regimens under investigation are XP, FP, or FLOT, and the primary endpoints of the study are OS, event-free survival (EFS), and pCR rate. The potential survival benefits and efficacy of ICI are also being evaluated in the double-blind, randomized phase III MATTERHORN study, which is based on the FLOT backbone [ 46 ]. Patients with resectable GC will receive either perioperative FLOT or FLOT plus durvalumab (a PD-L1 antibody). The primary endpoint of the study is EFS, with secondary endpoints including OS and pCR rate.

For the dMMR/MSI-H subgroup, as discussed above, the value of chemotherapy was controversial. Considering dMMR/MSI-H is a predictive biomarker for immunotherapy in advanced GC, treatment with immune checkpoint inhibitors in the perioperative setting has the potential to improve the response rate and survival. The phase II GERCOR NEONIPIGA study evaluated the response rate and safety of the combination of neoadjuvant nivolumab and low-dose ipilimumab followed by adjuvant nivolumab in patients with dMMR/MSI-H locally advanced G/GEJ adenocarcinoma. Among 29 patients who underwent surgery, 17 (58.6%; 90% CI, 41.8–74.1) achieved pCR[ 47 ]. Similarly, the pCR rate of tremelimumab plus durvalumab was 60% in the neoadjuvant setting (cohort 1) in the phase II INFINITY study[ 48 ]. Based on these encouraging results, it is possible for patients who achieved pCR after neoadjuvant immunotherapy to avoid surgery. Cohort 2 of the INFINITY study has started enrollment to investigate the activity of tremelimumab plus durvalumab as the definitive treatment for dMMR/MSI-H locally advanced GC.

Management for unresectable/metastatic GC

Chemotherapy.

Cytotoxic agents, including fluoropyrimidine, platinum, taxanes and irinotecan, are the main treatment in advanced gastric cancer. Generally, fluoropyrimidine (fluorouracil, capecitabine, and S-1) combined with platinum is used as the backbone therapy in the first line. Oxaliplatin is considered to be as effective as cisplatin. In the phase III SOX-GC trial, the SOX regimen showed improved survival compared to the SP regimen in diffuse or mixed-type GC[ 49 ]. For patients who are not fit for intensive chemotherapy (older age or poor performance status), the phase III GO2 trial showed that a modified dose of two-drug chemotherapy (60% of the full dose) provided a better tolerance but did not compromise the clinical outcome[ 50 ]. Paclitaxel, docetaxel, and irinotecan are commonly used in the second line of chemotherapy. In the ABSOLUTE phase III clinical trial conducted in Japan, weekly use of albumin-bound paclitaxel (nab-paclitaxel) was not inferior to weekly solvent-based paclitaxel in terms of overall survival[ 51 ]. In third-line treatment, trifluridine-tipiracil (TAS-102), an oral cytotoxic agent, has been proven in the phase III TAGS trial to improve overall survival compared with placebo (5.7 vs.3.6 months, HR 0.69, 95% CI 0.56–0.85)[ 52 ].

Immune Checkpoint Inhibitors (ICIs) in unresectable/metastatic GC

Immune checkpoint inhibitors (ICIs) (monotherapy or combined with other treatments) have shown anti-tumor effects across a spectrum of solid tumors, including gastrointestinal tumors. Here, we present an overview of current evidence of ICI treatment in GC (Table 2 ) and discuss different predictive biomarkers for ICIs.

KEYNOTE-062 was the first global, randomized phase III trial to compare the efficacy and safety of immuno-monotherapy (pembrolizumab) or immunotherapy plus chemotherapy versus standard chemotherapy in HER2-negative advanced GC in the first-line setting [ 53 ]. According to the last update in ASCO 2022, it was suggested that pembrolizumab monotherapy was non-inferior to chemotherapy alone (cisplatin and fluorouracil/capecitabine) in patients with PD-L1 CPS ≥ 1 (median OS 10.6 vs. 11.1 months, HR 0.90, 95% CI 0.75–1.08) but was superior in the CPS ≥ 10 population (median OS 17.4 vs. 10.8 months; HR, 0.62; 95% CI, 0.45–0.86) [ 54 ]. However, the combination of pembrolizumab and chemotherapy did not bring OS benefit compared to chemotherapy alone in either CPS ≥ 1 (12.5 vs. 11.1 months; HR, 0.85; 95% CI, 0.71–1.02) or CPS ≥ 10 (12.3 vs. 10.8 months; HR, 0.76; 95% CI, 0.56–1.03) subgroup [ 54 ]. In another double-blind, placebo-controlled phase III KEYNOTE-859 study, the addition of pembrolizumab to chemotherapy (FP or CAPOX) demonstrated slight survival benefit compared with chemotherapy alone (OS 12.9 vs. 11.5 months, HR, 0.78; 95% CI, 0.70–0.87. PFS 6.9 vs. 5.6 months, HR, 0.76; 95% CI, 0.67–0.85). The results were generally consistent in different PD-L1 CPS subgroups[ 55 ].

CheckMate-649 is another global, randomized, phase III trial investigating the effects of ICIs (nivolumab plus ipilimumab, a CTLA-4 inhibitor) or ICI (nivolumab) plus chemotherapy versus chemotherapy (CAPOX or FOLFOX) alone in metastatic HER2-negative GC patients [ 56 ]. One thousand five hundred eighty-one patients were assigned to nivolumab plus chemotherapy arm or chemotherapy arm. The addition of nivolumab to chemotherapy improved the OS (14.4 vs. 11.1 months; HR 0.71; 98.4% CI, 0.59 to 0.86; P < 0.0001) and PFS (7.7 vs. 6.05 months; HR 0.68; 98% CI, 0.56 to 0.81; P < 0.0001) for the patients with PD-L1 CPS ≥ 5; therefore both primary endpoints were met. For all-randomized patients, nivolumab combined with chemotherapy also improved OS (13.8 vs. 11.6 months; HR 0.80; 99.3% CI, 0.68 to 0.94; P = 0.0002). Moreover, all CPS subgroups exhibited an increased objective response rate in the nivo-chemotherapy arm. However, the chemo-free treatment with nivolumab and ipilimumab did not show OS improvement compared to chemotherapy alone [ 57 ]. Based on these findings, nivolumab combined with chemotherapy was listed as one of the recommended first-line treatments in the NCCN, ESMO, and CSCO guidelines [ 5 , 17 , 18 ].

ATTRACTION-04 was a randomized, double-blind, placebo-controlled, multicenter phase II/III trial that evaluated the effects of nivolumab plus chemotherapy (SOX or CAPOX) compared with chemotherapy alone in the first-line treatment for HER2-negative advanced GC in the Asian population, regardless of PD-L1 expression [ 58 ]. The combination therapy significantly improved the PFS (HR 0·68; 98·51% CI 0·51–0·90; P = 0·0007) but not the OS (both groups achieved > 17 months of median OS). One of the possible reasons for the different results of OS between ATTRACTION-04 and CheckMate-649 could be the subsequent anticancer therapies, whereby the proportion of patients who received subsequent anticancer treatments or ICIs therapy was much higher in ATTRACTION-04 (66% vs. 39% in CheckMate-649).

The efficacy of immunotherapy plus chemotherapy was further confirmed in the Asian phase III ORIENT-16 trial, which compared sintilimab plus chemotherapy (CAPOX) to chemotherapy alone as the first-line treatment [ 59 ]. The pre-specified interim result was reported at ESMO 2021. Sintilimab plus chemotherapy showed a survival benefit versus chemotherapy alone in patients with CPS ≥ 5 (18.4 vs. 12.9 months; HR 0.660; 95% CI 0.505–0.864) and all randomized patients (15.2 vs. 12.3 months; HR 0.766; 95% CI 0.626–0.936). Another PD-1 antibody, tislelizumab, is currently being investigated in the phase III RATIONALE-305 trial [ 60 ]. Advanced GC patients are randomized to receive tislelizumab plus chemotherapy (CAPOX/FP regimen) or chemotherapy alone. The primary endpoints are PFS and OS. Results from the interim analysis of the PD-L1 + (i.e., PD-L1 TAP score ≥ 5%) population were represented at 2023 ASCO-GI, showing that tislelizumab plus chemotherapy led to significant OS (17.2 vs. 12.6 months; HR 0·74; 95% CI 0·59–0·94) and PFS (7.2 vs. 5.9 months; HR 0·67; 95% CI 0·55–0·83) improvement compared to chemotherapy alone[ 61 ]. The ITT population outcomes will be reported after the final analysis.

In summary, in first-line treatment for HER2-negative advanced GC, the addition of anti-PD-1 therapy could improve clinical outcomes in patients with high PD-L1 expression, according to the results from CheckMate-649, ORIENT-16, and RATIONALE-305. For patients with low PD-L1 expression or unknown PD-L1 status, the survival benefit of adding PD-1 antibodies is still controversial (discussed below), and the risk–benefit balance of ICIs treatment should be considered, and decisions should be discussed case by case.

The role of maintenance therapy with ICIs after first-line chemotherapy was evaluated in the phase III JAVELIN Gastric 100 trial [ 62 ]. Patients with HER2-negative advanced GC without progression after at least 12 weeks of first-line chemotherapy (oxaliplatin plus fluoropyrimidine) were randomly assigned to avelumab (a PD-L1 inhibitor) maintenance or continued chemotherapy. Avelumab maintenance did not show OS benefit compared to chemotherapy (24-month OS rate: 22.1% versus 15.5%; HR 0.91; 95% CI, 0.74–1.11; P = 0.1779).

Second line and beyond

The randomized, open-label, phase III KEYNOTE-061 trial compared pembrolizumab monotherapy with paclitaxel in patients with advanced GC or GEJ cancer in the second-line setting [ 53 ]. Though the primary endpoints (the OS and PFS in patients with PD-L1 CPS ≥ 1) were not met, it was suggested that the efficacy of pembrolizumab monotherapy was associated with the PD-L1 CPS level. Patients with CPS ≥ 10 had a better outcome in the pembrolizumab group than in the chemotherapy group.

KEYNOTE-059 was a phase II study that explored the effect of pembrolizumab in patients with advanced GC after progression from ≥ 2 lines of treatment [ 63 ]. Among the 259 patients enrolled, the ORR and median duration of response (DoR) was 11.6% and 8.4 months, respectively. Moreover, pembrolizumab showed higher efficacy in the subgroup with PD-L1-positive cancer (CPS ≥ 1) compared to PD-L1-negative cancers (ORR 15.5% vs. 6.4%; DoR 16.3 vs. 6.9 months, respectively). The phase III ATTRACTION-2 study compared nivolumab monotherapy versus placebo in advanced GC patients after two lines of therapy, regardless of the PD-L1 expression [ 64 ], and survival benefit was observed in the nivolumab group (OS 5.3 vs. 4.1 months; HR 0·63, 95% CI 0·51–0·78; P < 0·0001). Based on the results of this study, nivolumab is recommended as monotherapy in third-line treatment for GC in the CSCO guideline but not in the ESMO or NCCN guidelines due to the patients enrolled being exclusively Asian. The role of avelumab in the third-line treatment for advanced GC was investigated in the phase III JAVELIN Gastric 300 trial [ 65 ]. Though avelumab showed a more manageable safety than the physician's choice of chemotherapy, it did not improve OS (primary endpoint, 4.6 vs. 5.0 months; HR 1.1, 95% CI 0·9–1.4; P = 0.81), PFS, or ORR.

Molecular Biomarkers of Immunotherapy in GC

HER2-positive GC, defined as immunohistochemical (IHC) expression 3+ or 2 + combined with positive fluorescent in situ hybridization (FISH) verification, accounts for approximately 15–20% of gastric or gastroesophageal cancer. The phase III ToGA study has established trastuzumab combined with chemotherapy as the standard first-line treatment for HER2-positive advanced GC [ 14 ]. In preclinical models, HER2 signaling could regulate the recruitment and activation of tumor-infiltrating immune cells [ 66 ]. Besides, trastuzumab has been shown to upregulate the expression of PD-1 and PD-L1 [ 67 , 68 ], and anti-PD-1 antibodies could significantly increase the therapeutic activity of HER2 inhibitors [ 69 ]. Several phase I/II studies demonstrated the promising efficacy of the addition of ICIs to trastuzumab and chemotherapy in HER2-positive GC. In the phase Ib Ni-HIGH study conducted in Japan, patients with HER2-positive advanced GC received nivolumab, trastuzumab, and chemotherapy (CAPOX or SOX regimen) in the first-line setting, and the ORR was 75%, as reported at ASCO 2020 [ 70 ]. The multi-institutional phase Ib/II PANTHERA trial explored the efficacy and safety of the combination of pembrolizumab, trastuzumab and chemotherapy as first-line therapy for HER2-positive advanced GC [ 71 ]. The updated data at ASCO-GI 2021 showed that the ORR was 76.7% (CR 16.3%, PR 60.5%), the PFS was 8.6 months (95% CI 7.2–16.5 months), and the OS was 19.3 months (95% CI 16.5-NR). The striking efficacy was also reported in another phase II study, in which patients with HER2-positive GC received pembrolizumab, trastuzumab and chemotherapy (oxaliplatin/cisplatin + capecitabine/5-FU) [ 72 ]. Overall, the ORR was 91% and DCR was 100%. The median PFS and OS was 13·0 months and 27·3 months, respectively, which was much better than the OS reported in the ToGA study. Recently, the randomized, double-blind, placebo-controlled phase III KEYNOTE-811 trial reported the results of its first interim analysis [ 73 ], in which patients with metastatic HER2-positive GC or GEJ cancer received pembrolizumab or placebo plus trastuzumab and chemotherapy. The results showed that adding pembrolizumab to trastuzumab and chemotherapy could markedly increase the ORR (74.4% vs. 51.9%; the estimated difference between the two groups was 22.7%; 95% CI, 11.2–33.7%; P = 0.00006). Based on this result, the FDA approved pembrolizumab combined with trastuzumab and chemotherapy as the first-line treatment for advanced HER2-positive gastric or GEJ adenocarcinoma. The results of the primary endpoints (PFS and OS) are still immature.

MSI-H tumor is one of the four subtypes of GC according to The Cancer Genome Atlas (TCGA) Research Network [ 11 ]. The incidence of MSI-H status in GC was reported to range from 8 to 25%, which was much lower in metastatic disease [ 74 ]. Mismatch repair (MMR) proteins are supposed to fix the errors that occur during DNA replication. When MMR proteins are deficient, the defects of DNA replication will lead to the accumulation of mutations and the expression of neoantigens, which may act as potential targets of immune cells [ 75 ]. Hence, it is reasonable that tumors with MSI-H/dMMR status may attract more immune cell infiltration and enhance the effect of immune checkpoint inhibitors. A post hoc analysis of KEYNOTE-059 (third-line treatment), KEYNOTE-061 (second-line treatment), and KEYNOTE-062 (first-line treatment) was conducted to evaluate the efficacy of pembrolizumab versus chemotherapy in the patients with MSI-H advanced G/GEJ adenocarcinoma [ 15 ]. Overall, 7 of 174 patients (4.0%) in KEYNOTE-059, 27 of 514 (5.3%) in KEYNOTE-061, and 50 of 682 (7.3%) in KEYNOTE-062 with MSI-H status were enrolled. By the time of analysis, the OS of the patients with MSI-H was not reached for pembrolizumab monotherapy in KEYNOTE-059, 061 and 062, or for pembrolizumab combined with chemotherapy in KEYNOTE-062, compared with an OS of around 8 months for chemotherapy alone. Besides, the ORR was much higher in the immunotherapy groups. In another meta-analysis including four phase III trials (KEYNOTE-062, CheckMate-649, JAVELIN Gastric 100, and KEYNOTE-061), 2545 patients with known MSI status were enrolled, and the proportion of MSI-H was 4.8% [ 76 ]. In the MSI-H group, the HR for OS benefit with immunotherapy was 0.34 (95% CI 0.21–0.54), compared to 0.85 (95% CI 0.71–1.00) for the MSS group. Among the patients with MSI-H status, the HR for PFS was 0.57 (95% CI 0.33–0.97; P = 0.04), and the odds ratio (OR) for ORR was 1.76 (95% CI 1.10–2.83; P = 0.02). Altogether, these findings suggested that MSI-H status was a predictive biomarker for immune checkpoint inhibitor treatments, regardless of the line of therapy.

Epstein-Barr virus-associated GC (EBVaGC) is another distinct molecular subtype of the TCGA classification [ 11 ], accounting for about 9% of GC in the TCGA cohort and approximately 5% in China [ 77 , 78 ]. EBV has been linked to CD8 + T cell infiltration and increased expression of PD-L1 and PD-L2 [ 11 , 79 ], making it a potential biomarker for ICI treatment. While a Korean study with a small sample size (n = 6) once reported a 100% response rate in EBV-positive advanced GC [ 80 ], several other studies did not demonstrate a high response rate [ 81 , 82 , 83 ]. Differences in response rates across studies may be attributed to confounding factors such as tumor mutational burden (TMB) and PD-L1 expression. Therefore, the role of EBV positivity in immunotherapy for GC remains unclear and requires further investigation.

As discussed earlier, the level of PL-L1 expression, especially the CPS score, has been considered a predictive biomarker for response to ICIs. However, the reliable cut-off value to predict the benefit of immunotherapy is needed to be determined. The cut-off points often used in clinical trials are 1, 5 and 10. In the KEYNOTE-059 trial, CPS ≥ 1 was used to separate the patients that could benefit from third-line pembrolizumab treatment [ 63 ]. However, this benefit was not seen compared to chemotherapy in the KEYNOTE-061/062 trials [ 53 , 84 ]. In KEYNOTE-061/062, CPS ≥ 10 effectively differentiated the response to pembrolizumab. Patients with CPS ≥ 10 had better OS benefits than those with CPS ≥ 1. A comprehensive analysis of patients with CPS ≥ 10 in KEYNOTE-059, 061 and 062 also showed consistent improvement toward better outcomes with pembrolizumab in different lines of treatment in this subgroup [ 85 ]. In the CheckMate-649 and ORIENT-16 studies, CPS ≥ 5 was used as the cut-off value for the primary endpoint OS. Though the OS benefit of nivolumab plus chemotherapy was also observed in all randomized patients in CheckMate-649, the subgroup analysis suggested that the benefit was insignificant in the CPS < 5 or < 1 group [ 86 ]. A recent study reconstructed unreported Kaplan–Meier plots of PD-L1 CPS subgroups of three phase III trials (CheckMate-649, KEYNOTE-062, and KEYNOTE-590) and investigated the outcome of low CPS subgroup [ 87 ]. The result suggested that patients with low PD-L1 expression (CPS 1–4 and CPS 1–9) did not benefit from adding ICIs to chemotherapy. In summary, although the predictive role of PD-L1 CPS for immunotherapy efficacy has been demonstrated in multiple clinical trials, there is still a need to determine the optimal cut-off value for CPS and to develop further classifications for patients with low CPS scores. Recently, the result of the phase III RATIONALE-305 trial suggested that the TAP score > 5% also had predictive value for ICI treatment in gastric cancer[ 61 ], and further exploration is needed.

Tumor mutation burden (TMB)

It is hypothesized that a high TMB status results in the high expression of neoantigens, which are immunogenic and can induce the response of the immune system and potentially increase the efficacy of ICI treatment. In a phase Ib/II study that explored the efficacy of the PD-1 antibody toripalimab in patients with advanced GC, patients with TMB-high (TMB-H, TMB ≥ 12 mut/Mb) showed a higher ORR and better OS compared with patients with TMB-L status (ORR 33.3% vs. 7.1%, P = 0.017; OS 14.6 vs. 4.0 months, P = 0.038)[ 88 ]. In the subgroup analysis of the KEYNOTE-061 study, the TMB status (≥ 10 or < 10 mut/Mb) was associated with response rate, PFS, and OS in patients treated with pembrolizumab. In the TMB-H subgroup, pembrolizumab demonstrated a better OS compared with paclitaxel, and this benefit remained even when MSI-H patients were excluded[ 89 ]. Though FDA granted approval for the use of pembrolizumab in patients with TMB-H (i.e., TMB ≥ 10 mutations/Mb) advanced solid tumors that progressed after standard treatments, according to the subgroup analysis of KEYNOTE-158 study[ 90 ], the evidence is still not enough for the use of ICIs in TMB-H gastric cancer, and phase III studies to illustrate the predictive value of TMB are needed.

Molecular targeted therapy in unresectable/metastatic GC

Molecular targeted therapy remains an essential treatment option for patients with advanced GC, aimed to inhibit tumor proliferation and increase survival rates. Targeted therapies, including anti-HER2, anti-angiogenesis, and other biomarker-directed therapies, have demonstrated promising efficacy in treating GC, with significant benefits observed in biomarker-enriched patients (Table 3 ). Therefore, next-generation sequencing or ctDNA detection is crucial for mGC patients to establish a comprehensive molecular profile, including the status of HER2, fibroblast growth factor receptor (FGFR), Claudin18.2 (CLDN18.2), PD-L1 and EGFR.

HER2, also known as ERBB2, is a member of the ERBB protein families that includes the epidermal growth factor receptor (EGFR or HER1), HER3, and HER4 [ 91 ]. HER2 overexpression or amplification has been found in a range of 7.3% to 20.2% in advanced gastric and gastroesophageal junction adenocarcinomas, with the overexpression rate varying globally [ 92 ]. In addition, intestinal-type gastric cancers and those arising from the proximal stomach or gastroesophageal junction are more likely to exhibit HER2 positivity. [ 11 , 93 ].

Trastuzumab is a humanized monoclonal antibody that targets HER2 extracellular domain 4, then inhibits downstream signal activation and cancer cell proliferation. Trastuzumab plus chemotherapy has been established as the standard first-line treatment for HER2-positive advanced GC. The landmark ToGA trial revealed that trastuzumab plus chemotherapy significantly improved the overall survival of patients with advanced GC [ 14 ], especially for patients with HER2 positivity, who were identified as having HER2 immunohistochemistry (IHC) scores of 2 + and fluorescence in situ hybridization (FISH)-positive or HER2 IHC 3 + based on a post-hoc exploratory analysis [ 92 ]. The EVIDENCE trial has demonstrated that combining first-line trastuzumab with chemotherapy was associated with improved clinical outcomes in Chinese patients with HER2-positive metastatic GC, providing real-world evidence. [ 94 ].

However, subsequent attempts of HER2-targeted therapy in advanced GC were not as successful as expected. Even though pertuzumab [ 95 , 96 ], trastuzumab emtansine (T-DM1) [ 97 ], and lapatinib [ 98 , 99 ] were all investigated in several first-line and second-line trials, no survival improvement was observed in any of these trials. Additionally, trastuzumab beyond progression also failed to show a survival benefit in pre-treated HER2-positive GC patients in the T-ACT trial [ 100 ].

Potential resistance mechanisms of HER2-targeted therapy

Primary or acquired resistance is a major impediment to the management of mGC patients, while mechanisms underlying the poor efficacy of HER2-directed therapy in GC are not fully understood. Multiple potential resistance mechanisms have been researched, as listed below, and further studies are warranted to improve treatment resistance in GC patients treated with HER2-targeted therapy in clinical settings.

HER2 heterogeneity

Intratumoral HER2 heterogeneity is observed in 23% to 79% of GC patients and is associated with patients’ survival [ 101 , 102 , 103 ]. Specifically, Shusuke et al. reported prolonged survival in homo-HER2 positive GC patients, defined as all tumor cells overexpressing HER2 in biopsy specimens [ 101 ]. Tumor cells with HER2 overexpression or amplification are killed during HER2-targeted therapy, while residual drug-resistant colonies keep proliferating and eventually take control, leading to tumor recurrence. As a result, resistance to HER2-targeted therapy has been associated with the heterogeneity of HER2 expression [ 101 , 104 , 105 ]. Discordance between next-generation sequencing and FISH/IHC may also indicate intratumoral heterogeneity and result in an unfavorable treatment outcome. In addition, there still exist discrepancies in HER2 status between primary tumor and metastatic sites, which increases the risk of HER2-targeted therapy failure due to false-positive HER2 detection [ 106 , 107 ].

Loss of HER2 expression

For mGC patients experiencing progression on trastuzumab, 29–69% of them may experience loss of HER2 expression, which is an important factor responsible for resistance [ 108 , 109 , 110 ]. Given the risk of HER2 expression loss during treatment, patients should re-evaluate HER2 status upon progression after anti-HER2 therapy to determine the most optimal treatment.

Gene amplification

Receptor tyrosine kinase (RTK) amplification was commonly detected in MET-amplified metastatic GC, with 40% to 50% of cases exhibiting co-amplification of either HER2 or EGFR. These patients did not usually respond to HER2-targeted therapy, but MET and HER2 combination inhibition could sometimes bring extra clinical benefit [ 111 ]. CCNE1, which encodes the cell cycle regulator cyclin E1, is another oncogene co-amplified with HER2 in metastatic GC. CCNE1 co-amplification has been found to be more strongly related to HER2-positive AGC than to HER2-positive breast cancer [ 112 ]. In a phase II study of lapatinib with capecitabine and oxaliplatin in HER2-positive AGC patients, CCNE1 amplification was demonstrated to play a role in resistance to HER2-targeted therapy [ 113 ]. A high level of copy number variation for CCNE1 has also been associated with worse survival in patients with HER2-positive metastatic GC treated with trastuzumab [ 114 ]. Other studies have also reported that deletion of ErbB2 16 exon and co-mutation and/or amplification of KRAS, HER3, EGFR, PI3K or PTEN could contribute to the resistance of anti-HER2 therapy [ 109 , 113 , 115 , 116 ].

Alterations in intracellular signaling

HER2-targeted therapy suppresses downstream signaling pathways by blocking the binding of HER2 receptors and ligands, which inhibits the migration and proliferation of tumor cells and leads to apoptosis. RTK/RAS/PI3K signaling alterations have been shown to be involved in the development of resistance to trastuzumab. [ 109 ]. Furthermore, activation of the bypass pathway might also result in resistance. Sampera et al. discovered that SRC-mediated persistent activation of the MAPK-ERK and PI3K-mTOR pathways was connected to the treatment resistance in HER2-positive GC cell lines [ 117 ]. NRF2 has also been associated with HER2 resistance by activating the PI3K-mTOR signaling pathway [ 118 ].

Newer HER2-targeted agents

To overcome intrinsic and acquired resistance to trastuzumab, various clinical trials have explored newer agents and combinations. The following innovative HER2-targeted agents for advanced metastatic GC are currently under investigation (Table 4 ): monoclonal antibodies (mAbs) (e.g., margetuximab), bispecific antibodies (BsAbs) (e.g., ZW25, KN026), antibody–drug conjugates (ADCs) (e.g., T-DXd, Disitamab vedotin, ARX788), tyrosine kinase inhibitors (TKIs) (e.g., tucatinib), and other novel therapeutic approaches.

Monoclonal antibodies

Margetuximab

Margetuximab is an Fc-engineered anti-HER2 mAb that targets the same epitope as trastuzumab but with a higher affinity for single-nucleotide polymorphisms of the activating Fc receptor (CD16A) [ 119 , 120 ]. Margetuximab can recruit CD16A-expressing natural killer cells, macrophages and monocytes and further promote antibody-dependent cell-mediated cytotoxicity (ADCC) [ 119 ]. The first phase I study of margetuximab in humans illustrated that margetuximab was well-tolerated with promising efficacy in relapsed HER2-overexpressing carcinoma [ 121 ]. Later in the phase Ib/II CP-MGAH22-05 study, patients with previously treated HER2-positive GC responded effectively to a chemotherapy-free treatment consisting of margetuximab plus pembrolizumab. Patients with HER2 IHC3 + and PD-L1 positive (CPS ≥ 1, by IHC) had an ORR of 44% and a DCR of 72% [ 122 ]. More recently, the phase II/III MAHOGANY trial has reported the efficacy of margetuximab plus anti-PD-1 antibody retifanlimab (Cohort A) for the first-line treatment of patients with G/GEJ adenocarcinoma, with an ORR and a DCR of 53% and 73% [ 123 ]. The ORR reported in this trial was superior to the ORR observed with other history chemotherapy-free treatments; nonetheless, given that chemotherapy-based regimens remain the predominant treatment for GC, the MAHOGANY trial has been halted for commercial reasons.

Bispecific antibodies (BsAbs)

Zanidatamab (ZW25)

Zanidatamab (ZW25) is a novel HER2-targeted bispecific antibody that binds to HER2 extracellular domain (ECD) II and IV. According to a phase I study, ZW25 was well tolerated with durable response in heavily pretreated GEA patients (including prior HER2-targeted therapy) [ 86 ]. Later in a phase II trial involving patients with advanced/metastatic HER2-positive GEA, zanidatamab plus chemotherapy (CAPOX or FP) showed a confirmed ORR of 75%, mDOR of 16.4 months and mPFS of 12.0 months in the first-line setting [ 124 ]. Based on these findings, a global phase III study (HERIZON-GEA-01) has been designed to assess the efficacy and safety profiles of zanidatamab plus chemotherapy with or without tislelizumab versus standard of care (trastuzumab plus chemotherapy) for patients with metastatic HER2-positive GEAs in first-line settings [ 125 ].

KN026 mimics the dual effects of trastuzumab and pertuzumab by simultaneously binding to HER2 ECD II and IV [ 126 ]. In a phase II clinical study, KN026 showed favorable results in patients with HER2-overexpressing G/GEJ adenocarcinoma (IHC3 + or IHC 2 + ISH +) with an ORR of 56% [ 127 ]. The ongoing phase II/III trial (KN026-001) is planned to evaluate the survival benefit of KN026 plus chemotherapy in patients with HER2-positive unresectable or advanced G/GEJ adenocarcinoma upon progression after trastuzumab-containing treatment (NCT05427383). Most recently, the preliminary data presented at ESMO 2022 illustrated that KN026 plus KN046, a recombinant humanized PD-L1/CTLA-4 bispecific antibody, had remarkable efficacy and tolerable safety in HER2-positive G/GEJ patients without prior systemic treatment [ 128 ]. In this phase II study, the ORR was 77.8%, and the DCR was 92.6%, indicating the need for a future randomized clinical trial to confirm the efficacy of KN026 plus KN046 treatment versus standard of care.

Other BsAbs

PRS-343 is a BsAb that targets HER2 and the costimulatory immunoreceptor 4-1BB on immune cells. In patients with advanced HER2-positive solid tumors, including GC, PRS-343 showed anticancer efficacy both alone and in combination with the anti-PD-L1 antibody atezolizumab in a phase I clinical study [ 129 ]. A phase II study (NCT05190445) is ongoing to investigate the efficacy of PRS-343 in combination with ramucirumab and paclitaxel in patients who have already received treatment for HER2-high (IHC 3+ or IHC 2+ with HER2/neu gene amplification) G/GEJ adenocarcinoma and in combination with tucatinib in HER2-low (IHC 1+ or IHC 2+ without HER2/neu gene amplification) G/GEJ adenocarcinoma.

Antibody–drug conjugates (ADCs)

Trastuzumab deruxtecan (T-DXd)

Trastuzumab deruxtecan (T-DXd) is an antibody–drug conjugate (ADC) composed of an anti-HER2 antibody connected to a cytotoxic topoisomerase I inhibitor via a cleavable tetrapeptide-based linker [ 130 ]. Different from T-DM1, T-DXd has a bystander effect on nearby cells, including those not expressing HER2, thus greatly enhancing the antitumor effect [ 131 ]. This action method is inspiring, particularly for advanced GC patients with diverse intratumoral HER2 expression. In the Asia DESTINY-Gastric01 trial, T-DXd significantly improved overall survival in patients with HER2 + advanced GC compared with chemotherapy in the later-line settings [ 132 ]. Interestingly, the efficacy and safety of T-DXd were also evaluated in exploratory cohorts of patients with HER2-low G/GEJ cancers in the DESTINY-Gastric01 trial (cohort 1, IHC 2 + /ISH–; cohort 2, IHC 1 +). The confirmed ORR was 26.3% in Cohort 1 and 9.5% in Cohort 2. The median OS was 7.8 months in cohort 1 and 8.5 months in cohort 2[ 133 ]. These results provide initial evidence that T-DXd has clinical benefits in patients with heavily pretreated HER2-low G/GEJ cancers.

Similarly, T-Dxd in the DESTINY-Gastric02 trial also achieved encouraging results in 2L western GC patients with a cORR of 41.8% and a median PFS of 5.6 months [ 134 ]. Other trials, such as phase III 2L DESTINY-Gastric04 and phase III 1L DESTINY-Gastric03, are also in progress (NCT04379596, NCT04704934).

Disitamab vedotin (RC48)

Disitamab vedotin (RC48) is a novel HER2-ADC drug independently developed in China, which is composed of three parts: anti-HER2 extracellular domain antibody, MC-Val-Cit-PAB linker, and cytotoxin monomethyl auristatin E (MMAE) [ 135 ]. This novel antibody has a stronger affinity to HER2 than the standard of care. Unlike T-DM1, disitamab vedotin has a bypass-killing effect on nearby tumor cells regardless of HER2 status, which could help overcome spatial heterogeneity and enhance anti-tumor effects. RC48 was well tolerated and showed promising antitumor activity in patients with HER2-positive advanced GC in a phase I trial [ 136 ]. The phase II RC48-C008 trial revealed a significant benefit of RC48 with HER2-overexpressing GC patients who had undergone at least two prior lines of therapy, in which the ORR was 24.8%, mPFS was 4.1 months and mOS was 7.9 months [ 137 ]. Of note, the ORR of RC48 in patients with HER2 IHC2 + /FISH- was 16.7%, slightly lower than in HER2-positive patients. These findings indicated that RC48 exerted considerable anti-tumor effectiveness and tolerable safety in patients with HER2-positive GC, as well as in those with HER2 low expression GC. In June 2021, disitamab vedotin was approved in China for the treatment of patients with HER2-overexpressing advanced or metastatic G/GEJ adenocarcinoma who received at least two systemic chemotherapy regimens. The ongoing phase III RC48-C007 (NCT04714190) trial aims to evaluate the efficacy and safety of RC48 as a third-line treatment and beyond in patients with advanced HER2-positive GC.

ARX788 is another investigational anti-HER2 antibody–drug conjugate consisting of HER2-targeted monoclonal antibody (mAb) coupled with a highly effective tubulin inhibitor (AS269). ARX788 was well tolerated and had a promising anti-tumor effect in HER2-positive GC patients previously treated with trastuzumab-based regimens in a phase I multicenter dosage expansion trial [ 138 ]. The ORR was confirmed to be 37.9%, and the DCR was 55.2%. With a median follow-up period of 10 months, the mPFS and OS were 4.1 and 10.7 months, respectively. On March 18, 2021, the FDA granted ARX788 as an orphan drug for treating HER2-positive GC. A randomized controlled, multicenter, open-label phase II/III study is underway to assess the efficacy of ARX788 as second-line treatment for HER2-positive advanced G/GEJ adenocarcinoma (Chinadrugtrials.org.cn: CTR20211583).

Tyrosine kinase inhibitors

Tucatinib, a highly selective HER2-directed tyrosine kinase inhibitor (TKI), was approved by FDA for HER2-positive metastatic breast cancer in 2020 and is under exploration in GC. In preclinical studies, tucatinib plus trastuzumab demonstrated superior activity compared to a single agent in GEC xenograft models [ 139 ]. Recently, the phase II/III MOUNTAINEER-02 (NCT04499924) was initiated to evaluate the efficacy of tucatinib, trastuzumab combined with ramucirumab, and paclitaxel in previously treated HER2 + advanced G/GEJ adenocarcinoma [ 140 ].

Other novel therapeutic approaches are being under investigation, including anti-HER2 CAR-T-cell therapy (NCT04511871, NCT04650451), CAR-natural killer cell (NK) therapy [ 141 ], and CAR-macrophage (CAR-M) therapy (NCT04660929), B-cell and monocyte-based immunotherapeutic vaccines (BVAC-B), BAY2701439 and CAM-H2 targeted HER2 radiotherapy (NCT04147819, NCT04467515). These widespread attempts at HER2-targeted CAR cell therapy in solid tumors may hopefully lead to the development of new drug candidates in patients with HER2-positive GC.

Antiangiogenic therapy

Blocking angiogenesis is a key strategy in GC therapy, including anti-VEGF monoclonal antibodies, VEGF-binding proteins, and VEGF receptor TKIs (Table 5 ) [ 142 ]. Ramucirumab, a typical antiangiogenic monoclonal antibody, targets VEGFR-2 and is approved by the FDA for treating advanced GC [ 143 ]. In the second-line REGARD trial, ramucirumab demonstrated significant improvement in patient OS and PFS versus best supportive care in metastatic GC [ 144 ]. In the RAINBOW trial, when coupled with paclitaxel, ramucirumab significantly prolonged overall survival compared to paclitaxel alone [ 145 ]. Similarly, results from RAINBOW-Asia bridging study also supported the application of ramucirumab plus paclitaxel as second-line therapy in a predominantly Chinese population with advanced gastric or GEJ adenocarcinoma [ 146 ]. However, neither ramucirumab nor bevacizumab brought extra survival benefits when added to platinum or fluoropyrimidine chemotherapy in GC patients in the first-line settings [ 147 , 148 ].

Regorafenib is an oral multi-kinase inhibitor targeting angiogenic, stromal and oncogenic receptor tyrosine kinases (RTK). Results from a phase III trial (INTEGRATE IIa) presented at ASCO GI 2023 demonstrated that regorafenib significantly improved OS (4.5 months vs. 4.0 months; HR = 0.52; P = 0.011) in patients with advanced gastro-oesophageal cancer (AGOC) in later-line settings [ 149 ]. Meanwhile, other studies exploring the efficacy of anti-VEGF and anti-PD1 combination in GC populations are also under investigation. The combination of regorafenib and nivolumab had a manageable safety profile and effective antitumor activity in a phase I trial for the GC subgroup [ 150 ]. INTEGRATE IIb ((NCT0487936)), an international randomized phase 3 trial, is ongoing to compare regorafenib plus nivolumab to standard chemotherapy in pre-treated patients with AGOC. Besides, lenvatinib plus pembrolizumab showed promising anti-tumor activity with an ORR of 69% in the first-line and second-line treatment of advanced GC [ 151 ].

Apatinib is a small molecule VEGFR inhibitor with China Food and Drug Administration (CFDA) approval for the treatment of advanced or metastatic chemotherapy-refractory GC. Apatinib improved median PFS and OS versus placebo in Chinese patients with advanced gastric or gastroesophageal junction adenocarcinoma in the third line and beyond[ 152 ]. Most of the patients in this trial did not receive prior antiangiogenic therapies since they were not standard treatments in China at that time, so clinical evidence is still lacking for the use of apatinib in patients who previously received ramucirumab. Unfortunately, no significant improvements were observed in overall survival (OS) in western populations in the phase III ANGEL clinical trial [ 153 ].

Fruquintinib is a highly selective VEGFR family kinase inhibitor that targets VEGFR1, 2 and 3 and is independently developed in China. Fruquintinib was approved in China by the NMPA in September 2018 and commercially launched in late November 2018 as a third-line treatment for patients with metastatic colorectal cancer. In a phase Ib/II study, adding fruquintinib to paclitaxel as second-line treatment for mGC patients at recommended phase 2 dose (RP2D) showed an mPFS of 4 months and mOS of 8.5 months. In the 4 mg dose cohort of 27 patients with evaluable tumor response, the ORR was 25.9% and the DCR was 66.7%[ 154 ]. A randomized phase III FRUTIGA study has investigated fruquintinib plus paclitaxel versus paclitaxel alone in patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma who had progressed after first-line standard chemotherapy (NCT03223376). Initial results from FRUTIGA showed that fruquintinib combined with paclitaxel showed significant improvements in PFS, ORR and DCR. Full detailed results are still being analyzed and will be revealed soon.

Other biomarker-targeted therapy

Novel diagnostic techniques have contributed to characterizing the genetic profile of GC and identifying new potential molecular targets. Recently, researchers have looked into Claudin-18.2-targeted therapy, fibroblast growth receptor (FGFR) pathway inhibitors, and EGFR inhibitors as effective targeted therapies to treat advanced GC (Table 5 ). Although emerging innovative drugs have made remarkable progress in GC treatments, extensive clinical explorations are needed to advance precision medicine.

CLAUDIN 18.2-targeted therapy

Claudin 18.2 (CLDN18.2), a component of intercellular junctions [ 155 ], is exclusively detected in gastric mucosa and absent from other healthy tissues. Upon malignant transformation, CLDN18.2 expression can be retained in various tumor tissues, including G/GEJ cancer and especially diffuse-type GC [ 156 ]. The prevalence of CLDN18.2 overexpression in GC varies wildly among studies ranging from 14.1% to 72% [ 157 , 158 , 159 ].

Zolbetuximab is a chimeric IgG1 monoclonal antibody that binds to CLDN18.2 and induces antibody-dependent and complement-dependent cytotoxicity [ 160 ]. To date, zolbetuximab has shown great potential to become a valuable target in GC. In the phase II MONO study, single-agent zolbetuximab achieved an ORR of 9% and a disease control rate of 23% in 43 patients with previously treated oesophageal or G/GEJ cancers [ 161 ]. A randomized phase II study (FAST) indicated that zolbetuximab plus first-line chemotherapy significantly improved PFS and OS in patients with CLDN18.2-positive G/GEJ cancer [ 159 ]. Subgroup analysis indicated a correlation between moderate-to-strong CLDN18.2 expression and a better overall survival rate. In the phase III SPOTLIGHT trial, zolbetuximab plus mFOLFOX6 significantly improved mPFS (10.61 vs 8.67 months, HR 0.751, P = 0.0066) and mOS (18.23 vs 15.54 months, HR 0.750, P = 0.0053) in patients with CLDN18.2-positive and HER-2-negative advanced G/GEJ cancer[ 162 ].

GLOW (NCT03653507) is another phase III trial investigating zolbetuximab plus CAPOX as first-line treatment in patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or GEJ cancer. In this study, zolbetuximab plus CAPOX showed a significant improvement in mPFS (8.21 vs 6.80 months, HR 0.687, P = 0.0007) and mOS (14.39 vs 12.16 months, HR 0.771, P = 0.0118) compared to placebo plus CAPOX[ 163 ]. Additionally, zolbetuximab is also being studied in combination with immunotherapy in patients with CLDN18.2-positive advanced gastric or GEJ cancer in the ILUSTRO study (NCT03505320).

Another promising therapeutic approach targeting CLDN18.2 employs CLDN18.2-specific chimeric antigen receptor (CAR) T cells. CLDN18.2-specific CAR T cells achieved partial or complete tumor regression in CLDN18.2-positive PDX models [ 164 ]. A phase I study of CLDN18.2-specific CAR T cells in gastrointestinal cancers conducted by Prof. Shen Lin's team demonstrated that in GC patients, the ORR and DCR were 57.1% and 75.0%, respectively, and the 6-month overall survival rate was 81.2% [ 165 ]. Claudin 18.2 served as a new target for the later-line treatment of GC, with considerable ORR improvement achieved in Claudin 18.2 CAR-T therapy, which has become a hallmark event for cellular immunotherapy in solid tumors. Currently, several new drugs focusing on Claudin 18.2, such as Claudin 18.2 bispecific antibodies (Claudin 18.2/CD3, Claudin 18.2/PD-L1) and ADC analogs, are being developed. Although these drugs have not been approved for clinical applications, some of them showed promising preclinical data and are being widely studied in different clinical trials. Since Claudin 18.2 is also expressed on the normal gastric mucosal epithelial surface, the risk of adverse reactions and whether ADC drugs may aggravate normal mucosal damage should also be a concern.

FGFR-targeted therapy

FGFR1 mutations, FGFR2 amplifications, and FGFR3 rearrangements are the most common FGFR alterations in GC [ 166 ]. Different types of FGFR targeting agents were explored or developed in GC, including multikinase inhibitors, pan-FGFR inhibitors, FGFR1-3 inhibitors, selective FGFR inhibitors and ADC. Nevertheless, most multikinase inhibitor studies were preclinical or single case reports in GC without robust clinical evidence [ 167 ]. Futibatinib, an irreversible and highly selective FGFR1–4 inhibitor that permanently disables FGFR2, has been tested in a phase II trial involving patients with advanced-stage solid tumors harboring FGFR alterations, including those with FGFR2-amplified G/GEJ cancers [ 168 ]. Although the ORR was reported to be 22.2% in the GC cohort [ 169 ], more data are needed to support the efficacy of multiple FGFR inhibitors in different FGFR gene alterations in GC.

Currently, bemarituzumab has shown some promising results in the treatment of mGC [ 170 ]. It is a first-in-class afucosylated monoclonal antibody against the FGFR2b splice variant frequently overexpressed in FGFR2- amplified G/GEJ cancers. In a phase I trial, 17.9% of patients with FGFR2 amplifications had a confirmed response to bemarituzumab [ 171 ]. Based on the safety and activity profile of bemarituzumab monotherapy in GC, the phase II FIGHT trial was designed to evaluate the efficacy of bemarituzumab plus mFOLFOX6 regimen in previously untreated, FGFR2b-overexpressing advanced-stage G/GEJ cancers [ 172 ]. The trial showed a 2-month improvement in PFS, and the OS was not reached (NR) in the experimental arm (bemarituzumab + mFOLFOX6). However, the experimental arm had a higher incidence of adverse events than the control chemotherapy arm, particularly in regard to ocular toxicity.

EGFR-targeted therapy

Approximately 5–10% of patients with G/GEJ cancers have EGFR amplifications or EGFR overexpression, both of which are associated with poor prognosis [ 173 ]. Previous large randomized clinical trials have failed to demonstrate any significant survival benefit with EGFR-targeted agents [ 92 , 174 ], perhaps because most of the studies were performed in unselected patient populations regardless of EGFR status. Besides, biomarker analysis of the EXPAND and COG trials suggests activity in patients with tumors expressing high levels of EGFR, thus supporting the significance of patient selection for future trials [ 175 , 176 ]. In a prospective cohort, patients with metastatic gastroesophageal adenocarcinoma were screened for EGFR amplification and subsequently treated with anti-EGFR therapy (cetuximab). The ORR was 58% (4 of 7 patients), and the DCR was 100% (7 of 7 patients), implying that EGFR inhibition should be further studied in selected patients [ 177 ]. Many of the ongoing EGFR inhibitor studies should test EGFR alterations in the GC patients prior to enrollment to overcome resistance to EGFR-targeted therapies.

MET/HGF pathway inhibitors

c-Mesenchymal-Epithelial Transition (c-MET) is a tyrosine kinase receptor from MET families, and hepatocyte growth factor (HGF) is the common ligand to c-MET [ 178 ]. MET/HGF pathway activation is associated with tumor invasiveness and poor disease prognosis. The anti-MET monoclonal antibody, onartuzumab, has been studied in a phase III trial of onartuzumab plus mFOLFOX6 vs placebo plus mFOLFOX6 in patients with metastatic HER2-negative G/GEJ cancers. However, the addition of onartuzumab to mFOLFOX6 did not improve clinical outcomes in the ITT population or in the MET-positive population [ 179 ]. Rilotumumab is a humanized monoclonal antibody targeting HGF. Two phase III trials (RILOMET-1 and RILOMET-2) investigated rilotumumab plus chemotherapy in advanced MET-positive G/GEJ cancers. Unfortunately, both studies were terminated due to increased number of deaths in the rilotumumab group[ 180 , 181 ]. Additionally, several selective/non-selective c-MET TKIs, such as tinvatinib, AMG 337 and foretinib, have also been tested in MET-positive GC, but no significant benefit was seen in clinical trials[ 182 , 182 , 184 ].

Challenges and future perspectives

Even though substantial advances have been made in the treatment of GC, further research and development are still necessary. Improving early detection, reducing recurrence and optimizing treatment strategies are the primary challenges and prospects for GC management. To increase GC early detection and promote patients’ overall survival, endoscopic screening programs should be implemented in high-risk regions, and more precise early detection technologies are of great value. In a previous study, we demonstrated an artificial intelligence (AI) diagnostic platform, GRAIDS, to detect upper gastrointestinal cancers using real-world endoscopic imaging data from six Chinese hospitals with varying experience in the endoscopic diagnosis of upper gastrointestinal cancer [ 185 ]. GRAIDS provided both real-time and retrospective assistance for enhancing the effectiveness of upper gastrointestinal cancer screening and diagnosis, with high diagnostic accuracy and sensitivity in detecting upper gastrointestinal cancers. In the near future, the AI system will help many physicians in community-based hospitals identify upper gastrointestinal cancers more efficiently and accurately [ 186 ].

In addition, recurrence of GC remains common despite the multimodality treatment, so many studies in progress aim to identify individuals at risk of recurrence after treatment. Circulating tumor DNA (ctDNA) can be detected in the circulation of cancer patients and has the potential to predict minimal residual disease [ 187 ]. Liquid biopsies can detect a broader spectrum of abnormalities in a heterogeneous tumor compared to conventional tissue biopsies. According to a study investigating perioperative therapies in patients in the CRITICS trial with resectable GC, the presence of ctDNA could predict recurrence when analyzed within nine weeks after preoperative treatment and after surgery in patients eligible for multimodal treatment [ 187 ]. These findings highlight the significance of ctDNA as a biomarker for predicting patient outcomes following perioperative cancer treatment and surgical resection in patients with GC. In another 1630-patient cohort of ctDNA results, genomic alterations were correlated with clinicopathologic characteristics and outcomes and provided prognostic and predictive information [ 188 ]. As for advanced GC, ctDNA also serves as a potential biomarker of immunotherapy response, and its potential role in predicting irAEs is worth further investigation [ 189 ]. Further research aimed at prospectively collecting ctDNA is needed to confirm these findings. The existence of persistent ctDNA following curative-intent treatment of GC may indicate minimal residual disease, and trials are underway to determine whether additional adjuvant therapy can result in the clearance of ctDNA.

Intratumoral, intrapatient, and interpatient heterogeneity in GC is the major barrier to drug development for systemic therapies. Most GC patients are not susceptible to immune checkpoint inhibitor monotherapies. Thus, one of the major challenges in systemic treatments for GC is overcoming resistance to ICI therapy. One strategy is to develop novel ICIs with better efficacy. Recently, many novel immune checkpoint modulators have been widely investigated, including LAG-3, VISTA, TIM-3, TIGIT, CD38, CD39, and CD73[ 190 ]. Another key strategy is combining ICI and other therapies, such as other ICI, targeted therapies, other immune-modulating agents, chemotherapy (as discussed above), and radiotherapy [ 191 ]. As mentioned above, in the CheckMate-649 study, the combination of anti-PD-1 and anti-CTLA-4 agents (nivolumab plus ipilimumab) failed to improve treatment outcomes compared to traditional chemotherapy [ 57 ]. In the EPOC1706 study, lenvatinib, an anti-angiogenic multiple receptor tyrosine kinase inhibitor, combined with pembrolizumab showed an exciting activity with an ORR of 69% in the first-line and second-line treatment of advanced GC[ 151 ]. ICI combined with other anti-immunosuppressive factor agents, such as anti-transforming growth factor-β (TGF-β), is also being investigated in clinical trials (NCT04856774). To fully understand the mechanism of resistance to immunotherapy, factors such as epigenetics, metabolism, immune suppression, and microbiota must be considered. Therefore, the development of combined therapies should be based on understanding the underlying mechanisms of immune modulation and resistance, rather than simply combining available therapies in a haphazard manner.

Rapid developments are ongoing in the clinical use of ADCs and are now considered one of the current hot spots for antitumor drug development. In particular, ADCs have emerged as a new era of targeted therapy in the field of GC treatment. The latest generation of ADCs has expanded the treatment population to include novel targets and demonstrated superior clinical outcomes compared to traditional chemotherapy drugs. Nevertheless, certain aspects of ADCs remain to be addressed. Firstly, it is necessary to explore ways to advance ADCs as first-line therapy to benefit a larger number of patients. Secondly, to make better use of medical resources, a more differentiated target layout needs to be established, moving beyond the focus on distinct targets such as HER2. To address these challenges, optimization of the toxin, linker and toxicity of ADCs is essential, along with the development of ADC-combination therapies to improve efficacy. We anticipate the discovery of more potential ADC drugs and expect a breakthrough in first-line treatment.

Currently, many clinical trials have complex treatment regimens, including mono-immunotherapy, double-checkpoint inhibitors, anti-angiogenic drugs, and biomarker-directed therapies [ 190 , 192 ]. However, the challenge of determining the optimal treatment strategy and the appropriate timing of molecular biomarker screening has yet to be resolved. We expect that extensive translational research, preclinical investigations, and multi-omics-based clinical trials will lead to breakthroughs in the diagnosis and treatment of GC. Therefore, we eagerly anticipate future studies that have the potential to improve clinical practice in the coming years.

Availability of data and materials

Not applicable.

Abbreviations

Antibody–drug conjugates

Antibody-dependent cell-mediated cytotoxicity

Advanced gastro-oesophageal cancer

Artificial intelligence

American Society of Clinical Oncology

Bispecific antibodies

Best supportive care

Capecitabine and oxaliplatin

Chimeric antigen receptor

Cisplatin and fluorouracil

China Food and Drug Administration

Confidence interval

Claudin18.2

Combined positive score

Chemoradiotherapy

Chinese Society for Clinical Oncology

Circulating tumor DNA

Cytotoxic T lymphocyte antigen-4

Disease control rate

Disease-free survival

Mismatch-repair deficiency

Duration of response

Docetaxel, oxaliplatin, and S-1

Epstein-Barr virus

Epstein-Barr virus-associated gastric cancer

Extracellular domain

Epirubicin, cisplatin, and fluorouracil

Event-free survival

Epidermal growth factor receptor

Epirubicin and oxaliplatin

Erythroblastic leukemia viral oncogene homolog

Extracellular regulated protein kinase

European Society for Medical Oncology

Food and Drug Administration

Fibroblast growth factor receptor

Fluorescent in situ hybridization

Fluorouracil, leucovorin, oxaliplatin, and docetaxel

Fluorouracil, leucovorin, and oxaliplatin

Fluorouracil and cisplatin

Gastric cancer

Gastroesophageal junction adenocarcinoma

Gastroesophageal junction

Human epidermal growth factor receptor 2

Hazard ratio

Immune checkpoint inhibitor

Immunohistochemistry

Kirsten rats sarcomaviral oncogene homolog

Lymphocyte-activation gene 3

Mitogen-activated protein kinase

Mesenchymal epithelial transition

Cytotoxin monomethyl auristatin E

Microsatellite instability

Mammalian target of rapamycin

National Comprehensive Cancer Network

Not evaluable

Natural killer

Objective response rate

Overall survival

Pathological complete response

Programmed cell death 1

Programmed cell death ligand 1

Progression-free survival

Phosphatidylinositol-3-kinase

Phosphatase and tensin homolog

Relapse-free survival

Recommended phase 2 dose

Receptor tyrosine kinase

S-1 and oxaliplatin

S-1, oxaliplatin and radiotherapy

S-1 and cisplatin

Tumor area positivity

The Cancer Genome Atlas

Trastuzumab emtansine

Trastuzumab deruxtecan

Transforming growth factor-β

T cell immunoreceptor with Ig and ITIM domain

T cell immunoglobulin and mucin domain 3

Tumor mutational burden

Vascular endothelial growth factor

V-domain Ig suppressor of T cell activation

Capecitabine and cisplatin

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant No. 82203678 to Y.H.), the Science and Technology Program of Guangdong (Grant No. 2019B020227002 to R.-H.X.), the CAMS Innovation Fund for Medical Sciences (Grant No. 2019-I2M-5-036 to R.-H.X.).

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Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People’s Republic of China

Wen-Long Guan, Ye He & Rui-Hua Xu

Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, 510060, People’s Republic of China

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Rui-Hua Xu designed this review. Rui-Hua Xu, Wen-Long Guan, and Ye He drafted the manuscript and prepared the figures. Rui-Hua Xu, Wen-Long Guan, and Ye He collected the related references and participated in the discussion. All authors contributed to this manuscript and revised the manuscript. All authors read and approved the final manuscript.

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Guan, WL., He, Y. & Xu, RH. Gastric cancer treatment: recent progress and future perspectives. J Hematol Oncol 16 , 57 (2023). https://doi.org/10.1186/s13045-023-01451-3

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DOI : https://doi.org/10.1186/s13045-023-01451-3

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Gastric cancer epidemiology: current trend and future direction.

1. Introduction

2. materials and methods, 3. current global trends in measures of gastric cancer, 4. etiology and known risk factors of gastric cancer, 4.1. helicobacter pylori, 4.2. other risk factors and susceptible population, 5. pathogenesis and hallmarks of gastric cancer, 6. treatment and prevention of gastric cancer, 7. study strengths and limitations, 8. conclusions and future direction, author contributions, data availability statement, conflicts of interest.

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Iwu, C.D.; Iwu-Jaja, C.J. Gastric Cancer Epidemiology: Current Trend and Future Direction. Hygiene 2023 , 3 , 256-268. https://doi.org/10.3390/hygiene3030019

Iwu CD, Iwu-Jaja CJ. Gastric Cancer Epidemiology: Current Trend and Future Direction. Hygiene . 2023; 3(3):256-268. https://doi.org/10.3390/hygiene3030019

Iwu, Chidozie Declan, and Chinwe Juliana Iwu-Jaja. 2023. "Gastric Cancer Epidemiology: Current Trend and Future Direction" Hygiene 3, no. 3: 256-268. https://doi.org/10.3390/hygiene3030019

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The diagnosis and...

The diagnosis and management of gastric cancer

Related content
Peer review
Sri G Thrumurthy , honorary research fellow 1 ,
M Asif Chaudry , oesophagogastric surgeon 2 ,
Daniel Hochhauser , Kathleen Ferrier professor of medical oncology 3 ,
Muntzer Mughal , honorary clinical professor and head 1
1 Department of Upper Gastrointestinal Surgery, University College London Hospital, London NW1 2BU, UK
2 Department of Upper Gastrointestinal Surgery, St Thomas’ Hospital, London, UK
3 UCL Cancer Institute, University College London, London, UK
Correspondence to: M Mughal muntzer.mughal{at}uclh.nhs.uk
Accepted 18 October 2013

Summary points

The incidence of gastric cancer is highest in eastern Asia, eastern Europe, and South America, and it affects twice as many men as women

Risk factors for gastric cancer include Helicobacter pylori infection, cigarette smoking, high alcohol intake, excess dietary salt, lack of refrigeration, inadequate fruit and vegetable consumption, and pernicious anaemia

Patients present with weight loss and abdominal pain, although those with proximal or gastro-oesophageal junction tumours may present with dysphagia

Upper gastrointestinal endoscopy with biopsy is used to confirm the diagnosis; precise tumour stage is defined by more sophisticated radiological investigations

Multidisciplinary approach to treatment: early gastric cancer is treated with surgery alone, whereas advanced disease is usually managed with chemotherapy before and after surgery, or postoperative chemoradiation

Metastatic disease is managed with chemotherapy or chemoradiation as well as supportive care measures

Age standardised mortality rates for gastric cancer are 14.3 per 100 000 in men and 6.9 per 100 000 in women worldwide. 1 Incidence shows clear regional and sex variations—rates are highest in eastern Asia, eastern Europe, and South America and lowest in northern and southern Africa. 1 Early diagnosis is crucial because of the possibility of early metastasis to the liver, pancreas, omentum, oesophagus, bile ducts, and regional and distant lymph nodes. 2 Using evidence from large randomised controlled trials, meta-analyses, cohort studies, and case-control studies this review aims to outline preventive strategies, highlight the presenting features of gastric cancer, and guide generalists in early diagnosis, referral, and treatment.

Sources and selection criteria

We searched PubMed to identify peer reviewed original articles, meta-analyses, and reviews. Search terms were gastric cancer, cancer of the stomach, gastric adenocarcinoma, gastro-oesophageal cancer, gastric neoplasm, and neoplasm of the stomach. We considered only those papers that were written in English, published within the past 10 years, and which described studies that had adequate scientific validity.

What is gastric cancer?

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Stomach Cancer Research

In a recent study, more than 90% of people who’d had their stomach surgically removed to prevent cancer experienced a least one chronic complication 2 years out from their surgery. For some, the complications are life altering.

FDA has changed its 2021 approval of pembrolizumab (Keytruda) along with trastuzumab (Herceptin) and chemotherapy for treating HER2-positive stomach or GEJ cancer. The agency also announced a new approval of pembrolizumab for HER2-negative forms of these same cancers.

For some people with advanced stomach cancer, the drug nivolumab (Opdivo) plus chemotherapy may improve how long they live, results from a large clinical trial show. The trial also included patients with gastric cancers that involve the esophagus.

A type of cancer that occurs in the lower stomach has been increasing among some Americans under the age of 50, even though in the general population the incidence of all stomach cancers has been declining for decades, according to a new study.

The FDA has granted accelerated approval to the immunotherapy drug pembrolizumab (Keytruda®) for use in patients with advanced gastric (stomach) cancer that is PD-L1 positive.

Stomach cancers fall into four distinct molecular subtypes, researchers with The Cancer Genome Atlas (TCGA) Network have found. Scientists report that this discovery could change how researchers think about developing treatments for stomach cancer, also called gastric cancers or gastric adenocarcinomas.

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Gastric cancer articles within Nature Reviews Gastroenterology & Hepatology

In Brief | 21 April 2023

Zolbetuximab treatment in metastatic gastric cancer

Eleni Kotsiliti

In Brief | 08 February 2023

Effect of bariatric surgery on risk of oesophagogastric cancer

Jordan Hindson

In Brief | 28 November 2022

A novel pathomics signature for gastric cancer

Review Article | 07 November 2022

Current developments in gastric cancer: from molecular profiling to treatment strategy

Gastric and gastro-oesophageal cancer is a leading cause of cancer-related death worldwide with a poor prognosis. This Review provides a comprehensive overview of current treatment strategies set on a molecular basis, and discusses future therapeutic avenues.

Maria Alsina
, Virginia Arrazubi
& Josep Tabernero

In Brief | 06 June 2022

Promising phase I interim results for CAR T cells in gastrointestinal cancers

Katrina Ray

Review Article | 14 March 2022

The immune microenvironment in gastric adenocarcinoma

In this Review, the authors describe how the chronic inflammatory microenvironment in the gastric mucosal epithelia during Helicobacter pylori infection can stimulate intracellular signalling pathways that lead to the development of gastric adenocarcinoma.

Yana Zavros
& Juanita L. Merchant

In Brief | 11 January 2022

KEYNOTE-811: pembrolizumab in advanced HER2 + gastric cancer

In Brief | 22 June 2021

Nivolumab plus chemotherapy for advanced gastric cancer and oesophageal adenocarcinoma

Research Highlight | 26 February 2020

New markers and models of premalignancy and the early development of gastric cancer

In Brief | 21 February 2020

H. pylori elimination reduces gastric cancer risk

Iain Dickson

Research Highlight | 07 September 2018

Exploring human gastric cancers through organoid culture

Hugh Thomas

Research Highlight | 20 August 2018

Immunotherapy-responsive gastric cancers identified

Peter Sidaway

News & Views | 30 April 2018

Gastric cancer: evidence boosts Helicobacter pylori eradication

The efficacy of Helicobacter pylori eradication therapy for the prevention of preneoplastic lesions in gastric cancer remains controversial. A new placebo-controlled trial and a large-scale observational study tackle this problem and show the positive effects of eradication therapy.

Hidekazu Suzuki
& Juntaro Matsuzaki

Review Article | 21 February 2018

Acid and the basis for cellular plasticity and reprogramming in gastric repair and cancer

The stomach responds to injury via two main patterns, the superficial response and the glandular response. In this Review, Sáenz and Mills discuss cellular plasticity and reprogramming in the stomach in the context of disease (such as gastric cancer) and during repair and homeostasis.

José B. Sáenz
& Jason C. Mills

In Brief | 02 November 2017

The ATTRACTION of nivolumab for gastric and gastro-oesophageal junction cancer

News & Views | 18 October 2017

The gastric microbiota — bacterial diversity and implications

Although Helicobacter pylori is associated with gastric cancer, bacterial communities that reside in the stomach are mostly unacknowledged. A new study shows that some gastric bacterial communities have emigrated from our mouth, prefer certain neighbours and prefer certain environments. By understanding the interactions of these bacteria, we hope to understand the environment most conducive to gastric cancer carcinogenesis.

Manish A. Shah

Research Highlight | 06 September 2017

R-spondin 3 is a critical regulator of gastric antral stem cell homeostasis

Research Highlight | 21 June 2017

A chief role for Lgr5 + cells

Review Article | 17 May 2017

How to stomach an epigenetic insult: the gastric cancer epigenome

Gastric cancer is a deadly malignancy and accumulating evidence suggests that epigenetic abnormalities promote carcinogenesis. Here, the authors summarize the gastric cancer epigenome, highlighting key advances from studies of DNA methylation and histone modifications, and how these findings might lead to therapeutic opportunities.

Nisha Padmanabhan
, Toshikazu Ushijima
& Patrick Tan

Review Article | 05 January 2017

Population screening and treatment of Helicobacter pylori infection

Helicobacter pylori remains an important human pathogen with links to both malignant (gastric cancer) and non-malignant diseases (such as peptic ulcer). Here, the authors discuss issues related to implementation of population screening and eradication of H. pylori infection.

Anthony O'Connor
, Colm A. O'Morain
& Alexander C. Ford

Research Highlight | 12 October 2016

Settling the stomach — tracing gastric stem cells

Research Highlight | 21 September 2016

DARPP-32 : a link between infection and gastric cancer

Charlotte Ridler

Research Highlight | 20 July 2016

Dysregulation of RNA editing in gastric cancer

News & Views | 05 May 2016

Pathogenic enablers — toxic relationships in the stomach

Chronic infection with Helicobacter pylori is the strongest known risk factor for the development of gastric cancer. Saju et al . shed new light on mechanisms by which Epstein–Barr virus, a viral initiator of gastric cancer, potentiates the oncogenic effects of Helicobacter pylori in the stomach.

Lydia E. Wroblewski
& Richard M. Peek Jr

Research Highlight | 28 April 2015

Breathing a sigh of relief for noninvasive cancer detection

Gillian Patman

Research Highlight | 27 January 2015

Metformin improves survival and recurrence rate in patients with diabetes and gastric cancer

Claire Greenhill

In Brief | 20 January 2015

New model for Helicobacter pylori infection developed

In Brief | 25 November 2014

Distinct tumour signatures observed in Asian and non-Asian patients with gastric cancer

Review Article | 19 August 2014

Genetics of gastric cancer

Gastric cancer accounts for a notable proportion of cancer mortality around the world. Over the past few decades, advances in technology and high-throughput analysis have improved understanding of the molecular aspects of the pathogenesis of gastric cancer. This Review discusses these genetic aspects of the pathogenesis of gastric cancer.

Mairi H. McLean
& Emad M. El-Omar

Research Highlight | 12 August 2014

New molecular classification of gastric adenocarcinoma proposed by The Cancer Genome Atlas

Mina Razzak

Research Highlight | 27 May 2014

Revealing the genomic landscape of gastric cancer

In Brief | 15 April 2014

Helicobacter pylori infection improves response to cisplatin

Research Highlight | 15 October 2013

New biologic therapy effective as second-line treatment in gastric cancer

Katherine Smith

In Brief | 09 April 2013

Breath test for gastric cancer

Research Highlight | 22 May 2012

Integrated epigenomic analysis sheds light on role of BMP4 in regulating cisplatin sensitivity in gastric cancer

Natalie J. Wood

News & Views | 06 March 2012

Localized gastric cancer—a CLASSIC shift in the paradigm?

The management of localized gastric cancer has evolved globally to region-specific approaches with little convergence. The unifying theme, however, is that surgery alone is insufficient for best outcomes, and adjunctive therapy must be offered. Multidisciplinary evaluation before therapy is highly recommended, but postoperative approaches are not conducive to this scenario.

Mariela A. Blum
& Jaffer A. Ajani

Research Highlight | 14 February 2012

Folate prevents gastric cancer

Andy McLarnon

News & Views | 14 February 2012

Secondary prevention of gastric cancer

The natural history of 'epidemic' intestinal-type gastric cancer provides consistent data that enable clinicians to design multidisciplinary strategies for secondary prevention. A recent paper by Dinis-Ribeiro et al . reports guidelines for the management of patients with precancerous stomach lesions.

Massimo Rugge
, Matteo Fassan
& David Y. Graham

Research Highlight | 13 December 2011

Bone-marrow-derived cells could cause gastric preneoplasia in chronic Helicobacter pylori infection

Research Highlight | 05 October 2011

ESD is associated with a moderate risk of deep vein thrombosis that may be determined by D-dimer levels

Review Article | 04 July 2011

Anti-HER agents in gastric cancer: from bench to bedside

Despite some advances, the search for effective treatment modalities for advanced gastric and gastro-esophageal junction cancer (GEJC) is far from over. However, using biologic agents to target key molecular pathways, such as those regulated by human epidermal growth factor receptor (HER) family members, may be an effective approach. This Review briefly describes HER biology, summarizes available data regarding the clinical activity of anti-HER agents and their use in gastric cancer and GEJC, and provides insight into treatment personalization strategies.

Lorenzo Fornaro
, Maurizio Lucchesi
& Alfredo Falcone

Research Highlight | 06 June 2011

Gene fusion identified in gastric cancer

Research Highlight | 05 April 2011

Helicobacter pylori ancestry associated with cancer risk

Research Highlight | 07 March 2011

Value of CLE for gastric cancer detection

Rachel Thompson

Research Highlight | 01 November 2010

FAK autophosphorylation independently predicts recurrence of gastric cancer

Shreeya Nanda

Review Article | 12 October 2010

Mechanisms of disease: Helicobacter pylori virulence factors

Helicobacter pylori has an essential role in the development of various gastroduodenal diseases, but only a small proportion of people infected with H. pylori develop these diseases. In this Review, Yoshio Yamaoka discusses current knowledge of the H. pylori virulence factors CagA, VacA, OipA and DupA. In particular, he considers how these virulence factors contribute to differing geographic gastric cancer disease patterns and to the development of both gastric cancer and duodenal ulcer.

Yoshio Yamaoka

Browse broader subjects

Stomach diseases
Gastrointestinal cancer

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A pathway for detection of gastric cancer biomarkers via using a layer-by-layer coated D-shaped grinding long-period fiber grating sensor

Chiang, Chia-Chin
Yeh, Yao-Tsung
Wang, Tung-En
Hsu, Hsiang-Cheng
Wen, Hsin-Yi

Gastric cancer significantly contributes to global cancer mortality, often leading to inoperable stages and high recurrence rates post-surgery. Elevated levels of G-17 and G-gly have been identified as potential risk factors, particularly in patients with duodenal ulcers. This study introduces an innovative D-shaped grinding long-period fiber grating sensor (D-LLPFGs) designed for non-invasive detection of the gastrin G-17 antigen, employing a layer-by-layer chemical self-assembly to bond G-17 antibodies onto the fiber surface through hydrogen bonding. The D-LLPFGs sensor demonstrated significant spectral shifts within 1 min of antigen-antibody interaction, highlighting its rapid detection capability. At an optimized antibody concentration of 4 μg/ml, antigen testing across different concentrations (10, 12.5, 20, 50 μg/ml) showed peak changes at 12.5 μg/ml antigen, with a 1.186 nm shift and 0.503 dB loss. The sensor exhibited a wavelength sensitivity of 0.095 nm/μg/ml, indicating its high sensitivity and potential in gastric cancer classification, diagnosis, and treatment. This research concludes that the D-shaped fiber sensor is an effective and sensitive tool for detecting G-17 antigen levels, presenting a significant advancement in non-invasive gastric cancer diagnosis. Its quick response time and high sensitivity highlight its potential for broad biomedical applications, offering a new avenue for early cancer detection and improving patient prognosis. The success of this study opens the door to further exploration and implementation of fiber optic sensors in clinical settings, marking a significant step forward in the fight against gastric cancer.

Long-period fiber grating;
D-shaped grinding;
Laser-assisted etching;
Biomedical measurement of gastrin G-17

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Cancer Control
v.28; Jan-Dec 2021

Cancer Biology, Epidemiology, and Treatment in the 21st Century: Current Status and Future Challenges From a Biomedical Perspective

Patricia piña-sánchez.

1 Oncology Research Unit, Oncology Hospital, Mexican Institute of Social Security, Mexico

Antonieta Chávez-González

Martha ruiz-tachiquín, eduardo vadillo, alberto monroy-garcía, juan josé montesinos, rocío grajales.

2 Department of Medical Oncology, Oncology Hospital, Mexican Institute of Social Security, Mexico

Marcos Gutiérrez de la Barrera

3 Clinical Research Division, Oncology Hospital, Mexican Institute of Social Security, Mexico

Hector Mayani

Since the second half of the 20th century, our knowledge about the biology of cancer has made extraordinary progress. Today, we understand cancer at the genomic and epigenomic levels, and we have identified the cell that starts neoplastic transformation and characterized the mechanisms for the invasion of other tissues. This knowledge has allowed novel drugs to be designed that act on specific molecular targets, the immune system to be trained and manipulated to increase its efficiency, and ever more effective therapeutic strategies to be developed. Nevertheless, we are still far from winning the war against cancer, and thus biomedical research in oncology must continue to be a global priority. Likewise, there is a need to reduce unequal access to medical services and improve prevention programs, especially in countries with a low human development index.

Introduction

During the last one hundred years, our understanding of the biology of cancer increased in an extraordinary way. 1 - 4 Such a progress has been particularly prompted during the last few decades because of technological and conceptual progress in a variety of fields, including massive next-generation sequencing, inclusion of “omic” sciences, high-resolution microscopy, molecular immunology, flow cytometry, analysis and sequencing of individual cells, new cell culture techniques, and the development of animal models, among others. Nevertheless, there are many questions yet to be answered and many problems to be solved regarding this disease. As a consequence, oncological research must be considered imperative.

Currently, cancer is one of the illnesses that causes more deaths worldwide. 5 According to data reported in 2020 by the World Health Organization (WHO), cancer is the second cause of death throughout the world, with 10 million deaths. 6 Clearly, cancer is still a leading problem worldwide. With this in mind, the objective of this article is to present a multidisciplinary and comprehensive overview of the disease. We will begin by analyzing cancer as a process, focusing on the current state of our knowledge on 4 specific aspects of its biology. Then, we will look at cancer as a global health problem, considering some epidemiological aspects, and discussing treatment, with a special focus on novel therapies. Finally, we present our vision on some of the challenges and perspectives of cancer in the 21 st century.

The Biology of Cancer

Cancer is a disease that begins with genetic and epigenetic alterations occurring in specific cells, some of which can spread and migrate to other tissues. 4 Although the biological processes affected in carcinogenesis and the evolution of neoplasms are many and widely different, we will focus on 4 aspects that are particularly relevant in tumor biology: genomic and epigenomic alterations that lead to cell transformation, the cells where these changes occur, and the processes of invasion and metastasis that, to an important degree, determine tumor aggressiveness.

Cancer Genomics

The genomics of cancer can be defined as the study of the complete sequence of DNA and its expression in tumor cells. Evidently, this study only becomes meaningful when compared to normal cells. The sequencing of the human genome, completed in 2003, was not only groundbreaking with respect to the knowledge of our gene pool, but also changed the way we study cancer. In the post-genomic era, various worldwide endeavors, such as the Human Cancer Genome Project , the Cancer Genome ATLAS (TCGA), the International Cancer Genome Consortium, and the Pan-Cancer Analysis Working Group (PCAWG), have contributed to the characterization of thousands of primary tumors from different neoplasias, generating more than 2.5 petabytes (10 15 ) of genomic, epigenomic, and proteomic information. This has led to the building of databases and analytical tools that are available for the study of cancer from an “omic” perspective, 7 , 8 and it has helped to modify classification and treatment of various neoplasms.

Studies in the past decade, including the work by the PCAWG, have shown that cancer generally begins with a small number of driving mutations (4 or 5 mutations) in particular genes, including oncogenes and tumor-suppressor genes. Mutations in TP53, a tumor-suppressor gene, for example, are found in more than half of all cancer types as an early event, and they are a hallmark of precancerous lesions. 9 - 12 From that point on, the evolution of tumors may take decades, throughout which the mutational spectrum of tumor cells changes significantly. Mutational analysis of more than 19 000 exomes revealed a collection of genomic signatures, some associated with defects in the mechanism of DNA repair. These studies also revealed the importance of alterations in non-coding regions of DNA. Thus, for example, it has been observed that various pathways of cell proliferation and chromatin remodeling are altered by mutations in coding regions, while pathways, such as WNT and NOTCH, can be disrupted by coding and non-coding mutations. To the present date, 19 955 genes that codify for proteins and 25 511 genes for non-coding RNAs have been identified ( https://www.gencodegenes.org/human/stats.html ). Based on this genomic catalogue, the COSMIC (Catalogue Of Somatic Mutations In Cancer) repository, the most robust database to date, has registered 37 288 077 coding mutations, 19 396 fusions, 1 207 190 copy number variants, and 15 642 672 non-coding variants reported up to August 2020 (v92) ( https://cosmic-blog.sanger.ac.uk/cosmic-release-v92/ ).

The genomic approach has accelerated the development of new cancer drugs. Indeed, two of the most relevant initiatives in recent years are ATOM (Accelerating Therapeutics for Opportunities in Medicine), which groups industry, government and academia, with the objective of accelerating the identification of drugs, 13 and the Connectivity Map (CMAP), a collection of transcriptional data obtained from cell lines treated with drugs for the discovery of functional connections between genes, diseases, and drugs. The CMAP 1.0 covered 1300 small molecules and more than 6000 signatures; meanwhile, the CMAP 2.0 with L1000 assay profiled more than 1.3 million samples and approximately 400 000 signatures. 14

The genomic study of tumors has had 2 fundamental contributions. On the one hand, it has allowed the confirmation and expansion of the concept of intratumor heterogeneity 15 , 16 ; and on the other, it has given rise to new classification systems for cancer. Based on the molecular classification developed by expression profiles, together with mutational and epigenomic profiles, a variety of molecular signatures have been identified, leading to the production of various commercial multigene panels. In breast cancer, for example, different panels have been developed, such as Pam50/Prosigna , Blue Print , OncotypeDX , MammaPrint , Prosigna , Endopredict , Breast Cancer Index , Mammostrat, and IHC4 . 17

Currently, the genomic/molecular study of cancer is more closely integrated with clinical practice, from the classification of neoplasms, as in tumors of the nervous system, 18 to its use in prediction, as in breast cancer. 17 Improvement in molecular methods and techniques has allowed the use of smaller amounts of biological material, as well as paraffin-embedded samples for genomic studies, both of which provide a wealth of information. 19 In addition, non-invasive methods, such as liquid biopsies, represent a great opportunity not only for the diagnosis of cancer, but also for follow-up, especially for unresectable tumors. 20

Research for the production of genomic information on cancer is presently dominated by several consortia, which has allowed the generation of a great quantity of data. However, most of these consortia and studies are performed in countries with a high human development index (HDI), and countries with a low HDI are not well represented in these large genomic studies. This is why initiatives such as Human Heredity and Health in Africa (H3Africa) for genomic research in Africa are essential. 21 Generation of new information and technological developments, such as third-generation sequencing, will undoubtedly continue to move forward in a multidisciplinary and complex systems context. However, the existing disparities in access to genomic tools for diagnosis, prognosis, and treatment of cancer will continue to be a pressing challenge at regional and social levels.

Cancer Epigenetics

Epigenetics studies the molecular mechanisms that produce hereditable changes in gene expression, without causing alterations in the DNA sequence. Epigenetic events are of 3 types: methylation of DNA and RNA, histone modification (acetylation, methylation, and phosphorylation), and the expression of non-coding RNA. Epigenetic aberrations can drive carcinogenesis when they alter chromosome conformation and the access to transcriptional machinery and to various regulatory elements (promoters, enhancers, and anchors for interaction with chromatin, for example). These changes may activate oncogenesis and silence tumor-suppressor mechanisms when they modulate coding and non-coding sequences (such as micro-RNAs and long-RNAs). This can then lead to uncontrolled growth, as well as the invasion and metastasis of cancer cells.

While genetic mutations are stable and irreversible, epigenetic alterations are dynamic and reversible; that is, there are several epigenomes, determined by space and time, which cause heterogeneity of the “epigenetic status” of tumors during their development and make them susceptible to environmental stimuli or chemotherapeutic treatment. 22 Epigenomic variability creates differences between cells, and this creates the need to analyze cells at the individual level. In the past, epigenetic analyses measured “average states” of cell populations. These studies revealed general mechanisms, such as the role of epigenetic marks on active or repressed transcriptional states, and established maps of epigenetic composition in a variety of cell types in normal and cancerous tissue. However, these approaches are difficult to use to examine events occurring in heterogeneous cell populations or in uncommon cell types. This has led to the development of new techniques that permit marking of a sequence on the epigenome and improvement in the recovery yield of epigenetic material from individual cells. This has helped to determine changes in DNA, RNA, and histones, chromatin accessibility, and chromosome conformation in a variety of neoplasms. 23 , 24

In cancer, DNA hypomethylation occurs on a global scale, while hypermethylation occurs in specific genomic loci, associated with abnormal nucleosome positioning and chromatin modifications. This information has allowed epigenomic profiles to be established in different types of neoplasms. In turn, these profiles have served as the basis to identify new neoplasm subgroups. For example, in triple negative breast cancer (TNBC), 25 and in hepatocellular carcinoma, 26 DNA methylation profiles have helped to the identification of distinct subgroups with clinical relevance. Epigenetic approaches have also helped to the development of prognostic tests to assess the sensitivity of cancer cells to specific drugs. 27

Epigenetic traits could be used to characterize intratumoral heterogeneity and determine the relevance of such a heterogeneity in clonal evolution and sensitivity to drugs. However, it is clear that heterogeneity is not only determined by genetic and epigenetic diversity resulting from clonal evolution of tumor cells, but also by the various cell populations that form the tumor microenvironment (TME). 28 Consequently, the epigenome of cancer cells is continually remodeled throughout tumorigenesis, during resistance to the activity of drugs, and in metastasis. 29 This makes therapeutic action based on epigenomic profiles difficult, although significant advances in this area have been reported. 30

During carcinogenesis and tumor progression, epigenetic modifications are categorized by their mechanisms of regulation ( Figure 1A ) and the various levels of structural complexity ( Figure 1B ). In addition, the epigenome can be modified by environmental stimuli, stochastic events, and genetic variations that impact the phenotype ( Figure 1C ). 31 , 32 The molecules that take part in these mechanisms/events/variations are therapeutic targets of interest with potential impact on clinical practice. There are studies on a wide variety of epidrugs, either alone or in combination, which improve antitumor efficacy. 33 However, the problems with these drugs must not be underestimated. For a considerable number of epigenetic compounds still being under study, the main challenge is to translate in vitro efficacy of nanomolar (nM) concentrations into well-tolerated and efficient clinical use. 34 The mechanisms of action of epidrugs may not be sufficiently controlled and could lead to diversion of the therapeutic target. 35 It is known that certain epidrugs, such as valproic acid, produce unwanted epigenetic changes 36 ; thus the need for a well-established safety profile before these drugs can be used in clinical therapy. Finally, resistance to certain epidrugs is another relevant problem. 37 , 38

An external file that holds a picture, illustration, etc.
Object name is 10.1177_10732748211038735-fig1.jpg

Epigenetics of cancer. (A) Molecular mechanisms. (B) Structural hierarchy of epigenomics. (C) Factors affecting the epigenome. Modified from Refs. 31 and 32 .

As we learn about the epigenome of specific cell populations in cancer patients, a door opens to the evaluation of sensitivity tests and the search for new molecular markers for detection, prognosis, follow-up, and/or response to treatment at various levels of molecular regulation. Likewise, the horizon expands for therapeutic alternatives in oncology with the use of epidrugs, such as pharmacoepigenomic modulators for genes and key pathways, including methylation of promoters and regulation of micro-RNAs involved in chemoresponse and immune response in cancer. 39 There is no doubt that integrated approaches identifying stable pharmagenomic and epigenomic patterns and their relation with expression profiles and genetic functions will be more and more valuable in our fight against cancer.

Cancer Stem Cells

Tumors consist of different populations of neoplastic cells and a variety of elements that form part of the TME, including stromal cells and molecules of the extracellular matrix. 40 Such intratumoral heterogeneity becomes even more complex during clonal variation of transformed cells, as well as influence the elements of the TME have on these cells throughout specific times and places. 41 To explain the origin of cancer cell heterogeneity, 2 models have been put forward. The first proposes that mutations occur at random during development of the tumor in individual neoplastic cells, and this promotes the production of various tumor populations, which acquire specific growth and survival traits that lead them to evolve according to intratumor mechanisms of natural selection. 42 The second model proposes that each tumor begins as a single cell that possess 2 functional properties: it can self-renew and it can produce several types of terminal cells. As these 2 properties are characteristics of somatic stem cells, 43 the cells have been called cancer stem cells (CSCs). 44 According to this model, tumors must have a hierarchical organization, where self-renewing stem cells produce highly proliferating progenitor cells, unable to self-renew but with a high proliferation potential. The latter, in turn, give rise to terminal cells. 45 Current evidence indicates that both models may coexist in tumor progression. In agreement with this idea, new subclones could be produced as a result of a lack of genetic stability and mutational changes, in addition to the heterogeneity derived from the initial CSC and its descendants. Thus, in each tumor, a set of neoplastic cells with different genetic and epigenetic traits may be found, which would provide different phenotypic properties. 46

The CSC concept was originally presented in a model of acute myeloid leukemia. 47 The presence of CSCs was later proved in chronic myeloid leukemia, breast cancer, tumors of the central nervous system, lung cancer, colon cancer, liver cancer, prostate cancer, pancreatic cancer, melanoma, and cancer of the head and neck, amongst others. In all of these cases, detection of CSCs was based on separation of several cell populations according to expression of specific surface markers, such as CD133, CD44, CD24, CD117, and CD15. 48 It is noteworthy that in some solid tumors, and even in some hematopoietic ones, a combination of specific markers that allow the isolation of CSCs has not been found. Interestingly, in such tumors, a high percentage of cells with the capacity to start secondary tumors has been observed; thus, the terms Tumor Initiating Cells (TIC) or Leukemia Initiating Cells (LIC) have been adopted. 46

A relevant aspect of the biology of CSCs is that, just like normal stem cells, they can self-renew. Such self-renewal guarantees the maintenance or expansion of the tumor stem cell population. Another trait CSCs share with normal stem cells is their quiescence, first described in chronic myeloid leukemia. 49 The persistence of quiescent CSCs in solid tumors has been recently described in colorectal cancer, where quiescent clones can become dominant after therapy with oxaliplatin. 50 In non-hierarchical tumors, such as melanoma, the existence of slow-cycling cells that are resistant to antimitogenic agents has also been proved. 51 Such experimental evidence supports the idea that quiescent CSCs or TICs are responsible for both tumor resistance to antineoplastic drugs and clinical relapse after initial therapeutic success.

In addition to quiescence, CSCs use other mechanisms to resist the action of chemotherapeutic drugs. One of these is their increased numbers: upon diagnosis, a high number of CSCs are observed in most analyzed tumors, making treatment unable to destroy all of them. On the other hand, CSCs have a high number of molecular pumps that expulse drugs, as well as high numbers of antiapoptotic molecules. In addition, they have very efficient mechanisms to repair DNA damage. In general, these cells show changes in a variety of signaling pathways involved in proliferation, survival, differentiation, and self-renewal. It is worth highlighting that in recent years, many of these pathways have become potential therapeutic targets in the elimination of CSCs. 52 Another aspect that is highly relevant in understanding the biological behavior of CSCs is that they require a specific site for their development within the tissue where they are found that can provide whatever is needed for their survival and growth. These sites, known as niches, are made of various cells, both tumor and non-tumor, as well as a variety of non-cellular elements (extracellular matrix [ECM], soluble cytokines, ion concentration gradients, etc.), capable of regulating the physiology of CSCs in order to promote their expansion, the invasion of adjacent tissues, and metastasis. 53

It is important to consider that although a large number of surface markers have been identified that allow us to enrich and prospectively follow tumor stem cell populations, to this day there is no combination of markers that allows us to find these populations in all tumors, and it is yet unclear if all tumors present them. In this regard, it is necessary to develop new purification strategies based on the gene expression profiles of these cells, so that tumor heterogeneity is taken into account, as it is evident that a tumor can include multiple clones of CSCs that, in spite of being functional, are genetically different, and that these clones can vary throughout space (occupying different microenvironments and niches) and time (during the progression of a range of tumor stages). Such strategies, in addition to new in vitro and in vivo assays, will allow the development of new and improved CSC elimination strategies. This will certainly have an impact on the development of more efficient therapeutic alternatives.

Invasion and Metastasis

Nearly 90% of the mortality associated with cancer is related to metastasis. 54 This consists of a cascade of events ( Figure 2 ) that begins with the local invasion of a tumor into surrounding tissues, followed by intravasation of tumor cells into the blood stream or lymphatic circulation. Extravasation of neoplastic cells in areas distant from the primary tumor then leads to the formation of one or more micrometastatic lesions which subsequently proliferate to form clinically detectable lesions. 4 The cells that are able to produce metastasis must acquire migratory characteristics, which occur by a process known as epithelial–mesenchymal transition (EMT), that is, the partial loss of epithelial characteristics and the acquirement of mesenchymal traits. 55

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Invasion and metastasis cascade. Invasion and metastasis can occur early or late during tumor progression. In either case, invasion to adjacent tissues is driven by stem-like cells (cancer stem cells) that acquire the epithelial–mesenchymal transition (EMT) (1). Once they reach sites adjacent to blood vessels, tumor cells (individually or in clusters) enter the blood (2). Tumor cells in circulation can adhere to endothelium and extravasation takes place (3). Other mechanisms alternative to extravasation can exist, such as angiopelosis, in which clusters of tumor cells are internalized by the endothelium. Furthermore, at certain sites, tumor cells can obstruct microvasculature and initiate a metastatic lesion right there. Sometimes, a tumor cells that has just exit circulation goes into an MET in order to become quiescent (4). Inflammatory signals can activate quiescent metastatic cells that will proliferate and generate a clinically detectable lesion (5).

Although several of the factors involved in this process are currently known, many issues are still unsolved. For instance, it has not yet been possible to monitor in vivo the specific moment when it occurs 54 ; the microenvironmental factors of the primary tumor that promote such a transition are not known with precision; and the exact moment during tumor evolution in which one cell or a cluster of cells begin to migrate to distant areas, is also unknown. The wide range of possibilities offered by intra- and inter-tumoral heterogeneity 56 stands in the way of suggesting a generalized strategy that could resolve this complication.

It was previously believed that metastasis was only produced in late stages of tumor progression; however, recent studies indicate that EMT and metastasis can occur during the early course of the disease. In pancreatic cancer, for example, cells going through EMT are able to colonize and form metastatic lesions in the liver in the first stages of the disease. 52 , 57 Metastatic cell clusters circulating in peripheral blood (PB) are prone to generate a metastatic site, compared to individual tumor cells. 58 , 59 In this regard, novel strategies, such as the use of micro-RNAs, are being assessed in order to diminish induction of EMT. 60 It must be mentioned, however, that the metastatic process seems to be even more complex, with alternative pathways that do not involve EMT. 61 , 62

A crucial stage in the process of metastasis is the intravasation of tumor cells (alone or in clusters) towards the blood stream and/or lymphatic circulation. 63 These mechanisms are also under intensive research because blocking them could allow the control of spreading of the primary tumor. In PB or lymphatic circulation, tumor cells travel to distant parts for the potential formation of a metastatic lesion. During their journey, these cells must stand the pressure of blood flow and escape interaction with natural killer (NK) cells . 64 To avoid them, tumor cells often cover themselves with thrombocytes and also produce factors such as VEGF, angiopoietin-2, angiopoietin-4, and CCL2 that are involved in the induction of vascular permeability. 54 , 65 Neutrophils also contribute to lung metastasis in the bloodstream by secreting IL-1β and metalloproteases to facilitate extravasation of tumor cells. 64

The next step in the process of metastasis is extravasation, for which tumor cells, alone or in clusters, can use various mechanisms, including a recently described process known as angiopellosis that involves restructuring the endothelial barrier to internalize one or several cells into a tissue. 66 The study of leukocyte extravasation has contributed to a more detailed knowledge of this process, in such a way that some of the proposed strategies to avoid extravasation include the use of integrin inhibitors, molecules that are vital for rolling, adhesion, and extravasation of tumor cells. 67 , 68 Another strategy that has therapeutic potential is the use of antibodies that strengthen vascular integrity to obstruct transendothelial migration of tumor cells and aid in their destruction in PB. 69

Following extravasation, tumor cells can return to an epithelial phenotype, a process known as mesenchymal–epithelial transition and may remain inactive for several years. They do this by competing for specialized niches, like those in the bone marrow, brain, and intestinal mucosa, which provide signals through the Notch and Wnt pathways. 70 Through the action of the Wnt pathway, tumor cells enter a slow state of the cell cycle and induce the expression of molecules that inhibit the cytotoxic function of NK cells. 71 The extravasated tumor cell that is in a quiescent state must comply with 2 traits typical of stem cells: they must have the capacity to self-renew and to generate all of the cells that form the secondary tumor.

There are still several questions regarding the metastatic process. One of the persisting debates at present is if EMT is essential for metastasis or if it plays a more important role in chemoresistance. 61 , 62 It is equally important to know if there is a pattern in each tumor for the production of cells with the capacity to carry out EMT. In order to control metastasis, it is fundamental to know what triggers acquisition of the migratory phenotype and the intrinsic factors determining this transition. Furthermore, it is essential to know if mutations associated with the primary tumor or the variety of epigenetic changes are involved in this process. 55 It is clear that metastatic cells have affinity for certain tissues, depending on the nature of the primary tumor (seed and soil hypothesis). This may be caused by factors such as the location and the direction of the bloodstream or lymphatic fluid, but also by conditioning of premetastatic niches at a distance (due to the large number of soluble factors secreted by the tumor and the recruitment of cells of the immune system to those sites). 72 We have yet to identify and characterize all of the elements that participate in this process. Deciphering them will be of upmost importance from a therapeutic point of view.

Epidemiology of Cancer

Cancer is the second cause of death worldwide; today one of every 6 deaths is due to a type of cancer. According to the International Agency for Research on Cancer (IARC), in 2020 there were approximately 19.3 million new cases of cancer, and 10 million deaths by this disease, 6 while 23.8 million cases and 13.0 million deaths are projected to occur by 2030. 73 In this regard, it is clear the increasing role that environmental factors—including environmental pollutants and processed food—play as cancer inducers and promoters. 74 The types of cancer that produce the greatest numbers of cases and deaths worldwide are indicated in Table 1 . 6

Total Numbers of Cancer Cases and Deaths Worldwide in 2020 by Cancer Type (According to the Global Cancer Observatory, IARC).

	Cases
Both sexes	Women	Men
Breast (2.26 million)	Breast (2.26 million)	Lung (1.43 million)
Lung (2.20 million)	Colorectal (865 000)	Prostate (1.41 million)
Colorectal (1.93 million)	Lung (770 000)	Colorectal (1.06 million)
Prostate (1.41 million)	Cervical (604 000)	Stomach (719 000)
Stomach (1.08 million)	Thyroid (448 000)	Liver (632 000)

	Deaths
Both sexes	Women	Men
Lung (1.79 million)	Breast (684 000)	Lung (1.18 million)
Colorectal (935 000)	Lung (607 000)	Liver (577 000)
Liver (830 000)	Colorectal (419 000)	Colorectal (515 000)
Stomach (768 000)	Cervical (341 000)	Stomach (502 000)
Breast (684 000)	Stomach (266 000)	Prostate (375 000)

Data presented on this table were obtained from Ref. 6.

As shown in Figure 3 , lung, breast, prostate, and colorectal cancer are the most common throughout the world, and they are mostly concentrated in countries of high to very high human development index (HDI). Although breast, prostate, and colorectal cancer have a high incidence, the number of deaths they cause is proportionally low, mostly reflecting the great progress made in their control. However, these data also reveal the types of cancer that require further effort in prevention, precise early detection avoiding overdiagnosis, and efficient treatment. This is the case of liver, lung, esophageal, and pancreatic cancer, where the difference between the number of cases and deaths is smaller ( Figure 3B ). Social and economic transition in several countries has had an impact on reducing the incidence of neoplasms associated with infection and simultaneously produced an increase in the types related to reproductive, dietary, and hormonal factors. 75

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Incidence and mortality for some types of cancer in the world. (A) Estimated number of cases and deaths in 2020 for the most frequent cancer types worldwide. (B) Incidence and mortality rates, normalized according to age, for the most frequent cancer types in countries with very high/& high (VH&H; blue) and/low and middle (L&M; red) Human Development Index (HDI). Data include both genders and all ages. Data according to https://gco.iarc.fr/today , as of June 10, 2021.

In the past 3 decades, cancer mortality rates have fallen in high HDI countries, with the exception of pancreatic cancer, and lung cancer in women. Nevertheless, changes in the incidence of cancer do not show the same consistency, possibly due to variables such as the possibility of early detection, exposure to risk factors, or genetic predisposition. 76 , 77 Countries such as Australia, Canada, Denmark, Ireland, New Zealand, Norway, and the United Kingdom have reported a reduction in incidence and mortality in cancer of the stomach, colon, lung, and ovary, as well as an increase in survival. 78 Changes in modifiable risk factors, such as the use of tobacco, have played an important role in prevention. In this respect, it has been estimated that decline in tobacco use can explain between 35% and 45% of the reduction in cancer mortality rates, 79 while the fall in incidence and mortality due to stomach cancer can be attributed partly to the control of Helicobacter pylori infection. 80 Another key factor in the fall of mortality rates in developed countries has been an increase in early detection as a result of screening programs, as in breast and prostate cancer, which have had their mortality rates decreased dramatically in spite of an increase in their incidence. 76

Another important improvement observed in recent decades is the increase in survival rates, particularly in high HDI countries. In the USA, for example, survival rates for patients with prostate cancer at 5 years after initial diagnosis was 28% during 1947–1951; 69% during 1975–1977, and 100% during 2003–2009. Something similar occurred with breast cancer, with a 5-year survival rate of 54% in 1947–1951, 75% in 1975–1977, and 90% in 2003–2009. 81 In the CONCORD 3 version, age-standardize 5-year survival for patients with breast cancer in the USA during 2010–2014 was 90%, and 97% for prostate cancer patients. 82 Importantly, even among high HDI countries, significant differences have been identified in survival rates, being stage of disease at diagnosis, time for access to effective treatment, and comorbidities, the main factors influencing survival in these nations. 78 Unfortunately, survival rates in low HDI countries are significantly lower due to several factors, including lack of information, deficient screening and early detection programs, limited access to treatment, and suboptimal cancer registration. 82 It should be noted that in countries with low to middle HDI, neoplasms with the greatest incidence are those affecting women (breast and cervical cancer), which reflects not only a problem with access to health services, but also a serious inequality issue that involves social, cultural, and even religious obstacles. 83

Up to 42% of incident cases and 47% of deaths by cancer in the USA are due to potentially modifiable risk factors such as use of tobacco, physical activity, diet, and infection. 84 It has been calculated that 2.4 million deaths by cancer, mostly of the lung, can be attributed to tobacco. 73 In 2020, the incidence rate of lung cancer in Western Africa was 2.2, whereas in Polynesia and Eastern Asia was 37.3 and 34.4, respectively. 6 In contrast, the global burden of cancer associated with infection was 15.4%, but in Sub-Saharan Africa it was 30%. 85 Likewise, the incidence of cervical cancer in Eastern Africa was 40.1, in contrast with the USA and Canada that have a rate of 6.2. This makes it clear that one of the challenges we face is the reduction of the risk factors that are potentially modifiable and associated with specific types of cancer.

Improvement of survival rates and its disparities worldwide are also important challenges. Five-year survival for breast cancer—diagnosed during 2010-2014— in the USA, for example, was 90%, whereas in countries like South Africa it was 40%. 82 Childhood leukemia in the USA and several European countries shows a 5-year survival of 90%, while in Latin-American countries it is 50–76%. 86 Interestingly, there are neoplasms, such as pancreatic cancer, for which there has been no significant increase in survival, which remains low (5–15%) both in developed and developing countries. 82

Although data reported on global incidence and mortality gives a general overview on the epidemiology of cancer, it is important to note that there are great differences in coverage of cancer registries worldwide. To date, only 1 out of every 3 countries reports high quality data on the incidence of cancer. 87 For the past 50 years, the IARC has supported population-based cancer registries; however, more than one-third of the countries belonging to the WHO, mainly countries of low and middle income (LMIC), have no data on more than half of the 18 indicators of sustainable development goals. 88 High quality cancer registries only cover 4% of the population in Africa, 8% in Asia, and 7% in Latin America, contrasting with 83% in the USA and Canada, and 33% in Europe. 89 In response to this situation, the Global Initiative for Cancer Registry Development was created in 2012 to generate improved infrastructure to permit greater coverage and better quality registries, especially in countries with low and middle HDI. 88 It is expected that initiatives of this sort in the coming years will allow more and better information to guide strategies for the control of cancer worldwide, especially in developing regions. This will enable survival to be measured over longer periods of time (10, 15, or 20 years), as an effective measure in the control of cancer. The WHO has established as a target for 2025 to reduce deaths by cancer and other non-transmissible diseases by 25% in the population between the ages of 30–69; such an effort requires not only effective prevention measures to reduce incidence, but also more efficient health systems to diminish mortality and increase survival. At the moment, it is an even greater challenge because of the effects of the COVID-19 pandemic which has negatively impacted cancer prevention and health services. 90

Oncologic Treatments

A general perspective.

At the beginning of the 20th century, cancer treatment, specifically treatment of solid tumors, was based fundamentally on surgical resection of tumors, which together with other methods for local control, such as cauterization, had been used since ancient times. 91 At that time, there was an ongoing burst of clinical observations along with interventions sustained on fundamental knowledge about physics, chemistry, and biology. In the final years of the 19 th century and the first half of the 20th, these technological developments gave rise to radiotherapy, hormone therapy, and chemotherapy. 92 - 94 Simultaneously, immunotherapy was also developed, although usually on a smaller scale, in light of the overwhelming progress of chemotherapy and radiotherapy. 95

Thus began the development and expansion of disciplines based on these approaches (surgery, radiotherapy, chemotherapy, hormone therapy, and immunotherapy), with their application evolving ever more rapidly up to their current uses. Today, there is a wide range of therapeutic tools for the care of cancer patients. These include elements that emerged empirically, arising from observations of their effects in various medical fields, as well as drugs that were designed to block processes and pathways that form part of the physiopathology of one or more neoplasms according to knowledge of specific molecular alterations. A classic example of the first sort of tool is mustard gas, originally used as a weapon in war, 96 but when applied for medical purposes, marked the beginning of the use of chemicals in the treatment of malignant neoplasms, that is, chemotherapy. 94 A clear example of the second case is imatinib, designed specifically to selectively inhibit a molecular alteration in chronic myeloid leukemia: the Bcr-Abl oncoprotein. 97

It is on this foundation that today the 5 areas mentioned previously coexist and complement one another. The general framework that motivates this amalgam and guides its development is precision medicine, founded on the interaction of basic and clinical science. In the forecasts for development in each of these fields, surgery is expected to continue to be the fundamental approach for primary tumors in the foreseeable future, as well as when neoplastic disease in the patient is limited, or can be limited by applying systemic or regional elements, before and/or after surgical resection, and it can be reasonably anticipated for the patient to have a significant period free from disease or even to be cured. With regards to technology, intensive exploration of robotic surgery is contemplated. 98

The technological possibilities for radiotherapy have progressed in such a way that it is now possible to radiate neoplastic tissue with an extraordinary level of precision, and therefore avoid damage to healthy tissue. 99 This allows administration of large doses of ionizing radiation in one or a few fractions, what is known as “radiosurgery.” The greatest challenges to the efficacy of this approach are related to radio-resistance in certain neoplasms. Most efforts regarding research in this field are concentrated on understanding the underlying biological mechanisms of the phenomenon and their potential control through radiosensitizers. 100

“Traditional” chemotherapy, based on the use of compounds obtained from plants and other natural products, acting in a non-specific manner on both neoplastic and healthy tissues with a high proliferation rate, continues to prevail. 101 The family of chemotherapeutic drugs currently includes alkylating agents, antimetabolites, anti-topoisomerase agents, and anti-microtubules. Within the pharmacologic perspective, the objective is to attain a high concentration or activity of such molecules in specific tissues while avoiding their accumulation in others, in order to achieve an increase in effectiveness and a reduction in toxicity. This has been possible with the use of viral vectors, for example, that are able to limit their replication in neoplastic tissues, and activate prodrugs of normally nonspecific agents, like cyclophosphamide, exclusively in those specific areas. 102 More broadly, chemotherapy also includes a subgroup of substances, known as molecular targeted therapy, that affect processes in a more direct and specific manner, which will be mentioned later.

There is no doubt that immunotherapy—to be explored next—is one of the therapeutic fields where development has been greatest in recent decades and one that has produced enormous expectation in cancer treatment. 103 Likewise, cell therapy, based on the use of immune cells or stem cells, has come to complement the oncologic therapeutic arsenal. 43 Each and every one of the therapeutic fields that have arisen in oncology to this day continue to prevail and evolve. Interestingly, the foreseeable future for the development of cancer treatment contemplates these approaches in a joint and complementary manner, within the general framework of precision medicine, 104 and sustained by knowledge of the biological mechanisms involved in the appearance and progression of neoplasms. 105 , 106

Immunotherapy

Stimulating the immune system to treat cancer patients has been a historical objective in the field of oncology. Since the early work of William Coley 107 to the achievements reached at the end of the 20 th century, scientific findings and technological developments paved the way to searching for new immunotherapeutic strategies. Recombinant DNA technology allowed the synthesis of cytokines, such as interferon-alpha (IFN-α) and interleukin 2 (IL-2), which were authorized by the US Food and Drug Administration (FDA) for the treatment of hairy cell leukemia in 1986, 108 as well as kidney cancer and metastatic melanoma in 1992 and 1998, respectively. 109

The first therapeutic vaccine against cancer, based on the use of autologous dendritic cells (DCs), was approved by the FDA against prostate cancer in 2010. However, progress in the field of immunotherapy against cancer was stalled in the first decade of the present century, mostly due to failure of several vaccines in clinical trials. In many cases, application of these vaccines was detained by the complexity and cost involved in their production. Nevertheless, with the coming of the concept of immune checkpoint control, and the demonstration of the relevance of molecules such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), and programmed cell death molecule-1 (PD-1), immunotherapy against cancer recovered its global relevance. In 2011, the monoclonal antibody (mAb) ipilimumab, specific to the CTLA-4 molecule, was the first checkpoint inhibitor (CPI) approved for the treatment of advanced melanoma. 110 Later, inhibitory mAbs for PD-1, or for the PD-1 ligand (PD-L1), 111 as well as the production of T cells with chimeric receptors for antigen recognition (CAR-T), 112 which have been approved to treat various types of cancer, including melanoma, non-small cell lung cancer (NSCLC), head and neck cancer, bladder cancer, renal cell carcinoma (RCC), and hepatocellular carcinoma, among others, have changed the paradigm of cancer treatment.

In spite of the current use of anti-CTLA-4 and anti-PD-L1 mAbs, only a subgroup of patients has responded favorably to these CPIs, and the number of patients achieving clinical benefit is still small. It has been estimated that more than 70% of patients with solid tumors do not respond to CPI immunotherapy because either they show primary resistance, or after responding favorably, develop resistance to treatment. 113 In this regard, it is important to mention that in recent years very important steps have been taken to identify the intrinsic and extrinsic mechanisms that mediate resistance to CPI immunotherapy. 114 Intrinsic mechanisms include changes in the antitumor immune response pathways, such as faulty processing and presentation of antigens by APCs, activation of T cells for tumor cell destruction, and changes in tumor cells that lead to an immunosuppressive TME. Extrinsic factors include the presence of immunosuppressive cells in the local TME, such as regulatory T cells, myeloid-derived suppressor cells (MDSC), mesenchymal stem/stromal cells (MSCs), and type 2 macrophages (M2), in addition to immunosuppressive cytokines.

On the other hand, classification of solid tumors as “hot,” “cold,” or “excluded,” depending on T cell infiltrates and the contact of such infiltrates with tumor cells, as well as those that present high tumor mutation burden (TMB), have redirected immunotherapy towards 3 main strategies 115 ( Table 2 ): (1) Making T-cell antitumor response more effective, using checkpoint inhibitors complementary to anti-CTLA-4 and anti-PD-L1, such as LAG3, Tim-3, and TIGT, as well as using CAR-T cells against tumor antigens. (2) Activating tumor-associated myeloid cells including monocytes, granulocytes, macrophages, and DC lineages, found at several frequencies within human solid tumors. (3) Regulating the biochemical pathways in TME that produce high concentrations of immunosuppressive molecules, such as kynurenine, a product of tryptophan metabolism, through the activity of indoleamine 2,3 dioxygenase; or adenosine, a product of ATP hydrolysis by the activity of the enzyme 5’nucleotidase (CD73). 116

Current Strategies to Stimulate the Immune Response for Antitumor Immunotherapy.

Strategies	T cells	Myeloid cells	TME
Lymph node	Anti-CTLA4	TNF-α
To improve tumor antigen presentation by APCs	Anti-CD137	IFN-α
To optimize effector T-cell activation	Anti-OX40	IL-1
	Anti-CD27/CD70	GM-CSF
	HVEM	CD40L/CD40
	GITR	CDN
	L-2	ATP
	IL-12	HMGB1
		TLR
		STING
		RIG-1/MDA-5
Blood vessel	CX3CL1
To improve T-cell traffic to tumors	CXCL9
To favor T-cell infiltration into tumors	CXCL10
Transference of T cells bearing antigen-specific receptor	CCL5
	LFA1/ICAM1
	Selectins
	CAR-T cell
	TCR-T cell
Tumor	Anti-PD-L1	Anti-CSF1/CSF1R	Anti-VEGF
To improve tumor antigen uptake by APCs	Anti-CTLA-4	Anti-CCR2	Inhibitors of IDO anti-CD73
To improve recognition and killing of tumor cells by T cells	Anti-LAG-3	PI3Kγ	ARs antagonists
	Anti-TIM-3
	Anti-TIGIT
	TNFR-agonists
	IL-2
	IL-10

Abbreviations: TME, tumor microenvironment; IL, interleukin; TNF, Tumor Necrosis Factor; TNFR, TNF-receptor; CD137, receptor–co-stimulator of the TNFR family; OX40, member number 4 of the TNFR superfamily; CD27/CD70, member of the TNFR superfamily; CD40/CD40L, antigen-presenting cells (APC) co-stimulator and its ligand; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; STING, IFN genes-stimulator; RIG-I, retinoic acid inducible gene-I; MDA5, melanoma differentiation-associated protein 5; CDN, cyclic dinucleotide; ATP, adenosine triphosphate; HMGB1, high mobility group B1 protein; TLR, Toll-like receptor; HVEM, Herpes virus entry mediator; GITR, glucocorticoid-induced TNFR family-related gene; CTLA4, cytotoxic T lymphocyte antigen 4; PD-L1, programmed death ligand-1; TIGIT, T-cell immunoreceptor with immunoglobulin and tyrosine-based inhibition motives; CSF1/CSF1R, colony-stimulating factor-1 and its receptor; CCR2, Type 2 chemokine receptor; PI3Kγ, Phosphoinositide 3-Kinase γ; CXCL/CCL, chemokine ligands; LFA1, lymphocyte function-associated antigen 1; ICAM1, intercellular adhesion molecule 1; VEGF, vascular endothelial growth factor; IDO, indolamine 2,3-dioxigenase; TGF, transforming growth factor; LAG-3, lymphocyte-activation gene 3 protein; TIM-3, T-cell immunoglobulin and mucin-domain containing-3; CD73, 5´nucleotidase; ARs, adenosine receptors; Selectins, cell adhesion molecules; CAR-T, chimeric antigen receptor T cell; TCR-T, T-cell receptor engineered T cell.

Apart from the problems associated with its efficacy (only a small group of patients respond to it), immunotherapy faces several challenges related to its safety. In other words, immunotherapy can induce adverse events in patients, such as autoimmunity, where healthy tissues are attacked, or cytokine release syndrome and vascular leak syndrome, as observed with the use of IL-2, both of which lead to serious hypotension, fever, renal failure, and other adverse events that are potentially lethal. The main challenges to be faced by immunotherapy in the future will require the combined efforts of basic and clinical scientists, with the objective of accelerating the understanding of the complex interactions between cancer and the immune system, and improve treatment options for patients. Better comprehension of immune phenotypes in tumors, beyond the state of PD-L1 and TME, will be relevant to increase immunotherapy efficacy. In this context, the identification of precise tumor antigenicity biomarkers by means of new technologies, such as complete genome sequencing, single cell sequencing, and epigenetic analysis to identify sites or subclones typical in drug resistance, as well as activation, traffic and infiltration of effector cells of the immune response, and regulation of TME mechanisms, may help define patient populations that are good candidates for specific therapies and therapeutic combinations. 117 , 118 Likewise, the use of agents that can induce specific activation and modulation of the response of T cells in tumor tissue, will help improve efficacy and safety profiles that can lead to better clinical results.

Molecular Targeted Therapy

For over 30 years, and based on the progress in our knowledge of tumor biology and its mechanisms, there has been a search for therapeutic alternatives that would allow spread and growth of tumors to be slowed down by blocking specific molecules. This approach is known as molecular targeted therapy. 119 Among the elements generally used as molecular targets there are transcription factors, cytokines, membrane receptors, molecules involved in a variety of signaling pathways, apoptosis modulators, promoters of angiogenesis, and cell cycle regulators. 120

Imatinib, a tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia, became the first targeted therapy in the final years of the 1990s. 97 From then on, new drugs have been developed by design, and today more than 60 targeted therapies have been approved by the FDA for the treatment of a variety of cancers ( Table 3 ). 121 This has had a significant impact on progression-free survival and global survival in neoplasms such as non-small cell lung cancer, breast cancer, renal cancer, and melanoma.

FDA Approved Molecular Targeted Therapies for the Treatment of Solid Tumors.

Drug	Therapeutic target	Indications	Biomarkers
Abemaciclib	CDK4/6 inhibitor	Breast cancer	ER+/PR+
Abiraterone	Anti-androgen	Prostate cancer	AR+
Afatinib	TKI anti-ErbB, EGFR (ErbB1), HER2 (ErbB2), ErbB3, ErbB4	NSCLC	EGFR mutated
			Deletion of exon 19
			Substitution in exon 21 (L858R)
Aflibercept	Anti-VEGF fusion protein	Colorectal cancer
Alectinib	Anti-ALK TKI	NSCLC	ALK+
Alpelisib	PI3K inhibitor	Breast cancer	PI3K mutated
Apalutamide	Anti-androgen	Prostate cancer	AR+
Atezolizumab	Anti-PD-L1 mAb	Breast cancer	PD-L1
		Hepatocellular carcinoma
		NSCLC
		Bladder cancer
Avapritinib	Kinase inhibitor	GIST	PDGFRA mutated in exon 18 (D842V)
Avelumab	Anti-PD-L1 mAb	Renal cancer	PD-L1
		Bladder cancer
		Neuroendocrine tumors
Axitinib	Anti-VEGF TKI	Renal cancer
Bevacizumab	Anti-VEGF mAb	CNS tumors
		Ovarian cancer
		Cervical cancer
		Colorectal cancer
		Hepatocellular carcinoma
		NSCLC
		Renal cancer
Brigatinib	Anti-ALK TKI	NSCLC	ALK+
Cabozantinib	TKR inhibitor: anti-MET, anti-VEGF, anti-RET, ROS1, MER, KIT	Renal cancer
		Hepatocellular carcinoma
		Thyroid cancer
Ceritinib	Anti-ALK TKI	NSCLC	ALK+
Cetuximab	Anti-EGFR mAb	Colorectal cancer	KRAS
		Head and Neck cancer	EGFR+
Crizotinib	Anti-ALK TKI	NSCLC	ALK+, ROS1+
Dabrafenib	BRAF inhibitor	NSCLC	BRAF-V600E, V600K
		Thyroid cancer
		Melanoma
Dacomitinib	Anti-EGFR TKI	NSCLC	EGFR+
Darolutamide	Anti-androgen	Prostate cancer	AR+
Durvalumab	Anti-PD-L1 mAb	NSCLC	PD-L1
		Bladder cancer
Encorafenib	BRAF inhibitor	Colorectal cancer	BRAF-V600E
		Melanoma
Entrectinib	Anti-ROS1 TKI	NSCLC	ROS1+
Enzalutamide	Anti-androgen	Prostate cancer	AR+
Erdafitinib	Anti-FGFR-1 TKI	Bladder cancer
Erlotinib	Anti-EGFR TKI	NSCLC	EGFR mutated
		Pancreatic caner	Deletion of exon 19
			Substitution in exon 21 (L858R)
Everolimus	mTOR inhibitor	CNS tumors
		Pancreatic cancer
		Breast cancer
		Renal cancer
Fulvestrant	ER antagonist	Breast cancer	ER+/PR+
Gefitinib	Anti-EGFR TKI	NSCLC	EGFR mutated
			Deletion of exon 19
			Substitution in exon 21 (L858R)
Imatinib	Anti-KIT TKI	GIST	KIT+
		Dermatofibroma protuberans
Ipilimumab	Anti-CTLA-4 mAb	Colorectal cancer
		Hepatocellular carcinoma
		NSCLC
		Melanoma
		Renal cancer
Lapatinib	TKI: anti-EGFR, anti-HER2	Breast cancer	ERBB2 over-expression or amplification
Lenvatinib	TKR: anti-VEGF, VEGFR1 (FLT1), VEGFR2 (KDR) y VEGFR3 (FLT4); (FGF) FGFR1, 2, 3 y 4, PDGF, PDGFRA, KIT, RET	Endometrial cancer
		Hepatocellular carcinoma
		Renal cancer
		Thyroid cancer
Lorlatinib	TKI: anti-ALK, anti-ROS2	NSCLC	ALK+, ROS1+
Necitumumab	Anti-EGFR mAb	NSCLC	EGFR+
Neratinib	Anti-HER2 TKI
Anti-EGFR	Breast cancer	ERBB2 over-expression or amplification
Niraparib	PARP inhibitor	Ovarian cancer	BRCA1/2 mutations
		Fallopian tube cancer	Homologous recombination deficiency
		Peritoneal cancer
Nivolumab	Anti-PD-1 mAb	Colorectal cancer	PD-1
		Esophageal cancer
		Hepatocellular carcinoma
		NSCLC
		Melanoma
		Renal cancer
		Bladder cancer
		Head and Neck cancer
Olparib	PARP inhibitor	Breast cancer	BRCA1/2 mutations
		Ovarian cancer
		Pancreatic cancer
		Prostate cancer
Osimertinib	Anti-EGFR TKI	NSCLC	EGFR-T790M
Palbociclib	CDK4/6 inhibitor	Breast cancer	RE+/RP+
Pantitumumab	Anti-EGFR mAb	Colorectal cancer	KRAS
			EGFR+
Pazopanib	TKI: Anti-VEGF, anti-PDGFR, anti-FGFR, anti-cKIT	Renal cancer
		Soft tissues sarcoma
Pembrolizumab	PD-1 inhibitor	Cervical cancer	PD-1
		Endometrial cancer
		Esophageal cancer
		Gastric cancer
		Hepatocellular carcinoma
		NSCLC
		Bladder cancer
		Head and Neck cancer
Pertuzumab	Anti-HER2 mAb	Breast cancer	ERBB2 over-expression or amplification
Ramucirumab	Anti-VEGF mAb	Colorectal cancer
		Esophageal cancer
		Gastric cancer
		Hepatocellular carcinoma
		NSCLC
Regorafenib	Anti-cKIT TKI	Colorectal cancer	KIT+
		Hepatocellular carcinoma
		GIST
Ribociclib	CDK4/6 inhibitor	Breast cancer	ER+/PR+
Ripretinib	TKI: anti-KIT, anti-PDGFR	GIST	KIT+
Rucaparib	PARP inhibitor	Prostate cancer	BRCA1/2 mutations
		Ovarian cancer
		Fallopian tube cancer
		Peritoneal cancer
Sacituzumab-Govitecan	Conjugated Ab anti-trop-2	Breast cancer	RE- RP- HER2-
Selpercatinib	Kinase inhibitor	NSCLC	RET+
		Thyroid cancer
Sorafenib	Multi-kinase inhibitor: anti-PDGFR, VEGFR, cKIT, TKR	Renal cancer
		Hepatocellular carcinoma
		Thyroid cancer
Sunitinib	Multi-kinase inhibitor: anti-PDGFR, VEGFR, cKIT, TKR	Renal cancer
		Pancreatic cancer
		GIST
Tamoxifeno	SERM	Breast cancer	ER+/PR+
Talazoparib	PARP inhibitor	Breast cancer	BRCA1/2 mutations
Temsirolimus	mTOR inhibitor	Renal cancer
Trametinib	BRAF inhibitor	NSCLC	BRAF-V600E, V600K
		Thyroid cancer
		Melanoma
Trastuzumab	Anti-HER2 mAb	Gastric cancer	ERBB2 over-expression of amplification
		Gastro-esophageal junction cancer
		Breast cancer
Trastuzumab-Deruxtecan	Anti-HER2 conjugated Ab	Breast cancer	ERBB2 over-expression of amplification
Trastuzumab-Emtansine	Anti-HER2 conjugated Ab	Breast cancer	ERBB2 over-expression of amplification
Tucatinib	Anti-HER2 TKI	Breast cancer	ERBB2 over-expression of amplification
Vandetanib	TKI: anti-VEGF, anti-EGFR	Thyroid cancer	EGFR+
Vemurafenib	BRAF inhibitor	Melanoma	BRAF-V600E

Abbreviations: mAb, monoclonal antibody; ALK, anaplastic lymphoma kinase; CDK, cyclin-dependent kinase; CTLA-4, cytotoxic lymphocyte antigen-4; EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; GIST, gastrointestinal stroma tumor; mTOR, target of rapamycine in mammal cells; NSCLC, non-small cell lung carcinoma; PARP, poli (ADP-ribose) polimerase; PD-1, programmed death protein-1; PDGFR, platelet-derived growth factor receptor; PD-L1, programmed death ligand-1; ER, estrogen receptor; PR, progesterone receptor; TKR, tyrosine kinase receptors; SERM, selective estrogen receptor modulator; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor. Modified from Ref. [ 127 ].

Most drugs classified as targeted therapies form part of 2 large groups: small molecules and mAbs. The former are defined as compounds of low molecular weight (<900 Daltons) that act upon entering the cell. 120 Targets of these compounds are cell cycle regulatory proteins, proapoptotic proteins, or DNA repair proteins. These drugs are indicated based on histological diagnosis, as well as molecular tests. In this group there are multi-kinase inhibitors (RTKs) and tyrosine kinase inhibitors (TKIs), like sunitinib, sorafenib, and imatinib; cyclin-dependent kinase (CDK) inhibitors, such as palbociclib, ribociclib and abemaciclib; poli (ADP-ribose) polimerase inhibitors (PARPs), like olaparib and talazoparib; and selective small-molecule inhibitors, like ALK and ROS1. 122

As for mAbs, they are protein molecules that act on membrane receptors or extracellular proteins by interrupting the interaction between ligands and receptors, in such a way that they reduce cell replication and induce cytostasis. Among the most widely used mAbs in oncology we have: trastuzumab, a drug directed against the receptor for human epidermal growth factor-2 (HER2), which is overexpressed in a subgroup of patients with breast and gastric cancer; and bevacizumab, that blocks vascular endothelial growth factor and is used in patients with colorectal cancer, cervical cancer, and ovarian cancer. Other mAbs approved by the FDA include pembolizumab, atezolizumab, nivolumab, avelumab, ipilimumab, durvalumab, and cemiplimab. These drugs require expression of response biomarkers, such as PD-1 and PD-L1, and must also have several resistance biomarkers, such as the expression of EGFR, the loss of PTEN, and alterations in beta-catenin. 123

Because cancer is such a diverse disease, it is fundamental to have precise diagnostic methods that allow us to identify the most adequate therapy. Currently, basic immunohistochemistry is complemented with neoplastic molecular profiles to determine a more accurate diagnosis, and it is probable that in the near future cancer treatments will be based exclusively on molecular profiles. In this regard, it is worth mentioning that the use of targeted therapy depends on the existence of specific biomarkers that indicate if the patient will be susceptible to the effects of the drug or not. Thus, the importance of underlining that not all patients are susceptible to receive targeted therapy. In certain neoplasms, therapeutic targets are expressed in less than 5% of the diagnosed population, hindering a more extended use of certain drugs.

The identification of biomarkers and the use of new generation sequencing on tumor cells has shown predictive and prognostic relevance. Likewise, mutation analysis has allowed monitoring of tumor clone evolution, providing information on changes in canonic gene sequences, such as TP53, GATA3, PIK3CA, AKT1, and ERBB2; infrequent somatic mutations developed after primary treatments, like SWI-SNF and JAK2-STAT3; or acquired drug resistance mutations such as ESR1. 124 The study of mutations is vital; in fact, many of them already have specific therapeutic indications, which have helped select adequate treatments. 125

There is no doubt that molecular targeted therapy is one of the main pillars of precision medicine. However, it faces significant problems that often hinder obtaining better results. Among these, there is intratumor heterogeneity and differences between the primary tumor and metastatic sites, as well as intrinsic and acquired resistance to these therapies, the mechanisms of which include the presence of heterogeneous subclones, DNA hypermethylation, histone acetylation, and interruption of mRNA degradation and translation processes. 126 Nonetheless, beyond the obstacles facing molecular targeted therapy from a biological and methodological point of view, in the real world, access to genomic testing and specific drugs continues to be an enormous limitation, in such a way that strategies must be designed in the future for precision medicine to be possible on a global scale.

Cell Therapy

Another improvement in cancer treatment is the use of cell therapy, that is, the use of specific cells as therapeutic agents. This clinical procedure has 2 modalities: the first consists of replacing and regenerating functional cells in a specific tissue by means of stem/progenitor cells of a certain kind, 43 while the second uses immune cells as effectors to eliminate malignant cells. 127

Regarding the first type, we must emphasize the development of cell therapy based on hematopoietic stem and progenitor cells. 128 For over 50 years, hematopoietic cell transplants have been used to treat a variety of hematologic neoplasms (different forms of leukemia and lymphoma). Today, it is one of the most successful examples of cell therapy, including innovative modalities, such as haploidentical transplants, 129 as well as application of stem cells expanded ex vivo . 130 There are also therapies that have used immature cells that form part of the TME, such as MSCs. The replication potential and cytokine secretion capacity of these cells make them an excellent option for this type of treatment. 131 Neural stem cells can also be manipulated to produce and secrete apoptotic factors, and when these cells are incorporated into primary neural tumors, they cause a certain degree of regression. They can even be transfected with genes that encode for oncolytic enzymes capable of inducing regression of glioblastomas. 132

With respect to cell therapy using immune cells, several research groups have manipulated cells associated with tumors to make them effector cells and thus improve the efficacy and specificity of the antitumor treatment. PB leckocytes cultured in the presence of IL-2 to obtain activated lymphocytes, in combination with IL-2 administration, have been used in antitumor clinical protocols. Similarly, infiltrating lymphocytes from tumors with antitumor activity have been used and can be expanded ex vivo with IL-2. These lymphocyte populations have been used in immunomodulatory therapies in melanoma, and pancreatic and kidney tumors, producing a favorable response in treated patients. 133 NK cells and macrophages have also been used in immunotherapy, although with limited results. 134 , 135

One of the cell therapies with better projection today is the use of CAR-T cells. This strategy combines 2 forms of advanced therapy: cell therapy and gene therapy. It involves the extraction of T cells from the cancer patient, which are genetically modified in vitro to express cell surface receptors that will recognize antigens on the surface of tumor cells. The modified T cells are then reintroduced in the patient to aid in an exacerbated immune response that leads to eradication of the tumor cells ( Figure 4 ). Therapy with CAR-T cells has been used successfully in the treatment of some types of leukemia, lymphoma, and myeloma, producing complete responses in patients. 136

An external file that holds a picture, illustration, etc.
Object name is 10.1177_10732748211038735-fig4.jpg

CAR-T cell therapy. (A) T lymphocytes obtained from cancer patients are genetically manipulated to produce CAR-T cells that recognize tumor cells in a very specific manner. (B) Interaction between CAR molecule and tumor antigen. CAR molecule is a receptor that results from the fusion between single-chain variable fragments (scFv) from a monoclonal antibody and one or more intracellular signaling domains from the T-cell receptor. CD3ζ, CD28 and 4-1BB correspond to signaling domains on the CAR molecule.

Undoubtedly, CAR-T cell therapy has been truly efficient in the treatment of various types of neoplasms. However, this therapeutic strategy can also have serious side effects, such as release of cytokines into the bloodstream, which can cause different symptoms, from high fever to multiorgan failure, and even neurotoxicity, leading to cerebral edema in many cases. 137 Adequate control of these side effects is an important medical challenge. Several research groups are trying to improve CAR-T cell therapy through various approaches, including production of CAR-T cells directed against a wider variety of tumor cell-specific antigens that are able to attack different types of tumors, and the identification of more efficient types of T lymphocytes. Furthermore, producing CAR-T cells from a single donor that may be used in the treatment of several patients would reduce the cost of this sort of personalized cell therapy. 136

Achieving wider use of cell therapy in oncologic diseases is an important challenge that requires solving various issues. 138 One is intratumor cell heterogeneity, including malignant subclones and the various components of the TME, which results in a wide profile of membrane protein expression that complicates finding an ideal tumor antigen that allows specific identification (and elimination) of malignant cells. Likewise, structural organization of the TME challenges the use of cell therapy, as administration of cell vehicles capable of recognizing malignant cells might not be able to infiltrate the tumor. This results from low expression of chemokines in tumors and the presence of a dense fibrotic matrix that compacts the inner tumor mass and avoids antitumor cells from infiltrating and finding malignant target cells.

Further Challenges in the 21st Century

Beyond the challenges regarding oncologic biomedical research, the 21 st century is facing important issues that must be solved as soon as possible if we truly wish to gain significant ground in our fight against cancer. Three of the most important have to do with prevention, early diagnosis, and access to oncologic medication and treatment.

Prevention and Early Diagnosis

Prevention is the most cost-effective strategy in the long term, both in low and high HDI nations. Data from countries like the USA indicate that between 40-50% of all types of cancer are preventable through potentially modifiable factors (primary prevention), such as use of tobacco and alcohol, diet, physical activity, exposure to ionizing radiation, as well as prevention of infection through access to vaccination, and by reducing exposure to environmental pollutants, such as pesticides, diesel exhaust particles, solvents, etc. 74 , 84 Screening, on the other hand, has shown great effectiveness as secondary prevention. Once population-based screening programs are implemented, there is generally an initial increase in incidence; however, in the long term, a significant reduction occurs not only in incidence rates, but also in mortality rates due to detection of early lesions and timely and adequate treatment.

A good example is colon cancer. There are several options for colon cancer screening, such as detection of fecal occult blood, fecal immunohistochemistry, flexible sigmoidoscopy, and colonoscopy, 139 , 140 which identify precursor lesions (polyp adenomas) and allow their removal. Such screening has allowed us to observe 3 patterns of incidence and mortality for colon cancer between the years 2000 and 2010: on one hand, an increase in incidence and mortality in countries with low to middle HDI, mainly countries in Asia, South America, and Eastern Europe; on the other hand, an increase in incidence and a fall in mortality in countries with very high HDI, such as Canada, the United Kingdom, Denmark, and Singapore; and finally a fall in incidence and mortality in countries like the USA, Japan, and France. The situation in South America and Asia seems to reflect limitations in medical infrastructure and a lack of access to early detection, 141 while the patterns observed in developed countries reveal the success, even if it may be partial, of that which can be achieved by well-structured prevention programs.

Another example of success, but also of strong contrast, is cervical cancer. The discovery of the human papilloma virus (HPV) as the causal agent of cervical cancer brought about the development of vaccines and tests to detect oncogenic genotypes, which modified screening recommendations and guidelines, and allowed several developed countries to include the HPV vaccine in their national vaccination programs. Nevertheless, the outlook is quite different in other areas of the world. Eighty percent of the deaths by cervical cancer reported in 2018 occurred in low-income nations. This reveals the urgency of guaranteeing access to primary and secondary prevention (vaccination and screening, respectively) in these countries, or else it will continue to be a serious public health problem in spite of its preventability.

Screening programs for other neoplasms, such as breast, prostate, lung, and thyroid cancer have shown outlooks that differ from those just described, because, among other reasons, these neoplasms are highly diverse both biologically and clinically. Another relevant issue is the overdiagnosis of these neoplasms, that is, the diagnosis of disease that would not cause symptoms or death in the patient. 142 It has been calculated that 25% of breast cancer (determined by mammogram), 50–60% of prostate cancer (determined by PSA), and 13–25% of lung cancer (determined by CT) are overdiagnosed. 142 Thus, it is necessary to improve the sensitivity and specificity of screening tests. In this respect, knowledge provided by the biology of cancer and “omic” sciences offers a great opportunity to improve screening and prevention strategies. All of the above shows that prevention and early diagnosis are the foundations in the fight against cancer, and it is essential to continue to implement broader screening programs and better detection methods.

Global Equity in Oncologic Treatment

Progress in cancer treatment has considerably increased the number of cancer survivors. Nevertheless, this tendency is evident only in countries with a very solid economy. Indeed, during the past 30 years, cancer mortality rates have increased 30% worldwide. 143 Global studies indicate that close to 70% of cancer deaths in the world occur in nations of low to middle income. But even in high-income countries, there are sectors of society that are more vulnerable and have less access to cancer treatments. 144 Cancer continues to be a disease of great social inequality.

In Europe, the differences in access to cancer treatment are highly marked. These treatments are more accessible in Western Europe than in its Eastern counterpart. 145 Furthermore, highly noticeable differences between high-income countries have been detected in the cost of cancer drugs. 146 It is interesting to note that in many of these cases, treatment is too costly and the clinical benefit only marginal. Thus, the importance of these problems being approached by competent national, regional, and global authorities, because if these new drugs and therapeutic programs are not accessible to the majority, progress in biomedical, clinical and epidemiological research will have a limited impact in our fight against cancer. We must not forget that health is a universal right, from which low HDI countries must not be excluded, nor vulnerable populations in nations with high HDI. The participation of a well-informed society will also be fundamental to achieve a global impact, as today we must fight not only against the disease, but also against movements and ideas (such as the anti-vaccine movement and the so-called miracle therapies) that can block the medical battle against cancer.

Final Comments

From the second half of the 20th century to the present day, progress in our knowledge about the origin and development of cancer has been extraordinary. We now understand cancer in detail in genomic, molecular, cellular, and physiological terms, and this knowledge has had a significant impact in the clinic. There is no doubt that a patient who is diagnosed today with a type of cancer has a better prospect than a patient diagnosed 20 or 50 years ago. However, we are still far from winning the war against cancer. The challenges are still numerous. For this reason, oncologic biomedical research must be a worldwide priority. Likewise, one of the fundamental challenges for the coming decades must be to reduce unequal access to health services in areas of low- to middle income, and in populations that are especially vulnerable, as well as continue improving prevention programs, including public health programs to reduce exposure to environmental chemicals and improve diet and physical activity in the general population. 74 , 84 Fostering research and incorporation of new technological resources, particularly in less privileged nations, will play a key role in our global fight against cancer.

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.

Hector Mayani https://orcid.org/0000-0002-2483-3782

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