Paulo Pimentel de Assump??o ,Rommel Rodrigues Burbano,2

1Universidade Federal do Pará,Núcleo de Pesquisas em Oncologia,Belém-Pará-Brasil 66075-110,Brazil;2Hospital Ophir Loyola,Laboratório de Biologia Molecula,Belém-Pará-Brasil 66063-240,Brazil

Abstract Gastric adenocarcinoma (GC) is one of the most heterogeneous cancers,posing challenges to wide applications of the discoveries when compared to other cancers.Nevertheless,the benefits of research in the fight against GC are extraordinary,and even taking in mind the immense complexity of this disease,optimism is a great message to take home.Recent advances in GC research will pave the way for GC effective control,helping to save lives,together with permitting sustainable real-life support for those needing complex and high-expense interventions.

Keywords: Gastric cancer;research;innovations

Gastric adenocarcinoma (GC) is one of the most heterogeneous cancers,posing challenges to wide applications of discoveries when compared to other cancers.Nevertheless,recent initiatives,especially those pushed by the inclusion of consortiums of patients from different countries,have favored significant advances in the understanding of such cancers and the translation of this knowledge to clinical practice (1).

Many of the most important advances in GC research came from the molecular classifications proposed by The Cancer Genome Atlas (TCGA) and by the Asian Cancer Research Group.These classifications have similarities,therefore,the TCGA classification will be taken as a reference (1).

The identification of a microsatellite instability (MSI)type of GC,including about 20% of GC cases,allowed relevant translations of the molecular understanding,changing already established clinical practices.These GC present mismatch repair genes deficiency,and so a greater number of errors,during DNA replication,are not identified,or not fixed.Most of these errors will not have any consequence since much of the DNA will not be transcribed in the stomach.For those errors transcribed and coded for amino acids,the production of “different”peptides,functioning as “new antigens” can stimulate the immune system.The consequence of such molecular alteration is the production of an immunocompetent microenvironment since the immune system is challenged by the produced neo-immunogens (2).These discoveries provoked clinical practice modifications,including the possibility of changing from neoadjuvant fluoropyrimidinebased chemotherapies to up-front surgeries (3).

In parallel to the better understanding made possible by the GC molecular classifications,many other discoveries were very useful to clinical translation.Although MSI tumors promote an immunocompetent microenvironment,this can be counterattacked by one of the cancer hallmarks— avoiding immune destruction,a strategy of breaking the immune response by activating inhibitory pathways such as programmed cell death protein 1 (PD-1).Both cancer cells and immune cells in this microenvironment can express PD-1 ligands (and other immunoregulatory molecules) that result in avoiding the immune system and favor cancer cell persistence.To face this cancer cell’s strategy,antibodies against PD-1,or against the ligands,were launched and became one of the most important advances in GC management (4).

The translation of the discoveries to clinical practice among the other GC types is not yet as robust as for MSI tumors.

The Epstein-Barr virus (EBV) cancers also have an immune status that favors the use of immunotherapy against the PD-1 pathway,since in the EBV group,this pathway is overexpressed,and the prognosis is better than those of genome stable (GE) and chromosome instability groups (CIN) (1).The main limitation for translation of molecular features of EBV cancers is the low number of studied cases (26 cases at TCGA).Nonetheless,recently reported publications,including large number of cases,appear to confirm both the improved prognosis and the increased expression of the PD-1 pathway in these GCs (5).

The GE group is the one with the worst prognosis,and currently,the fewest options for clinical translation.It seems to be unsuitable for immunotherapy and does not,consistently,express targets for available therapies (1).Expression of isoform 2 of CLAUDIN 18 (CDLN18.2),although not exclusive of such tumors,appears as a promising target for GC therapy.This isoform expression seems to be highly selective of GC cells and antibodies against CDL18.2 are almost coming into clinical use due to great results in investigational trials.Another very important perspective is using CAR-T cells to treat gastric tumors expressing CDLN18.2 (6).The preliminary results with this innovation are quite exciting since this sophisticated therapy represents a phenomenal initiative for the management of individual patients,although the costs are high,limiting wide access.

CIN tumors are the most common molecular type of GC.There are some molecular targets actionable for therapy,such as antibodies against HER-2,one of the most important developments in GC therapy,that started the highly effective era of target therapy in GC.The prognosis of CIN tumors is not as good as that of MSI and EBV groups,but much better than that of GE tumors (1).

The main characteristic of this group is aneuploidy,due to imbalances in DNA amounts during cell division.Therefore,gains in genomic material affecting oncogenes may promote tumor growth,while loss of tumor suppressor genes also favors carcinogenesis.Targeting overexpressed oncogenes is less tricky than fixing or supplying products lacking tumor suppressor genes.So,antibodies against products of overexpressed genes are the most on-track molecules.Nevertheless,potential targets for therapy in this group are not available to clinical practice,due to the importance of such genes’ products to the normal cell’s homeostasis.This is the case of amplification of theMYCgene,recognized as one of the ten cancer pathways by the Pan-cancer Atlas initiative (7).Amplification of MYC is the most frequently found aneuploidy in CNI cancers.Great results from experimental data targeting theCDC25Bgene,which is regulated by MYC,encouraged an ongoing clinical trial testing this strategy in neoadjuvant combinations as a potential option for treating CNI tumors (8).

Although moving the current management of GC,innovations from GC research are mostly focused on already established and usually advanced cases.Improving GC treatment in such situations is notoriously important and saves many lives,but the costs of such sophisticated therapies are quite high,restricting access,and impairing both public and private budgets in an increasing and almost unsustainable trajectory.

Research efforts must also focus on prevention and early diagnostic attempts since reducing the burden of GC and/or favoring early diagnosis will change the game in a sustainable way.

Among the perspectives of finding potential interventions to stop the GC burden,a better understanding of the carcinogenesis process has produced a wealth of useful information (9).Currently,about half of GC causes are attributed to environmental factors,led byHelicobacter pylori(H.pylori) infections;a small number are related to hereditary causes;and the rest are supposed to result from aleatory errors during stem cells’ replication.The main opportunity for interventions comes from environmental causes such asH.pyloriinfection.A revolution in the knowledge of interactions between the gastric microbiota and the stomach microenvironment is on track.The identification of many microorganisms,beyondH.pylori,influencing both the carcinogenesis process and the response to therapy,including immunotherapy,represents a great opportunity to target and reduce the GC burden.AvoidingH.pyloriinfection and/or treating patients withH.pylori-related gastritis before the occurrence of atrophy,metaplasia,and dysplasia seems to be the best strategy to avoid GC.Interventions on other microbiota components will be critical in the future.As discussed,EBV tumors represent a molecular type of GC related to a virus,which potentially interacts with both the immune cells and other components of the microbiota(1).Advances in the understanding of these complex interactions will bring opportunities for future interventions.The microbiota has recently been included in the cancer hallmarks repertory and becoming able to manipulate the microbiota will be another important weapon in GC control.

Hereditary GC is another possibility for intervention,since being able to identify a hereditary GC case brings the chance to offer both genetic tests and surveillance for the patient’s relatives,and if indicated,proceed to risk reduction surgeries.The development of molecular editing technologies might also be used in the future to fix genetic errors,avoiding cancer development.

Regarding GC that arises due to aleatory errors during DNA replication of stem cells,while representing a great number of cases,interventions in these cases are quite tricky and need huge investments in research,aiming to identify potential mechanisms explaining part of the“supposed to be aleatory” errors,opening an avenue to clinical interventions.Focus on replication and DNA repair machinery might shed light on this field.

Vaccines might be another important weapon for future control of GC.Recent initiatives to provide financial support for the development of cancer vaccines will change the research scenario in this field.Identification of appropriate combinations of GC immunogens,and possibly microbial adjuvants,has surged as potential effective vaccines to avoid many GC in the future.

The magnitude of technological development,together with the expanding capacity of decoding immense amounts of molecular data,drives new discoveries in the mechanisms of GC carcinogenesis.Nevertheless,the complexity of such mechanisms,the great number of players,including human and non-human molecules,and the multiple interactions among them,challenges researchers,especially because of the combination of high costs,high demands,and limited resources (1).Among the strategies to overcome these difficulties,prioritizing looking for actionable targets,i.e.,the ones ready to be used in clinical practice,is one of the most chosen measures.Nevertheless,the list of actionable targets is dynamic and rises almost every month,adding complexity to this focused strategy.Another option is to try to obtain as much information as possible from every molecular experiment,and perform integrated analyses from each single sample,favoring both the optimization of the costs and the rationality of exploring multiple variables from the same clinical situation (same patient,same tumor,same time) instead of making inferences by joining pieces of data from different tumors,patients and moments.

The benefits of research in the fight against GC are extraordinary,and even taking into mind the immense complexity of this disease,optimism is the great message to take home.Advances in GC research will pave the way for its effective control,helping to save lives and provide sustainable real-life support for those needing complex and expensive interventions.

Acknowledgements

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.