Cancer (sometimes used synonymously with tumor) can be defined as an increase in volume that physically manifests a tumor, because of the increase in interstitial fluid pressure and the mass per volume of cells and stroma, compared to normal tissue. Also, it is manifested by functional alterations of the affected organ [1]. Gastric cancer is one of the most common types in the world. It is the fourth most common and the second most deadly. Yet, the incidence has decreased in North America and Europe, many cases remain in Latin America. Regarding Central America, Costa Rica is the leading country where this pathology is diagnosed [2].

Traditional treatment consists of endoscopic resection of the mucosa and subtotal or total gastrectomy [3]. In addition, chemoradiotherapy and radiotherapy improve the chances of survival [4].

Traditional therapies present a series of problems. With surgery, the tumor cannot be removed entirely. Likewise, some patients do not tolerate the surgical procedure or anesthesia and suffer complications during it, being a very invasive and ineffective method in case of metastasis. As a complement, radiation therapy may damage the surrounding tissues and, as with surgery, not be effective when there are metastases. On the other hand, chemotherapy cannot destroy a tumor independently. Moreover, it is not very specific, healthy tissues and cells are destroyed and systemic toxicity can be triggered, with an unequal death of cancer cells [4].

Therefore, targeted biological therapies have been considered [5]. Altered molecular events have been better understood, with the consequent discovery of new therapeutic targets and possible agents against this pathology. Said pharmacotherapy is directed to tumors, representing an improvement in the patients' quality of life. Against this background, the objective of this work is to describe current biological therapies directed against gastric cancer.

Gastric Cancer Overview

Gastric cancer is a term for any tumor (uncontrolled growth of malignant cells that outnumber benign ones) that arises in the cells of one of the stomach layers. According to the Spanish Society of Medical Oncology (SEOM, for its Spanish acronym), adenocarcinomas represent more than 90 % of the diagnostic cases [6]. According to Lauren, they are divided into two types: intestinal and diffuse. Histologically, this classification is one of the most employed [7].

The diffuse o undifferentiated type (associated with worse prognosis) [8]. tends to generate metastases earlier, is more frequent in young people and is related to certain genetic characteristics. For its part, intestinal adenocarcinoma mainly affects older men [9]. Others less frequent are lymphomas, gastrointestinal stromal tumors and carcinoid tumors [2].

The signs and symptoms are generally nonspecific and appear when there is a significant disease advance, making it challenging to have early diagnoses. 80 % of the cases are asymptomatic and in the remaining percentage, the symptoms do not cause alarm [10]. The most common ones are difficulty swallowing, feeling bloated after eating, feeling full after eating small amounts of food, heartburn, indigestion, nausea, stomach pain, vomiting and involuntary weight loss [11].

When faced with a diagnosis, staging is done using the TNM system (tumor, lymph nodes and metastasis) [12]. This classification makes it possible to establish the four stages of said cancer, each with its respective characteristics related to the three elements mentioned [13].

Factors That Predispose To Gastric Cancer

There are elements associated with gastric cancer, which increase the risk of developing it. They are set out below:

Nutritional Factors

It has been determined that an augmented risk occurs in people who eat large amounts of pickled vegetables (greater risk due to their high content of nitrosamines and salt and low in antioxidants), as well as smoked meats. In the latter, the pyrolysis of proteins originates derivatives of polycyclic aromatic hydrocarbons and heterocyclic amines from the group of pyridines and imidazole, which have carcinogenic effects [14].

Besides, nitrites and nitrates are substances generally found in cured meats. Some bacteria can convert them into compounds that favor gastric cancer development [15].

Additionally, consuming lots of fresh fruits and vegetables reduces the risk of suffering from it. Green vegetables are protective, even though their thermolabile vitamins (C, E and carotenes) are destroyed up to 50 % at the cooking time [14,16].

Genetic Factors

The first case of a molecular basis for familial gastric cancer was the hereditary diffuse gastric cancer (HDGC) secondary to mutations in the E-cadherin/CDH1 gene [17], which codes for proteins related to adhesion and intercellular communication [10]. The mutation presents itself in young individuals (20 to 30 years), usually the second or third decade of life [10. Approximately 25 % of the family history suffering from CGDH have had an alteration of the CDH1 gene, being transmitted in an autosomal dominant way [17]. 

When their levels decrease, the characteristics of epithelial cells are lost and those of mesenchymal cells are acquired, which in turn has an invasive capacity. Furthermore, the expression of non-epithelial cadherins, such as N-cadherin, has been seen in invasion and metastasis processes, together with a decrease in the E-cadherin expression in 70 % of infiltrating and poorly differentiated carcinomas [18].

Plus, there are proto-oncogenes. These components control cell division and when activated with mutations (nucleotide substitution, insertions, or deletions), they can cause cancer [19]. There are oncogenes associated with gastric cancer, including c-met, K-sam, erbB2 and K-ras [19-21]

There are also tumor suppressor genes. The possibility of a normal cell turning into a cancer one is reduced through mechanisms for detecting damaged cells and subsequent cell cycle progression arrest [19]. In gastric carcinogenesis, those to be considered are:

• Bcl-2: Blocks a common pathway of apoptosis in cells with damaged DNA, preventing premature death of mitotic cells and prolonging cell survival to promote more mutations [22]

• p53: Has functions such as cell cycle arrest when DNA damage or cell stress is detected, maintaining genome stability, collaboration with DNA repair and replication processes, apoptosis triggering and activation of genes involved in the normal cell cycle [23]

• p73: Encodes a protein with structural and functional homology to p53, so it is believed that it acts similarly, but there is not as much evidence [24]

• APC: Its inactivation promotes the development of some gastric cancers, such as very well-differentiated adenocarcinomas and signet-ring cell carcinomas [25]

Finally, the DNA repair genes are found. Genetic instability from the inactivation of mismatch repair system genes (mostly hMLH1 and hMSH2) is another molecular pathway involved in similar pathologies, especially colorectal cancer. However, studies on them are scarce and more investigations are required [26].

Environmental Factors

Helicobacter pylori is a Gram-negative bacterium, which colonizes the stomach and causes long-term infections in the gastric and duodenal mucosa [27]. Its discovery and identification were made by Marshall and Warrent in 1983. It was first known as a Campylobacter-like organism [28].

Approximately 65 to 80 % of diagnosed cases of adenocarcinoma of the distal stomach are related to it [28]. Therefore, it is a leading cause of gastric cancer. Its pathogenicity is associated with inducing chronic inflammation and resistance to apoptosis. The expression mechanism of pro-inflammatory cytokines is well studied. Nevertheless, resistance to apoptosis is not fully understood [29].

This organism has different strains with diverse virulence factors. Such molecules allow it to adapt to the acidic conditions of the stomach and cause constant mucosa damage. The most virulent ones produce a cytotoxic protein associated with gene A, which can develop gastritis, ulcers, and, finally, mucosa-associated lymphoid tissue (MALT) lymphoma [28].

Due to this situation, in 1994, the World Health Organization (WHO) and the International Agency for Research on Cancer (IARC) classified the bacterium as a group 1 carcinogen. Such designation means sufficient evidence to confirm that it can cause cancer in humans [28].

In addition, it was determined that the infection by the positive cag A strain and the family history associated are independent factors. Those who meet both conditions have a 16 times greater risk of developing non-cardia gastric carcinoma [30,31].

Other Factors

In pernicious anemia, cells in the stomach lining produce intrinsic factor (IF), used for the vitamin B12 absorption from food. People with a marked decrease in this component show a vitamin deficiency, affecting the body's ability to produce red blood cells and an increased risk of stomach cancer [15]. 

Being overweight can also be considered. In a review of 24 prospective studies and 41,791 cases, increased body mass index (BMI) for overweight and obesity was positively associated with their risk of gastric cardiac cancer [29]. 

Another aspect is smoking, especially for tumors in the stomach upper section, close to the esophagus. The incidence rate is about double for smokers [32].

As a complement, gender (more common in men than women), geography (more frequent in East Asia, Eastern Europe and Central and South America) [15] and age are found. Concerning this last element, in a study made in Central and South America, the incidence and mortality were closely related to age. In these nations, 80 to 97 % of all cases were diagnosed in people over 50 years old and 3 to 18 % in persons under 50. The mean age at the diagnosis time ranged between 61 and 68 years old and between 59 and 73 years old in men and women, respectively [33].

Epidemiology

Gastric cancer has been considered a high incidence and mortality disorder in society. For 2018, some studies were carried out, finding it as the fifth most common malignant neoplasm and the third leading cause of death worldwide [34-36].

Each year more than a million cases are diagnosed. The incidences adjusted by sex indicate that one in every 36 men and 84 women develop it before 79. Additionally, it is 2.2 times more likely to be diagnosed in men than in women. The cumulative risk of developing it from birth to 74 years is 1.87 % compared to 0.79 %, respectively [36,37].

Furthermore, its regionally adjusted incidence in rural areas is almost twice that in urban ones. The highest rates are found in China, Japan, South Korea, Eastern Europe, tropical countries in South America and Costa Rica. The lowest are seen in Southern Asia, North and East Africa, North America, Australia and New Zealand. Currently, three countries account for 60 % of the total world cases: Japan, China and South Korea [35,38,39].

Most cases are intestinal-type adenocarcinomas and are believed to progress through a specific pathway. Its predominant risk factor is H. pylori gastritis. The decrease in its prevalence has contributed significantly to the incidence decrease in many geographical parts [35].

However, the annual number of patients diagnosed and deceased continues increasing. This scenario is due to population growth in zones with a high prevalence of H. pylori [37].

Finally, the mortality rate continues to be very high. Less than 30 % of diagnosed subjects survive for more than five years [37,40].

Diagnosis

Endoscopy and biopsy have been used for the traditional diagnosis. Nonetheless, this procedure depends on the operator's skills, is invasive and expensive and causes discomfort and anxiety to the patient [41].

The main objective is its early detection to improve the chances of survival. Early diagnosis associated with the inner lining of the stomach wall increases the survival rate and the treatment success rate. Still, a substantial proportion of patients with early-stage illness are asymptomatic or have nonspecific symptoms, as mentioned previously [42].

Endoscopy, a standardized procedure to map the entire stomach, can be performed early. Approximate eight to 22 images are proposed. If subtle changes in the gastric mucosa are detected, advanced techniques such as magnifying endoscopy, Chromoendoscopy (CE), novel High-Resolution (HR) virtual chromoendoscopy techniques with Narrow-Band Imaging (NBI) with or without Magnification (NBI-ME), Flexible Spectral Imaging Color Enhancement (FICE) endoscopy with or without Magnification (FIME) and confocal laser endomicroscopy (CLE) are available. These techniques have yielded promising results, with NBI being the most outstanding [42].

Likewise, progress has been made in developing biomarker molecules for early diagnosis. Conventional serum tumor biomarkers are utilized, including Carcinoembryonic Antigen (CEA), cancer-associated antigens 19-9, 50, 72-4 and 125 and pepsinogen I and II [41, 43-47].

Traditional Treatments

The treatment of gastric cancer has required a multidisciplinary approach. The team includes a surgeon, a pathologist, a gastroenterologist and medical and radiation oncologists. Extensive therapies are required, including chemotherapy, radiation therapy and surgery, either alone or in combinations. Chemotherapy is beneficial in combination with surgery, with a 5-year progression-free rate of 23 to 36 %. In the case of people with metastases but good general condition, chemotherapy or palliative surgery is employed, while in patients with a poor functional status, supportive or adjuvant treatment has been the only recommendation since there is no longer a pathology reversal [39].

Surgery

The surgery is done by making an incision in the abdomen and removing all or part of the stomach. Depending on the section removed, the intestine may need to be reconnected to the remaining portion of the stomach (partial gastrectomy) or the esophagus (total gastrectomy) [48,49]. For those with advanced cancer, even with metastasis, partial stomach removal can relieve the signs and symptoms of a growing tumor [48].

Today, some surgeons perform the procedure with a camera. Laparoscopy is carried out with a few small surgical incisions. Its advantages are faster recovery, less pain and small incisions [49,50].

Chemotherapy

It is usually made routinely with three cycles of chemotherapy before surgery and three cycles after it. Each one lasts for three weeks [39].

The drugs travel throughout the body, beyond the stomach and kill cancer cells that spread outside the organ. It can be given as primary treatment for cancer that has spread to distant parts, helping to shrink or slow growth, relieving symptoms and allowing people to live longer [51].

For its part, neoadjuvant chemotherapy is administered before surgery. Its usefulness is to reduce the tumor size and make it easier to be removed. As a supplement, the adjuvant is administered after surgery to kill cancer cells that may remain in the body. Chemotherapy and radiotherapy are often combined [48,51].

Depending on the situation (including the cancer stage, the person's general health condition and whether chemotherapy is combined with radiation therapy), they can be utilized alone or in combination. Some common schemes include ECF (epirubicin, cisplatin and 5-fluorouracil or 5-FU), given before and after surgery, docetaxel, or paclitaxel plus 5-FU or capecitabine, cisplatin plus 5-FU or capecitabine and paclitaxel plus carboplatin. The last three can be combined with radiation before surgery [51].

Many doctors prefer two drugs for advanced cancer. There are combinations of three drugs, although such schemes cause a more significant number of side effects. Therefore, they are reserved for people with good health and closely followed by their physicians [51].

Radiotherapy

Radiotherapy requires high-energy rays or particles to kill cancer cells in specific body areas. For stomach cancer, it is employed before surgery and in some cases, it can be given with chemotherapy, reducing the tumor size and making the surgical procedure more manageable. After the operation, it destroys remnants that could not be seen or extirpated. As a supplement, when combined with drugs such as 5-FU, it can delay or prevent recurrence after surgery and help patients live longer. It also helps to slow growth and relieve late-stage symptoms, including pain, bleeding and eating problems [52].

Moreover, external radiotherapy is available. It focuses radiation from a machine outside the body. 3D conformal radiotherapy (3D-CRT) and Intensity Modulated Radiotherapy (IMRT) are available. 3D-CRT designs the treatment by delimiting the volumes corresponding to tumor targets and normal organs through serial axial tomographic sections. In this way, the total dose and the dose per fraction in the tumor are established, excluding the tissues without altering the high-dose areas. As a complement, IMRT, to carrying out everything done by the other technique, allows the establishment of dose restrictions necessary for the normal tissues' protection [50. In this way, such methods focus radiation on the tumor and limit damage to adjacent normal tissues [52].

Biological Therapies

The use of living organisms and substances derived from them to treat diseases is called biological therapy. The most employed in cancer treatment include monoclonal antibodies, cytokine therapies, vaccines, adoptive T-cell treatments, dendritic cell bases therapies, oncolytic virus therapies, gene therapies and DNA and RNA oligonucleotides products [53]. Those studied as therapeutic options against gastric cancer will be mentioned ahead.

Micro-RNAs

In recent years, research on micro RNAs (miRNAs) has expanded. They regulate gene expression by forming a silencing complex, preventing the translation of specific target genes, interfering with the reading and translation of their messenger RNA (mRNA). They can act as suppressors in gastric cancer through the negative regulation of genes that promote the tumors appearance [54]. Furthermore, each miRNA can interact with various cellular pathways [55]. Therefore, they are a fundamental tool for diagnosing, prognosis, monitoring and treating the pathology [54]. The following miRNAs have been investigated as the basis for future treatments. They are currently in the research stages and are not yet being commercialized.

MIR-218

It is a negatively deregulated tumor suppressor in gastric cancer that controls tumor differentiation, volume and the likelihood of metastasis by regulating oncogenes and growth pathways. It targets the homologous Roundabout gene 1. This genetic material encodes a receptor for one of the Slit proteins, responsible for neoplastic cell migration [54]. Plus, it suppresses the epidermal growth factor receptor (EGF), related to a significant activity of the nuclear transcription factor kappa B (NF-kB) [54,56], promoting the expression of genes related to proliferation, apoptosis, inflammation and migration, including POU2F2 [54].

Another target is GLI2. This gene codes for a mediator transcription factor in the Hedgehog signaling pathway, responsible for transmitting information for cell differentiation. Its overexpression is related to the development of malignant neoplasms, promoting oncogenes' expression that facilitates the cells' proliferation, protecting them from apoptosis and promoting their invasion. Likewise, miR-218 can inhibit the expression of the Smoothened protein, responsible for activating GLI2 [54].

MIR-375

It is a highly relevant tumor suppressor because of its negative dysregulation in gastric cancer. Additionally, it has been associated with H. pylori. A decrease in its levels has been found in its presence. It inhibits the Janus 2 kinase gene, regulating the signaling pathway of the Janus 2-STAT-3 kinase gene. The latter promotes proliferation, resistance to apoptosis, migration, invasion and metastasis. Furthermore, it causes angiogenesis, inflammation and evasion of the immune response and controls the expression of the 3-phosphoinositide-dependent protein kinase 1 (PI 3-kinase or PI3K), responsible for phosphorylating and activating the protein kinase that decreases cell death due to apoptosis. It also induces proliferation, angiogenesis, deregulates glycolysis by activating the mammalian cell target of rapamycin (mTOR) and promotes cell immortality by activating the telomerase reverse transcriptase (hTERT) [54].

Besides, HER-2 inhibits part of the MAP kinase signaling pathway (mitogen-activated protein kinase or MAPK). Thus, the expression of carcinogenic genes and angiogenesis is promoted, favoring tumor nutrition in the lamina propria of the gastric mucosa. Its inhibition can increase the sensitivity of cisplatin, resulting in an option for treating patients with chemoresistance [54].

MIR-7

It inhibits an essential carcinogenesis pathway, disabling the expression of two genes: the transcription factor p65 (known as RELA) and the rapid transcription proto-oncogene (FOS), which codes for the NF-kB and AP-1 proteins, respectively. Both are involved in pro-oncogenic signaling pathways. Through in vitro tests with human gastric cancer cell lines (BGC823, SGC7901, AGS, MKN28, MKN45, GC9811 and SGC7901/VCR) and a normal gastric epithelial cell line (GES), together with an in vivo study with mice, miR-7 overexpression repressed RELA and FOS expression and prevented cancer cell proliferation and tumorigenesis. Low miR-7 expression correlates with high RELA and FOS expression and poor survival in gastric cancer patients. Moreover, miR-7 downregulation can occur as a result of the activation of NF-κB signaling by H. pylori infection. These findings suggest that miR-7 may serve as a regulator in the development and progression of gastric cancer [57].

Vaccines

A vaccine is any preparation intended to protect against an illness, stimulating the organism to produce antibodies that will defend the body against future dangers since the immune system will recognize the foreign agent and destroy it. Its mode of administration is generally by intramuscular route, although some are dispensed orally [58].

Immunogenization through vaccines has saved many lives worldwide and has been one of medicine's great triumphs. Though, many variables need to be controlled. The most critical is the antigen choice. Regarding cancer, ideally, it must be expressed explicitly by cancer cells, it must be present in all of them, it must be necessary for their survival so that they cannot escape the immune attack and it must be highly immunogenic [59].

Most vaccines use tumor-associated antigens. Initially, those that cancer cells express abnormally were contemplated. Nevertheless, as they are autoantigens, the immune cells that strongly recognize them may have been eliminated from the immune repertoire by central and peripheral tolerance. For this reason, neoantigens (protein alterations caused by mutations) have been considered [59,60].

A cancer vaccine must break tolerance by stimulating low-affinity T cells. Some strategies include adjuvants and costimulators and repeat vaccination [59].

In the case of adjuvants, they increase the potency, quality and duration of the immune response. Likewise, they achieve an effective reaction at ages where the immune system is not sufficiently mature (first months of life) and in immunosuppressed individuals or advanced ages [61]. Table 1 shows those approved by the United States Food and Drug Administration (FDA).

Table 1: FDA-Approved Vaccine Adjuvants [61,113,114]

Even though the number of adjuvants available is small, research in this area is diligent. For example, polysaccharides have been investigated for the formulation of cancer vaccines since they have biocompatibility, low toxicity and adequate safety. At the same time, there are effects of humoral, cellular and mucosal immunities [62].

In the field of vaccine research, there are several for which preclinical and clinical trials have been made without reaching their commercialization. Some of them are detailed below.

RMVHu191

It is a live attenuated vaccine of the Hu-191 strain, a recombinant Chinese measles virus generated in the laboratory, with an oncolytic effect. In one study, its antitumor effect was evaluated. It provoked cytopathic effects and inhibited tumor proliferation in vitro and in vivo by inducing caspase-dependent apoptosis [63].

In the investigation, the BGC-823 and SGC-7901 cell lines were incubated with rMVHu191 for two hours. The virus was then replicated for 48 and 72 hours, respectively. The viability reduction was observed within 48 hours after infection and the antitumor potency was dose and time-dependent. Plus, in BGC-823 cells, the apoptotic rate after infection was 3, 23, 28 and 43 % at 24, 48, 72 and 96 hours, respectively and in SGC-7901 cells, it corresponded to 1, 6, 19 and 26 % at the same hours [63].

When cells were infected, the apoptosis was caused by the caspase cascade (cysteine family of proteases, which participate in the cellular apoptosis process) [64] and PARP (poly-ADP-ribose polymerase). This molecule is considered a sensor that determines the DNA breakdown in molecular lines. In addition, it has a relevant role in genetic material repair, genomic integrity and cell survival [65]. Through the hyperreactivity of this polymerase, programmed cell death is obtained by factors such as the loss of mitochondrial membrane potential and the release of the apoptosis-inducing factor [66,67].

Furthermore, in a preclinical trial, the Hu191 vaccine has an effect against gastric cancer. Intratumor injections significantly reduced tumor growth and improved survival time in mice bearing human SGC-7901 xenografts. Along with this data, there was no apparent toxicity [63].

G17DT

Gastrimmune is an immunogen formulated as an oil/water emulsion to make an intramuscular gastrin vaccine. It contains a nine amino acid epitope derived from the amino-terminal sequence of gastrin-17 [68,69], (gastrin gene found on chromosome 17) [70], which is conjugated with diphtheria toxin via a peptide spacer [69]. It generates antibodies capable of neutralizing the gastrin forms that mediate tumor proliferation [68].

In a phase II, multicenter study (five countries) with 103 patients, the G17DT vaccine was utilized intramuscularly (weeks 1, 5, 9 and 25) with cisplatin and 5-FU every 28 days. It was compared with chemotherapy treatment only (in the same range). A survival half-life of 9 months and a mean time to disease progression of 5.4 months (longer in immunocompetent patients) was demonstrated [68,71].

Monoclonal Antibodies

Antibodies are substances secreted by B lymphocytes. Each molecule comprises two light and two heavy chains linked by disulfide bridges, generating a structure like a Y. The upper region is called the antigen-binding fragment (Fab), formed by hypervariable regions, essential in antigen recognition. Besides, it has a lower region called the crystallizable fragment (Fc), found in the lower part of the antibody, that generates a response, depending on the binding type to certain cell membrane receptors and the ability to fix complement [72].

Thanks to this knowledge, it was possible to develop monoclonal antibodies. They are defined as clones of the same cell that produces the antibodies. Initially, they were obtained through hybridoma technology, composed of a murine myeloma cell and a spleen cell from an immunized animal. Using the established procedure, investigators select only hybrid cells and clones with known specificity [72].

However, the immunogenicity problem arose due to its murine origin, as the immune system responded to its administration as foreign bodies. Therefore, they were humanized, based on the theory that the more similar they were to the host, the more significant part of the problem would be solved. Today it has been possible to develop chimeric antibodies, where the Fab region would come from mice and the rest from humans and humanized ones (only the complementary determination regions or CDR are obtained from an animal). Finally, in the fully human, all parts are of human origin [73].

Thanks to these therapeutic options, immunotherapy was implemented. It can be defined as using the immune system features in a pathology treatment [74]. It is divided into passive and active. In the first, the patient received preformed antibodies against tumor-related antigens. For its part, the active one employs the humoral and cellular immunities of the person to fight against the tumor [75].

From now on, some therapeutic targets in gastric cancer will be addressed using both approaches.

Passive Immunotherapy

Human Epidermal Growth Factor Receptor 2 (HER2): The HER2 protein is a transmembrane tyrosine kinase receptor belonging to a family of epidermal growth factor receptors (EGFRs) [76]. It is a product of a proto-oncogene. It plays a vital role in the growth and development of epithelial cells at normal levels [77]. 

Each cell contains two copies of the HER2 gene, which must produce a specific amount of protein on the cell surface. In some cases, the gene is amplified, leading to multiple copies, with the consequent excessive protein production. Under such conditions, it transmits signals to cells to divide, multiply and grow at higher rates than normal ones. Thus, it contributes to cancer production and progression [77].

Different monoclonal antibodies were studied against this receptor located on tumor cells at the gastric level. The main characteristics associated with them are detailed below.

Trastuzumab

Trastuzumab is a recombinant humanized antibody specific for HER2 extracellular domain IV. It is the first-line treatment for advanced gastric cancer. Its direct mechanism involves blocking HER2 signaling pathways, reducing receptor expression to induce cellular apoptosis. The indirect is mediated by the antibody-dependent cellular cytotoxicity (ADCC) [76,78].

Two treatments were assigned in a phase III trial, one with cisplatin and capecitabine or 5-FU and another with trastuzumab and the chemotherapy drug combination. The study involved 594 patients and the distribution was random. There was a 26 % reduction in mortality risk for those patients that received the monoclonal antibody [76].

Additionally, these patients showed improvement in secondary endpoints when compared against chemotherapy alone, including progression-free survival (6.7 vs. 5.5 months), time to progression (7.1 vs. 5.6 months), duration response to treatment (6.9 versus 4.8 months) and overall response rate (47 versus 35 %) [76].

Similar results were obtained for 294 patients (584 patients in total). Adding trastuzumab to chemotherapy improved average survival by 2.5 months [78].

In another study, this molecule was evaluated in cancer types homogeneously HER2 (all cancer cells express the HER2 protein) and heterogeneously HER2. Overall survival and progression-free survival were higher in patients with homo-HER2 expression and exhibited the most significant reduction in tumor size [79].

As a complement, there is trastuzumab deruxtecan. It combines the antibody and a cytotoxic topoisomerase I inhibitor with a cleavable linker based on tetrapeptides [80].

In an open-label, randomized, phase II trial, the protein was evaluated against physician-chosen chemotherapy in patients with HER2-positive advanced gastric cancer. It was carried out with 187 patients, of whom 125 received the conjugated antibody and 62 chemotherapy (55 irinotecan and seven paclitaxel). Among the outcomes evaluated, a more prolonged overall survival was determined with biological therapy (mean 12.5 months) compared with elective chemotherapy (8.4 months) [80].

In 2020, it was established as an orphan drug for gastric cancer, including cases related to the gastroesophageal junction [81].

Pertuzumab

It is a humanized monoclonal antibody produced through recombinant DNA technology [82]. The growth and proliferation of cancer cells occur through the formation of HER2/HER3 heterodimers. As mentioned above, trastuzumab binds to domain IV of HER2 without inhibiting HER2 dimerization with ligand-activated HER3. In contrast, pertuzumab effectively blocks such heterodimerization [76,82,83]. In preclinical models, it has shown efficacy when combined with trastuzumab and trastuzumab-emtansine, another conjugated monoclonal antibody [76].

Still, in a phase III study with 780 patients, pertuzumab treatment was performed in combination with trastuzumab and chemotherapy against a control group that included a placebo, along with trastuzumab and chemotherapy. The results did not show a significant difference in overall survival between the two groups [84].

Epidermal Growth Factor Receptor (EGFR)

The EGFR is associated with the progression of diverse malignant tumors. Its physiological function regulates epithelial tissue development and homeostasis. When expressed in cancer, its signaling can substantially improve tumor cells' survival. Several monoclonal antibodies are produced against this receptor, including cetuximab and panitumumab.

Cetuximab

This protein is a chimeric IgG1 monoclonal antibody. It was the first approved for clinical utilization against EGFR [85].

Through various clinical trials, it was determined to have low antitumor activity when administered alone but increased when dispensed with single or double chemotherapy regimens. There is no statistical information regarding the best combination. Nonetheless, it has been considered a good option in the clinical part when given together with irinotecan [86].

In a phase II study, the protein was combined with irinotecan, folinic acid and 5-FU. It was applied in 10 medical centers in Germany to 48 patients with metastatic adenocarcinoma. The results obtained recorded an overall response rate of 46 %, stable disease in 33 % of the patients and a disease control rate of 79 %. In turn, patients with complete or partial response had longer overall survival times (19.1 versus 12 initial months, on average) and progression-free survival times (10.6 versus 6.0 months) [87].

Panitumumab

Panitumumab is a fully human IgG2 molecule with specificity for EGFR [88]. Between 2010 and 2011, a phase II study was conducted in Australia. 77 patients were enrolled and 90 % had metastases. The results evaluation with 71 patients determined that in the triple chemotherapy group (docetaxel, cisplatin and fluoropyrimidine), no patient had a complete response, 48.7 % had a partial response and 43.6 % had stable disease. Additionally, in the combination group (triple chemotherapy plus panitumumab), two patients had a complete response, 52.6 % partial response and 26.3 % stable disease [89].

With this, it was determined that the supplementation of panitumumab to chemotherapy with docetaxel, cisplatin and fluoropyrimidine did not significantly improve the tumor's objective response rate nor survival (general or progression-free) [89]. The same happened in a phase III trial conducted with a distinct chemotherapy regimen [90].

Vascular Endothelial Growth Factor (VEGF)

VEGF is a signaling protein that allows the growth of new blood vessels. It is part of the mechanism for replenishing blood to cells and tissues when deprived of oxygenated blood. Because VEGF stimulates cancer growth, research has sought to decrease its expression, preventing angiogenesis and tumor growth [91].

VEGF-A is the most biologically active form. It binds to 2 tyrosine kinase receptors: VEGFR-1 and VEGFR-2. Nevertheless, VEGFR-2 is the primary receptor through which VEGF sends signals to regulate angiogenesis and endothelial function. Binding to this receptor initiates a tyrosine kinase signaling cascade that promotes vasodilation through nitric oxide (NO) and prostacyclins, cell proliferation and survival and migration and differentiation in mature blood vessels. Regulating this cascade can stop tumor proliferation [92]. For that reason, drugs against this receptor have been investigated for gastric cancer.

Ramucirumab

It is a human IgG1 monoclonal antibody that selectively targets VEGFR-2. The FDA and the European Medicines Agency (EMA) approved it based on two randomized, double-blind, placebo-controlled phase III trials. In these studies, patients with disease progression, after first-line treatment (including fluoropyrimidine and cisplatin), were treated with ramucirumab versus placebo or the combination of ramucirumab plus paclitaxel versus placebo plus paclitaxel. The positive results of the trials led to the authorization in many countries for advanced or metastatic gastric cancer. For this reason, it is currently commercialized in several nations as a second-line treatment [93].

Another study, with a mean duration of 4 months, described the clinical outcome of employing this monoclonal antibody in 167 patients with the metastatic disease through a compassionate program. The results were obtained in a selected population with poorly differentiated tumors (57.4 %), peritoneal involvement (43 %), not previously resected (55.1 %) and with a progression time in first-line therapy of fewer than six months (40 %), defined as the period between the start of first-line treatment and progression. The main results include overall incidence toxicity (grade 3 to 4) of 9.6 % and neutropenia of 5.4 %. Besides, treatment was discontinued due to toxicity in 3 % of patients. The most common adverse events were grade 1 to 2 fatigue (27.5 %), grade 1 to 2 neuropathy (26.3 %) and grade 1 to 2 neutropenia (14.9 %). The overall response rate was 20.2 % and stable disease was observed in 39.2% of patients, with a disease control rate and an overall response rate of 59.4 and 20.2 %, respectively. These data demonstrate that ramucirumab is well tolerated by patients in daily clinical practice and generates efficacy for treating this pathology [93].

In another investigation, serum and tumor samples from patients after a phase III trial were analyzed. This investigation aimed to determine the correlation of biomarker expression and efficacy associated with ramucirumab. Analyzes focused on markers likely associated with the treatment efficacy, such as VEGF receptors and ligands and those related to gastric cancer biology. Given that monotherapy was utilized, any differential effect of the biomarkers' levels on the treatment efficacy could be attributed to ramucirumab. The data indicated that its benefit is more pronounced in patients with high VEGFR2 expression. This result corroborated the hypothesis that the VEGF/VEGFR2 pathway is involved in tumor growth and angiogenesis [94].

Active Immunotherapy

Cytotoxic T Lymphocyte-Associated Antigen-4 (CTLA-4): In maintaining immune system homeostasis, cell-to-cell contact mechanisms predominate through the function of the molecules CTLA-4 and LFA-1 (lymphocyte function-associated antigen 1) [95]. CTLA-4 is a molecule expressed on most activated T cells surface. It has been the subject of many studies. Diverse strategies were established to induce immunosuppression [96].

This molecule is one of the proteins called checkpoints, which help prevent robust immune responses and inhibit T lymphocytes from killing cancer cells. When their action is blocked, they can better eliminate the abnormal cells. Some immune checkpoint inhibitors are contemplated to treat cancer by targeting the receptors of these checkpoints [97].

This antigen has been the subject of many studies [96]. The following are monoclonal antibodies generated for it.

Tremelimumab

Tremelimumab is a fully human monoclonal antibody of the IgG2 type that targets CTLA-4. It was investigated as a second-line treatment for gastric cancer in a phase II, single-center, open-label, nonrandomized study. An objective response rate of 5 % was obtained for 18 patients with the involved pathologies. However, four patients achieved a stable condition with clinical benefits, including weight stabilization, pain resolution, cessation of vaginal bleeding (caused by pelvic metastasis) and libido return [98].

In another randomized, multicenter, open-label, phase Ib/II investigation, durvalumab and tremelimumab treatments were evaluated alone and in combination for chemotherapy-refractory gastric cancer or gastroesophageal junction cancer. Upon completion, the monoclonal antibody combination had an overall survival rate of 37 %, although response rates were low for the combination and the monotherapies. In addition, the sample was limited, which was a disadvantage of this study [99].

Ipilimumab

This is a recombinant human monoclonal antibody of the IgG1 type. The FDA approves it for melanoma and there are phase III trials for stomach/esophageal cancer [100]. Still, little information is available, or the results were not presented, as happened in a multicenter, randomized, open-label, phase III trial, developed to appreciate the effect when combined with nivolumab, which will be discussed later [101].

Programmed Cell Death Protein 1 (PD-1)

The role of the PD-1/PD-L1 (ligand) pathway in tumor immune evasion is essential. PD-1 is a transmembrane protein belonging to the CD28 family of cell surface receptors expressed on activated T cells, B cells, NK cells, monocytes and macrophages. The interaction with two ligands of the B7 family (PD-L1 and PD-L2) generates the induction of effector T cell depletion, the regulation of the immune response and the avoidance of exacerbated responses that lead to chronic inflammation or an immune disorder. Commonly, PD-L1 is expressed on antigen-presenting cells (B cells, dendritic cells and macrophages). Although, it is on the surface of cancer cells, taking advantage of the functional effects of the PD-1/PD-L1 interaction to escape the immune response against cancer. Therefore, this pathway's role in promoting tumor immune evasion mechanisms represents the foundation for developing monoclonal antibodies directed at PD-1 or PD-L1 [102].

It is important to note that PD-1, PD-L1 and CTLA-4 inhibitors have a similar mechanism of action. The difference is that the latter act at an earlier stage, promoting the activation of T cells in the lymph nodes, while anti-PD-1 and anti-PD-L1 molecules modulate their function at a later stage, specifically in peripheral tissues [102].

Nivolumab

The molecule is a human monoclonal IgG4 antibody that binds to the PD-1 receptor, inhibiting the interaction with PDL-1 and PD-L2 [103]. The FDA has approved it since 2015 for melanoma, renal carcinoma and non-small cell lung cancer [100].

According to different studies, it was the first immunological checkpoint inhibitor to show efficacy in patients with advanced gastric or gastroesophageal junction cancer who had previously received conventional treatment. The pharmacotherapy produced clinically significant improvements achieving overall survival when compared with placebo at 12 months [104].

Subsequently, it was approved in combination with select types of chemotherapy for the frontline treatment of individuals with advanced or metastatic gastric cancer, gastroesophageal cancer and esophageal adenocarcinoma [105]. In the multicenter, randomized, open-label, phase III study, 2,687 patients were chosen to receive nivolumab plus chemotherapy or chemotherapy alone. The results exhibited superior overall survival, progression-free survival benefit and a good safety profile for nivolumab plus chemotherapy [101].

Pembrolizumab

Pembrolizumab is a humanized monoclonal antibody of the IgG4 isotype that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2 [106]. The FDA granted accelerated approval in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2 positive gastric or gastroesophageal junction adenocarcinoma [107].

The approval was based on a multicenter, randomized, double-blind, placebo-controlled investigation in patients with HER2 positive advanced gastric or gastroesophageal junction adenocarcinoma who had not previously received systemic therapy for metastatic disease. Patients were randomized to receive pembrolizumab or placebo every three weeks, combined with trastuzumab and fluorouracil plus cisplatin or capecitabine plus oxaliplatin. The main results include an overall response rate of 74 % in the pembrolizumab arm and 52 % in the placebo arm. Likewise, the median duration response was 10.6 versus 9.5 months, respectively [107].

Avelumab

It is a human IgG1 monoclonal antibody that binds to PD-L1. Preclinical models show that it can induce innate effector cell functions. Therefore, it involves the adaptive and innate immune systems. Currently, it has been approved for metastatic Merkel cell carcinoma and locally advanced or metastatic urothelial carcinoma with progression following platinum-containing chemotherapy [108].

In a large phase I investigation cohort, this molecule showed antitumor activity and an acceptable safety profile when administered as second-line or switch-maintenance treatment to patients with or without disease progression after first-line chemotherapy. In this study, 40 patients who had received prior therapy were enrolled, of whom 21 and 7 people received three and four prior lines of treatment for advanced disease, respectively. 17 patients received the monoclonal antibody in ascending doses and there were no dose-limiting toxicities, nor was the maximum tolerated dose reached. Thus, it showed acceptable safety in persons with advanced solid tumors and clinical activity in people with advanced gastric cancer or cancer of the gastroesophageal junction and disease progression after chemotherapy [108].

Additionally, in a phase I cohort study, safety was evaluated as maintenance treatment (first-line) and patients with advanced gastric cancer, previously treated with chemotherapy (second-line). The research was done on 150 persons with histologically proven gastric or gastroesophageal cancer. Of these, only five people continued at the data cutoff, all belonging to the maintenance group. Of this group, two responded entirely to treatment [109].

In addition, of 81 patients evaluated, 13 had a lesion contraction equal to or greater than 30 %. The data obtained showed that treatment could be limited to a small population. Therefore, biomarkers are essential for identifying those who reap the most significant benefits treatment [109].

Durvalumab

The protein is a human monoclonal antibody that blocks the binding of PD-L1 to PD-1 and CD80. This interaction allows T cells to recognize and destroy tumor cells. After platinum-based chemoradiotherapy, monotherapy with this drug is contemplated for the first-line treatment of stage III non-small cell lung cancer (NSCLC). In turn, it has been studied as an intervention alone or in combination with tremelimumab in adenocarcinoma of the gastric/gastroesophageal junction [110].

Various studies are currently being carried out. For example, there is a phase I/II study in the recruitment process. It wants to evaluate durvalumab, tremelimumab and paclitaxel in 82 patients older than 19 years with metastatic gastric cancer [111].

On the other hand, one of the completed studies combines durvalumab and tremelimumab with first-line chemotherapy for gastric/gastroesophageal junction cancer. With it, the safety and tolerability of both monoclonal antibodies in combination with first-line chemotherapy regimens were evaluated [112].

Gastric cancer is a pathology that affects a significant population worldwide. For its treatment, new alternatives such as microRNAs, vaccines and distinct monoclonal antibodies have been sought.

Regarding microRNAs, their importance in the treatment and their mechanisms of action are still being investigated. Among those with the highest expectations are Mi-218, MiR-375 and MiR-7.

For vaccines, there are none approved because of the difficulty in obtaining an adequate response. Along with their development, the study of adjuvants to enhance the immune system's response is being done.

Finally, various clinical trials have been carried out considering several monoclonal antibodies. Of these, trastuzumab (its therapeutic target is HER-2), ramucirumab (VEGFR-2), pembrolizumab (PD-1) and nivolumab (PD-1) are approved for certain stages of gastric cancer.

Despite a shortage of currently available products, there is the hope of more options soon. What is essential is progress towards developing individualized therapies since not all organisms respond in the same way to a drug and the tumor characteristics vary from one individual to another, even though the type of cancer is identical.

1. Sausville, E.A. et al. “Principios del tratamiento del cáncer.” Harrison. Principios de Medicina Interna, 20th ed., McGraw-Hill, 2018.

2. Villasmil, M. et al. “Cáncer Gástrico Temprano o Precoz: Revisión de la Literatura.” Gen, vol. 65, no. 3, 2011, pp. 244–247.

3. López Carrillo, L. et al. “Cáncer Gástrico.” Gastroenterología, 3rd ed., McGraw-Hill, 2018.

4. Emory Winship Cancer Institute. “Cancer treatments.” 2021, www.cancerquest.org/patients/treatments.

5. Jomrich, G. et al. “Targeted therapy in gastric cancer.” European Surgery, vol. 48, no. 5, 2016, pp. 278–284.

6. Sociedad Española de Oncología Médica. “¿Qué es el cáncer gástrico?” 2020, seom.org/info-sobre-el-cancer/estomago? start=1.

7. Romero, H.E. et al. “Clasificación de los Adenocarcinomas de Estómago.” Revista de Gastroenterología del Perú, vol. 23, no. 3, 2003, pp. 199–212.

8. Martínez-Galindo, M.G. et al. “Características histopatológicas del adenocarcinoma gástrico en pacientes mexicanos.” Revista de Gastroenterología de México, vol. 80, no. 1, 2015, pp. 21–26.

9. Sierra, R. “Cáncer Gástrico, Epidemiología y Prevención.” Acta Médica Costarricense, vol. 44, no. 2, 2002, pp. 55–61.

10. García, C. “Actualización del Diagnóstico y Tratamiento del Cáncer Gástrico.” Revista Médica Clínica Las Condes, vol. 24, no. 4, 2013, pp. 627–636.

11. Mayo Clinic. “Stomach cancer: Symptoms & causes.” 2021, www.mayoclinic.org/diseases-conditions/stomach-cancer/symptoms-causes/syc-20352438

12. Figueroa-Giralt, M. “Factores Pronósticos de Sobrevida Alejada en Cáncer Gástrico.” Revista Chilena de Cirugía, vol. 70, no. 2, 2018, pp. 147–159.

13. American Cancer Society. “Stomach cancer stages.” 2021, www.cancer.org/cancer/stomach-cancer/detection-diagnosis-staging/staging.html.

14. González Medina, C. “Cáncer Gástrico: Factores de Riesgo, Carcinogénesis, Bases Molecular.” Gen, vol. 64, no. 3, 2010, pp. 214–220.

15. American Cancer Society. “Stomach cancer risk factors.” 2021, www.cancer.org/cancer/stomach-cancer/causes-risks-prevention/risk-factors.html.

16. González, C.A. et al. “Dietary factors and stomach cancer in spain: a multi-centre case-control study.” International Journal of Cancer, vol. 49, no. 4, 1991, pp. 513–519.

17. Caldas, C. et al. “Familial gastric cancer: Overview and guidelines for management.” Journal of Medical Genetics, vol. 36, no. 12, 1999, pp. 873–880.

18. Günther, J. et al. “E-Cadherina: Pieza Clave en la Transformación Neoplásica.” Revista de Evidencia e Investigación Clínica, vol. 4, no. 1, 2011, pp. 15–20.

19. Torres-Jasso, J.H. et al. “Cáncer Gástrico: Alteraciones Genéticas y Moleculares.” Gaceta Médica de México, vol. 147, 2011, pp. 72–73.

20. Hattori, Y. et al. “K-sam, an amplified gene in stomach cancer, is a member of the heparin-binding growth factor receptor genes.” Proceedings of the National Academy of Sciences of the United States of America, vol. 87, no. 15, 1990, pp. 5983–5987.

21. Jančík, S. et al. “Clinical relevance of kras in human cancers.”Journal of Biomedicine and Biotechnology, 2010, Article 150960. https://doi.org/10.1155/2010/150960.

22. García García, V. et al. “Expresión de bcl-2, ki-67 y caspasa-3 en lesiones cancerosas de la mucosa oral: Resultados preliminares.” Avances en Odontoestomatología, vol. 22, no. 5, 2006, pp. 263–269.

23. Pérez-Cala, T. et al. “Factores genéticos y epigenéticos del cáncer gástrico.” Actualidades Biológicas, vol. 39, no. 106, 2017, pp. 5–20.

24. Pilozzi, E. et al. “p73 Gene Mutations in Gastric Adenocarcinomas.” Molecular Pathology, vol. 56, no. 1, 2003, pp. 60–62.

25. Fang, D.C. et al. “Mutation Analysis of APC Gene in Gastric Cancer with Microsatellite Instability.” World Journal of Gastroenterology, vol. 8, no. 5, 2002, pp. 787–791.

26. Zhu, X. et al. “Deficiency of hMLH1 and hMSH2 expression is a poor prognostic factor in early gastric cancer (EGC).” Journal of Cancer, vol. 8, no. 8, 2017, pp. 1477–1483.

27. Con, S.A. et al. “Diversity of helicobacter pylori caga and vaca genes in costa rica: Its relationship with atrophic gastritis and gastric cancer.” Helicobacter, vol. 12, no. 5, 2007, pp. 547–552.

28. Ramírez Ramos, A. and R. Sánchez Sánchez. “Helicobacter pylori y cáncer gástrico.” Revista de Gastroenterología del Perú, vol. 28, no. 3, 2008, pp. 258–266.

29. Chen, Y. et al. “H. pylori infection confers resistance to apoptosis via brd4-dependent BIRC3 eRNA synthesis.” Cell Death & Disease, vol. 11, no. 8, 2020, Article 667. https://doi.org/10.1038/s41419-020-02807-7

30. Brenner, H. et al. “Individual and joint contribution of family history and helicobacter pylori Infection to the risk of gastric carcinoma.”Cancer, vol. 88, no. 2, 2000, pp. 274–279.

31. Chen, Y. et al. “Body mass index and risk of gastric cancer: A meta-analysis of a population with more than ten million from 24 prospective studies.” Cancer Epidemiology, Biomarkers & Prevention, vol. 22, no. 8, 2013, pp. 1395–1408.

32. Morales Díaz, M. et al. “Cáncer gástrico: Algunas Consideraciones sobre Factores de Riesgo y Helicobacter pylori.” Revista Médica Electrónica, vol. 40, no. 2, 2018, pp. 433–444.

33. Sierra, M.S. et al. “Stomach cancer burden in central and south America.” Cancer Epidemiology, vol. 44, Supp. 1, 2016, pp. S62–S73.

34. Arias Leiva, M.M. “Helicobacter pylori y Cáncer Gástrico.” Revista Médica de Costa Rica y Centroamérica, no. 608, 2013, pp. 689–692.

35. Csendes, A. and M. Figueroa. “Situación del Cáncer Gástrico en el Mundo y en Chile.” Revista Chilena de Cirugía, vol. 69, no. 6, 2017, pp. 502–507.

36. Rawla, P. and A. Barsouk. “Epidemiology of gastric cancer: Global trends, risk factors and prevention.” Przeglad Gastroenterologiczny, vol. 14, no. 1, 2019, pp. 26–38.

37. Venerito, M. et al. “Gastric cancer: Clinical and epidemiological aspects.” Helicobacter, vol. 21, Supp. 1, 2016, pp. 39–44.

38. Rojas-Montoya, V. and N. Montagné. “Generalidades del Cáncer Gástrico.” Revista Clínica de la Escuela de Medicina UCR-HSJD, vol. 9, no. 2, 2019, pp. 22–29.

39. Sitarz, R. et al. “Gastric cancer: Epidemiology, prevention, classification and treatment.”Cancer Management and Research, vol. 10, 2018, pp. 239–248.

40. Dávila Meneses, A. et al. “Caracterización Clínica y Epidemiológica de la Población Tamizada en el Centro de Detección Temprana de Cáncer Gástrico, Costa Rica: Período 1996–2015.” Revista Costarricense de Salud Pública, vol. 27, no. 2, 2018, pp. 68–81.

41. Wu, D.M. et al. “Serum biomarker panels for the diagnosis of gastric cancer.” Cancer Medicine, vol. 8, no. 4, 2019, pp. 1576–1583.

42. Pasechnikov, V. et al. “Gastric cancer: Prevention, screening and early diagnosis.” World Journal of Gastroenterology, vol. 20, no. 38, 2014, pp. 13842–13862.

43. Căinap, C. et al. “Classic tumor markers in gastric cancer: current standards and limitations.” Clujul Medical, vol. 88, no. 2, 2015, pp. 111–115.

44. Emoto, S. et al. “Clinical significance of ca125 and ca72-4 in gastric cancer with peritoneal dissemination.” Gastric Cancer, vol. 15, no. 2, 2012, pp. 154–161.

45. Mora, J. “Marcadores Tumorales en Oncología Digestiva: Cuáles Solicitar y Cuándo.” Gastroenterología y Hepatología Continuada, vol. 4, no. 4, 2005, pp. 178–181.

46. Martín Suárez, A. et al. “Utilidad Clínica de los Marcadores Tumorales Séricos.” Atención Primaria, vol. 32, no. 4, 2003, pp. 227–239.

47. Fernández, J.I. et al. “Detección de Lesiones Preneoplásicas Gástricas Mediante Niveles Séricos de Pepsinógeno en Población Chilena.” Revista Médica de Chile, vol. 135, no. 12, 2007, pp. 1519–1525.

48. Mayo Clinic. “Diagnosis & treatment.” Mayo Clinic, August 2021, www.mayoclinic.org/diseases-conditions/stomach-cancer/diagnosis-treatment/drc-20352443.

49. MedlinePlus. “Gastrectomía.” MedlinePlus, 2020, medlineplus.gov/spanish/ency/article/002945.htm.

50. Sola, A. “Radioterapia de Intensidad Modulada (IMRT).” Revista Médica Clínica Las Condes, vol. 22, no. 6, 2011, pp. 834–843.

51. American Cancer Society. “Chemotherapy for stomach cancer.” American Cancer Society, August 2021, www.cancer.org/cancer/stomach-cancer/treating/chemotherapy.html.

52. American Cancer Society. “Radiation therapy for stomach cancer.” American Cancer Society, August 2021, www.cancer.org/cancer/stomach-cancer/treating/radiation-therapy.html.

53. Phan, N.K. “Biological therapy: A new age of cancer treatment.” Biomedical Research and Therapy, vol. 1, no. 2, 2014, pp. 32–34.

54. Arias Sosa, L.A. et al. “Supresión Tumoral por microARN en el Cáncer Gástrico.” Gaceta Mexicana de Oncología, vol. 15, no. 4, 2016, pp. 222–230.

55. Rodríguez-Báez, A. et al. “Expresión de microARNs Circulantes como Opción para la Detección de Cáncer de Próstata.” Revista Mexicana de Urología, vol. 77, no. 3, 2017, pp. 199–206.

56. Staudt, L.M. “Oncogenic activation of NF-kB.” Cold Spring Harbor Perspectives in Biology, vol. 2, no. 6, 2010, Article a000109. https://doi.org/10.1101/cshperspect.a000109.

57. Zhao, X.D. et al. “MicroRNA-7/NF-κB signaling regulatory feedback circuit regulates gastric carcinogenesis.” The Journal of Cell Biology, vol. 210, no. 4, 2015, pp. 613–627.

58. Sanitas. “Vacunas: Qué Son, Cómo Actúan y Su Importancia.” Sanitas, August 2021, www.sanitas.es/sanitas/seguros/es/particulares/biblioteca-de-salud/prevencion-salud/importancia-vacunas/index.html.

59. Hollingsworth, R.E. and K. Jansen. “Turning the corner on therapeutic cancer vaccines.” NPJ Vaccines, vol. 4, 2019, Article 7. https://doi.org/10.1038/s41541-019-0103-3.

60. Sahin, U. and Ö. Türeci. “Personalized vaccines for cancer immunotherapy.” Science, vol. 359, no. 6382, 2018, pp. 1355–1360. https://doi.org/10.1126/science.aar7112. 

61. Center for Disease Control and Prevention. Adjuvants and Vaccines. 2020, https://www.cdc.gov/vaccinesafety/concerns/adjuvants.html.

62. Sun, B. et al. “Polysaccharides as vaccine adjuvants.” Vaccine, vol. 36, no. 35, 2018, pp. 5226–5234.

63. Lv, Y. et al. “A recombinant measles virus vaccine strain rmv-hu191 has oncolytic effect against human gastric cancer by inducing apoptotic cell death requiring integrity of lipid raft microdomains.” Cancer Letters, vol. 460, 2019, pp. 108–118.

64. Nuñez, G. et al. “Caspases: The proteases of the apoptotic pathway.” Oncogene, vol. 17, no. 25, 1998, pp. 3237–3245.

65. Schreiber, V. et al. “De la Découverte du Poly(ADP-Ribose) aux Inhibiteurs PARP en Thérapie du Cancer.” Bulletin du Cancer, vol. 102, no. 10, 2015, pp. 863–873.

66. Morales, J.C. et al. “Review of Poly (ADP-Ribose) polymerase (PARP) mechanisms of action and rationale for targeting in cancer and other diseases.” Critical Reviews in Eukaryotic Gene Expression, vol. 24, no. 1, 2014, pp. 15–28.

67. Lopategui Cabezas, I. and A. Herrera Batista. “Papel Crucial de la Mitocondria en la Muerte Celular Programada.” Revista Cubana de Investigaciones Biomédicas, vol. 29, no. 2, 2010, pp. 294–301.

68. Ajani, J.A. et al. “An open-label, multinational, multicenter study of g17dt vaccination combined with cisplatin and 5-fluorouracil in patients with untreated, advanced gastric or gastroesophageal cancer: The gc4 study.” Cancer, vol. 106, no. 9, 2006, pp. 1908–1916.

69. Gilliam, A.D. et al. “A phase II study of G17DT in gastric carcinoma.” European Journal of Surgical Oncology, vol. 30, no. 5, 2004, pp. 536–543.

70. Marambio, A. et al. “Gastrina: Hormona de Múltiples Funciones.” Revista Hospital Clínico Universidad de Chile, vol. 23, no. 2, 2012, pp. 139–147.

71. Rahma, O.E. and S.N. Khleif. “Therapeutic Vaccines for Gastrointestinal Cancers.” Gastroenterology & Hepatology, vol. 7, no. 8, 2011, pp. 517–564.

72. García Merino, A. “Anticuerpos Monoclonales. Aspectos Básicos.” Neurología, vol. 26, no. 5, 2011, pp. 301–306.

73. Waldmann, H. “Human monoclonal antibodies: The benefits of humanization.” Methods in Molecular Biology, vol. 1904, 2019, pp. 1–10.

74. Akkın, S. et al. “A review on cancer immunotherapy and applications of nanotechnology to chemoimmunotherapy of different cancers.” Molecules, vol. 26, no. 11, 2021, Article 3382.

75. Mucientes Rasilla, J. and L. Gutiérrez Sanz. “Criterios de Respuesta Metabólica a la Inmunoterapia.” Revista Española de Medicina Nuclear e Imagen Molecular, vol. 39, no. 1, 2020, pp. 51–56.

76. Pazo Cid, R.A. and A. Antón. “Advanced HER2-positive gastric cancer: Current and future targeted therapies.” Critical Reviews in Oncology/Hematology, vol. 85, no. 3, 2013, pp. 350–362.

77. Roche Farma, S.A. “¿Qué es el HER2?” 2022, https://rochepacientes.es/cancer/mama/her2.html.

78. Gunturu, K.S. et al. “Gastric cancer and trastuzumab: First biologic therapy in gastric cancer.” Therapeutic Advances in Medical Oncology, vol. 5, no. 2, 2013, pp. 143–151.

79. Wakatsuki, T. et al. “Clinical impact of intratumoral her2 heterogeneity on trastuzumab efficacy in patients with her2-positive gastric cancer.” Journal of Gastroenterology, vol. 53, no. 11, 2018, pp. 1186–1195.

80. Shitara, K. et al. et al. “Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer.” The New England Journal of Medicine, vol. 382, no. 25, 2020, pp. 2419–2430.

81. The American Journal of Managed Care. “Trastuzumab Deruxtecan gets orphan drug status for gastric cancer.” 2020, https://www.ajmc.com/view/trastuzumab-deruxtecan-gets-orphan-drug-status-for-gastric-cancer.

82. Colonia, A. et al. “HER-2: Un Marcador Molecular Usado en el Diagnóstico, Pronóstico y Tratamiento del Cáncer de Mama.” Revista Médica Risaralda, vol. 21, no. 1, 2015, pp. 31–37.

83. Richard, S. et al. “Pertuzumab and Trastuzumab: The rationale way to synergy.” Anais da Academia Brasileira de Ciências, vol. 88, suppl. 1, 2016, pp. 565–577.

84. abernero, J. et al. “Pertuzumab plus Trastuzumab and chemotherapy for her2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): Final analysis of a double-blind, randomised, placebo-controlled phase 3 study.” The Lancet Oncology, vol. 19, no. 10, 2018, pp. 1372–1384.

85. Carretero Colomer, M. “Cetuximab.” Offarm, vol. 24, no. 6, 2005, pp. 126–130.

86. Adua, D. et al. “Long-term survival in an advanced gastric cancer patient treated with cetuximab in association with folfiri: A case report.” Journal of Gastrointestinal Oncology, vol. 5, no. 1, 2014, pp. E13–E17.

87. Moehler, M. et al. “Cetuximab with Irinotecan, folinic acid and 5-fluorouracil as first-line treatment in advanced gastroesophageal cancer: A prospective multi-center biomarker-oriented phase II study.” Annals of Oncology, vol. 22, no. 6, 2011, pp. 1358–1366.

88. Yang, X.D. et al. “Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer therapy.” Critical Reviews in Oncology/Hematology, vol. 38, no. 1, 2001, pp. 17–23.

89. Tebbutt, N.C. et al. “Panitumumab added to docetaxel, cisplatin and fluoropyrimidine in oesophagogastric cancer: ATTAX3 Phase II Trial.” British Journal of Cancer, vol. 114, no. 5, 2016, pp. 505–509.

90. Lordick, F. et al. “Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): A randomised, open-label phase 3 trial.” The Lancet Oncology, vol. 14, no. 6, 2013, pp. 490–499.

91. Mandal, A. “¿Cuál es el VEGF?” 2019, https://www.news-medical.net/life-sciences/What-is-VEGF-(Spanish).aspx.

92. Neves, K.B. et al. “VEGFR (Vascular Endothelial Growth Factor Receptor) inhibition induces cardiovascular damage via redox-sensitive processes.” Hypertension, vol. 71, no. 4, 2018, pp. 638–647.

93. Di Bartolomeo, M. et al. “Ramucirumab as Second-Line therapy in metastatic gastric cancer: Real-world data from the ramoss study.” Targeted Oncology, vol. 13, no. 2, 2018, pp. 227–234.

94. Fuchs, C.S. et al. “Biomarker analyses in REGARD Gastric/GEJ carcinoma patients treated with vegfr2-targeted antibody ramucirumab.” British Journal of Cancer, vol. 115, no. 8, 2016, pp. 974–982.

95. Villegas Valverde, C.A. and M.C. Arango Prado. “Participación de los Linfocitos T Reguladores en el Cáncer de Ovario.” Revista Cubana de Obstetricia y Ginecología, vol. 39, no. 1, 2013, pp. 23–32.

96. Fernández Ponce, C. et al. “CTLA-4, Una Molécula que Inhibe la Activación de los Linfocitos T.” Revista Salud Uninorte, vol. 22, no. 2, 2006, pp. 168–181.

97. National Cancer Institute. “Immune checkpoint inhibitor.” 2022, https://www.cancer.gov/publications/dictionaries/cancer-terms/def/immune-checkpoint-inhibitor.

98. Ralph, C. et al. “Modulation of lymphocyte regulation for cancer therapy: A phase II trial of tremelimumab in advanced gastric and esophageal adenocarcinoma.” Clinical Cancer Research, vol. 16, no. 5, 2010, pp. 1662–1672.

99. Kelly, R.J. et al. “Safety and efficacy of durvalumab and tremelimumab alone or in combination in patients with advanced gastric and gastroesophageal junction adenocarcinoma.” Clinical Cancer Research, vol. 26, no. 4, 2020, pp. 846–854.

100. Rangel-Sosa, M.M. et al. “Inmunoterapia y Terapia Génica como Nuevos Tratamientos contra el Cáncer.” Colombia Médica, vol. 48, no. 3, 2017, pp. 138–147.

101. Janjigian, Y.Y. et al. “First-Line Nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction and oesophageal adenocarcinoma (checkmate 649): a randomised, open-label, phase 3 trial.” Lancet, vol. 398, no. 10294, 2021, pp. 27–40.

102. Akin Telli, T. et al. “PD-1 and PD-L1 Inhibitors in Oesophago-Gastric Cancers.” Cancer Letters, vol. 469, 2020, pp. 142–150.

103. De Bustos Núñez, C. Nuevos Tratamientos Anti-PD1 en el Tratamiento del Cáncer. Universidad Complutense, 2018.

104. Kang, Y.K. et al. “Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ono-4538-12, attraction-2): A randomised, double-blind, placebo-controlled, phase 3 trial.” Lancet, vol. 390, no. 10111, 2017, pp. 2461–2471.

105. OncLive Staff. “FDA approval insights: Nivolumab Plus chemo for frontline gastric cancer.” OncLive, 2021, www.onclive.com/view/fda-approval-insights-nivolumab-plus-chemo-for-frontline-gastric-cancer.

106. United States Food and Drug Administration. KEYTRUDA® (Pembrolizumab) for Injection, for Intravenous Use. FDA, 2014.

107. United States Food and Drug Administration. “FDA grants accelerated approval to pembrolizumab for her2-positive gastric cancer.” FDA, 2021, www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-her2-positive-gastric-cancer.

108. Doi, T. et al. “Phase 1 trial of avelumab (Anti-PD-L1) in Japanese patients with advanced solid tumors, including dose expansion in patients with gastric or gastroesophageal junction cancer: The javelin solid tumor JPN trial.” Gastric Cancer, vol. 22, no. 4, 2019, pp. 817–827.

109. Chung, H.C. et al. “Avelumab (Anti-PD-L1) as first-line switch-maintenance or second-line therapy in patients with advanced gastric or gastroesophageal junction cancer: Phase 1b results from the javelin solid tumor trial.” Journal for Immunotherapy of Cancer, vol. 7, no. 1, 2019, p. 30.

110. Bang, Y.J. et al. “Ramucirumab and Durvalumab for previously treated, advanced non-small-cell lung cancer, gastric/gastro-oesophageal junction adenocarcinoma, or hepatocellular carcinoma: An open-label, phase ia/b study (JVDJ).” European Journal of Cancer, vol. 137, 2020, pp. 272–284.

111. U.S. National Library of Medicine. GC 2nd Line Durvalumab (MEDI4736)/Tremelimumab Plus Paclitaxel Study. 2019, clinicaltrials.gov/ct2/show/NCT03751761.

112. U.S. National Library of Medicine. Durvalumab and Tremelimumab in Combination with First-Line Chemotherapy in Advanced Solid Tumors. 2020, clinicaltrials.gov/ct2/show/NCT02658214.

113. Batista-Duharte, A. et al. “Adyuvantes Inmunológicos. Determinantes en el balance Eficacia-Toxicidad de las Vacunas Contemporáneas.” Enfermedades Infecciosas y Microbiología Clínica, vol. 32, no. 2, 2014, pp. 106–114.

114. Del Giudice, G. et al. “Correlates of Adjuvanticity: A Review on Adjuvants in Licensed Vaccines.” Seminars in Immunology, vol. 39, 2018, pp. 14–21.