| Abstract|| |
Newer molecular diagnostics and improved understanding of cancer pathogenesis have identified multiple pathways that can be potentially targeted with the use of novel therapeutics in development. These developments have ushered cancer therapeutics in newer era of personalized medicine. Same is reflected on current management strategies for advanced gastrointestinal malignancies. Molecular profiling for BRAF and RAS is standard for colorectal cancer while Her2 and PDL1 status is needed for planning therapy of advanced gastroesophageal cancers. Tissue agnostic markers like MSI, TMB and NTRK are making headways in therapeutic armamentarium. While newer targeted therapies against FGFR, EGFR, PI3K-AKT, DDR pathways are showing promising results in initial studies. Here we review traditional as well as upcoming molecular markers in field of GI malignancies, methods of testing and evidence for rational use in clinical practice.
Keywords: Gastrointestinal cancer, molecular targets, monoclonal antibodies, targeted therapy, tyrosine kinase inhibitors
|How to cite this article:|
Pawar S, Sharma A. Molecular targets in GI malignancies – A pathologist's perspective. Indian J Pathol Microbiol 2021;64, Suppl S1:43-51
| Introduction|| |
Treatment of gastrointestinal (GI) cancers has changed drastically over the last few decades. With the advent of newer and rapid sequencing techniques, and discovery of molecular targets, the use of drugs targeting these pathways has increased dramatically. Antibodies targeting epidermal growth factor receptor (EGFR) and angiogenic pathways are routinely used in the management of colon cancer., Most recently, immunotherapy has shown promising clinical efficacy in multiple types of GI cancers. Although chemotherapy is the mainstay of treatments for the majority of GI cancers, novel agents either as single agents or in combination are being evaluated in clinical trials at an accelerated pace. Here, we review molecular biology of GI malignancies in short along with the major molecular targets that have demonstrated promising therapeutic activity in clinical trials. Literature search was done by PubMed using the Mesh headings “GI malignancy” and “molecular targets” or “targeted therapy”. We also searched Google Scholar with “allintitle: “GI Cancer” or “GI malignancy”, “Targeted therapy.”
Molecular alterations involved in pathogenesis of GI malignancies
With the description of hallmarks of cancers by Hanahan and Weinberg, we have understood that tumorigenesis involves complex interplay of various signaling pathways. These signals can be autocrine, paracrine or endocrine in nature and act via various membrane/nuclear receptors including, but not limited to, G-protein-coupled receptors or enzyme-linked receptors. Interactions of these various pathways and genes regulating them as well as their role in cancer development has attracted a lot of attention over the last few decades leading to better understanding of pathogenesis and development of newer treatment options. Here, we will be reviewing, in short, major molecular pathways involved in the pathogenesis of common GI malignancies.
Esophageal and gastric cancers
Gastroesophageal cancers (GEJ) represent a major public health burden and prognosis remains poor even with current multimodality management. Overall, a 5-year survival rate of gastric cancer (GC) is 30% while it is 19% for esophageal adenocarcinoma (EAC)., Currently, with the use of gene expression profiling The Cancer Genome Atlas (TCGA) research group and Asian Cancer Research Group (ACRG) has subdivided GC into four distinct molecular subtypes [Table 1] with different pathogenesis, prognosis and potentially targetable alterations., In contrast to GC, molecular mutational landscape for esophageal cancer (EC) is less well-studied. It is well-known that EC has two distinct clinic-pathological subtypes with different risk factors and molecular pathogenesis: adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC). EAC is preceded by Barret's esophagus while ESCC is preceded by dysplasia; while exome sequencing has revealed mutations in TP53 (72%), engulfment and cell motility 1 (ELMO1) (25%), dedicator of cytokinesis 2 (DOCK2) (12%) and cyclin-dependent kinase inhibitor 2A (CDNK2A (12%). In addition, potentially targetable alterations in several oncogenes were also identified: Kirsten rat sarcoma (KRAS) (21%), humane epidermal growth factor receptor 2 (HER2) (19%), epidermal growth factor receptor (EGFR) (16%) and mesenchymal-epithelial transition factor MET (6%), which are summarized in [Table 2].
Biliary tract cancers and carcinoma gall bladder
Biliary tract cancers (BTC) which include cholangiocarcinoma (CCA) and gallbladder cancer (GBC) carry poor prognosis with 5-year survival rates of 5-15%., Even after curative resection, the chances of relapse are high. With the ongoing research, it is now widely accepted that BTCs are a heterogeneous groups of disease with varied demographics, risk factors, pathogenesis, clinical presentation, treatment modalities and outcome [Table 3]. And these differences have paved the way for better understanding of molecular pathogenesis of BTCs. Multiple studies have identified various genetic alterations affecting specific molecular pathways [Table 3] based on whole-exome sequencing which can be exploited in clinical practice.,
Pancreatic ductal adenocarcinoma (PDA) is the most common type of pancreatic cancer accounting for >90% cases. As per surveillance, epidemiology, and end results (SEER) database, 5-year overall survival (OS) for localized, locally advanced and metastatic disease is 29%, 11% and 3%, respectively. Most commonly mutated pathways in PDA are those affecting telomere function and chromosome stability. Most commonly mutated gene in PDA is KRAS followed by p16. While rare but clinically actionable mutations are also seen in PDAs such as BRAC, BRAF, partner and localizer of BRCA2 (PALB2) and EGFR. The mutational landscape of most common and clinically actionable mutations in PDA is summarized in [Table 4]. Mutational signature patterns similar to breast cancer gene (BRCA2) are seen in around 12% cases, which can be targeted in clinical practice with the use of poly (ADP-ribose) polymerase (PARP) inhibitors. While mutations in microsatellite instability (MSI) genes are seen in around 1.5% cases.
|Table 4: Mutational landscape of PDA – Common and clinically actionable mutations|
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Globally, colorectal cancer (CRC) accounts for 10% of all the incidents of cancers, while it is accountable for 8% of cancer deaths. The 5-year relative survival rate for stage I CRC is 92%. It ranges from 90 to 53% for stage IIA to IIIC, while for stage IV it is only 12%. Whole-genome sequencing has identified molecular heterogeneity in colon cancer and has divided them into four consensus molecular subtypes (CMS): CMS1 (MSI immune), CMS2 (canonical), CMS3 (metabolic) and CMS4 (mesenchymal). CMS1 tumors are more common in females with right-sided lesions and are enriched in BRAF mutations. CMS2 tumors are mainly left sided. CMS4 tumors have a universally worse OS. Most commonly mutated gene in CRC is adenomatous polyposis coli (APC) (85%) followed by TP53 (50%). While clinically actionable mutations like KRAS (35-40%), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (18-20%), BRAF (7-15%), NRAS (9%), mesenchymal-epithelial transition factor (MET) (2-5%) and Her2 (2-3%) are also identified. This molecular heterogeneity is summarized in [Figure 1] and can be used for identifying subgroups of colon cancer patients who can benefit with the use of targeted therapy.
With the understanding of common molecular alterations and pathways involved according to specific site, we will now look into how each of these pathways can be targeted with the use of various agents in clinical practice.
Molecular pathways targeted in clinical trials
Angiogenesis is regulated by a complex interplay of various antiangiogenic and pro-angiogenic compounds like VEGF, platelet-derived growth factor (PDGF), transforming growth factor (TGF), FGF and angiopoietin. With the discovery of VEGF and its effect on tumor proliferation, antiangiogenic agents targeting the VEGF pathway have been tried in various malignancies. The VEGF family consists of five members (A, B, C, D and placental growth factor), which binds to VEGF receptors and are divided into three types (Types 1 to 3). In clinical trials, VEGF pathway is targeted with the use of antibodies against VEGF like bevacizumab (monoclonal antibody against VEGF-A), vascular endothelial growth factor receptor (VEGFR) like ramucirumab (antibody against VEGFR-2) or TKIs with activity against VEGFR such as regorafenib.
In metastatic gastroesophageal adenocarcinomas, drugs targeting VEGF have failed to show survival benefit when used as upfront setting based on data from RAINFALL and RAINSTORM (for ramucirumab) and AVAGAST (for bevacizumab).,, But when used in 2nd line with taxane -based chemotherapy, ramucirumab, which is a fully humanized IgG1 monoclonal antibody against VEGFR-2, had shown improvement in the OS (5.2 months vs 3.8 months; HR 0.776, P = 0.047). None of the TKIs targeting VEGF, like sorafenib (STARGATE), regorafenib (INTEGRATE) and pazopanib had shown benefit in gastroesophageal adenocarcinomas., Similarly, for BTCs, inhibition of VEGF pathway with the use of sorafenib and cediranib had failed to show any improvement in response rates as well as survival., In metastatic adenocarcinoma colon, addition of bevacizumab to chemotherapy has shown improvement in progression free survival (PFS) in both 1st and 2nd line settings., Other antiangiogenic agents like ramucirumab, regorafenib or aflibercept had not shown improvement in survival when used in 1st line, but had been approved for use in 2nd line setting after progression on bevacizumab.,,
Resistance to antiangiogenic agents is mediated by upregulation of bypass pathways like angiopoietin-mediated upregulation of RAS/RAF and PI3K/AKT pathway or upregulation of fibroblast growth factor receptor (FGFR) pathway. Dual blockage of VEGF along with angiopoietin-2 or FGF has shown positive effect in preclinical models and clinical trials are underway.
EGFR belongs to the ErbB/Her family, which has four members: ErbB1 to ErbB4. These get activated after homo- or heterodimerization through binding of specific ligands, mainly EGF and TGF-alpha. This leads to activation of downstream signaling pathways in the form of RAS/RAF/MEK/ERK, PI3K/AKT and JAK/STAT3 which are essential in cell growth, survival and migration. Methods to target the EGFR pathway include anti-EGFR antibodies and TKIs targeting intracellular kinases.
Targeting EGFR pathway has not met with much success in gastroesophageal or BTCs. Addition of anti-EGFR antibody to chemotherapy in 1st line metastatic GC has failed to improve PFS as shown in two phase III studies, EXPAND (Cetuximab) and REAL3 (Panitumumab)., Similarly, for metastatic BTCs, addition of EGFR antibody or TKI to chemotherapy has failed to improve survival. In contrast, the role of anti-EGFR antibodies is well-established in metastatic colorectal malignancies. Both Cetuximab and Panitumumab have been approved with chemotherapy in metastatic RAS wild-type CRC in 1st line, and 2nd line as well as in maintenance settings. In phase III CRYSTAL trial, it was found that Cetuximab plus had improved PFS (8.9 vs. 8 months, HR - 0.85; P - 0.048) than FOLFIRI alone, although the OS was not significant. Similarly, in the PRIME trial combination of panitumumab with FOLFOX had better PFS (10 vs. 8.6 months, HR 0.80, P = 0.01) as compared to panitumumab alone. Presence of RAS mutations (KRAS and NRAS exon 2, 3 and 4), BRAF mutations, Her2 amplifications as well as right-sided tumors are predictors for poor response to anti-EGFR therapy. Tumor sidedness has emerged as one of the important prognostic and predictive marker over the last few years in metastatic CRCs. Righ-sided tumors are enriched in MSI, BRAF or Her2 amplifications and respond poorly to anti-EGFR therapy than left-sided tumors.
RAF is a part of the MAPK pathway which is one of the most commonly mutated oncogenic pathways in cancers. It is one of the most important downstream signaling part of the RAS/RAF/MEK/ERK pathway. Mutations in RAS are most common, followed by RAF and MEK mutations. BRAF mutations are seen in 7-10% of all malignancies, commonly observed in melanoma, thyroid cancer, colon cancer and lung adenocarcinoma. These are divided into three classes, class 1 being most common. Class 1 mutations currently include only BRAFv600 mutations, which are seen in over 90% of all BRAF alterations. Currently, approved RAF inhibitors do not selectively inhibit BRAF and are active against ARAF and CRAF with similar potency, but they are approved only against class 1 mutations. Inhibition of RAF signaling leads to independent activation of downstream MEK/ERK pathways, which is responsible for the increase in incidence of cutaneous adverse events and malignancies in patients receiving BRAF inhibitors, hence, combined blockage of RAF and MEK is commonly employed in clinical trials.
In GI malignancies, the best evidence for clinical activity of RAF inhibitors comes from trials in CRCs. In phase III BEACON trial, a combination regime of encorafenib, binimetinib and cetuximab led to better OS in patients with BRAF-mutated metastatic CRC than that achieved historically with a comparable rate of adverse events (OS: 9 vs. 5.4 months, HR – 0.52, P < 0.001). Similarly, in gastric cancer, MEK inhibitor selumetinib combined with docetaxel has shown improvement in response rates in patients with RAS mutations.
Her2 is one of the four human epidermal growth factor receptors. It forms homo/heterodimers with other Her family members and leads to downstream signaling activation. Overexpression of Her2 can be detected using immuno-histo-chemistry (IHC), fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS). In GI malignancies, modified Hoffmann's method is used to determine degree of Her2 overexpression by IHC. Most of the clinical trials have used IHC as well as FISH to determine Her2 expression. Her2 overexpression is seen in approximately 20% of gastric cancers. It is more common in GEJ tumors (33%) than in distal tumors (20%). It is also less commonly seen in diffuse gastric cancers (6%). In BTCs, Her2 overexpression is common in gall bladder carcinomas ranging from 10 to 20% across various studies,, while around 2-3% of CRCs show Her2 amplifications. There are multiple drugs which act on Her2 pathway which include 1. Anti-Her2 antibodies – trastuzumab and pertuzumab 2. Anti-Her2 antibody drug conjugates (ADC) – TDM1 and TDXd 3. Anti-Her TKI – lapatinib and neratinib.
In metastatic Her2-positive gastroesophageal adenocarcinomas addition of chemotherapy with trastuzumab had shown to improve survival based on ToGA trial and is currently standard of care (SOC). While other drugs like lapatinib, TDM1 and pertuzumab had failed to show benefit in 1st as well as 2nd line. Recently, another ADC trastuzumab deruxtican (TDXd) had shown OS benefit based on results of DESTINY Gastric 01 study. There is limited retrospective data on the use of Her2-directed therapy in biliary cancers, and prospective trials are underway. Similarly, evidence for use of Her2-directed therapy in colonic adenocarcinomas is based on phase 2 studies like Mypathway (for pertuzumab + Trastuzumab) and HERACLES (for trastuzumab + lapatinib).,
Dysregulated MET pathway is an established oncogenic driver. MET is a proto-oncogene which codes for tyrosine kinase receptor c-MET for hepatocyte growth factor (HGF). Binding of HGF to MET receptors leads to dimerization and activation of downstream MAPK, PI3K, SRC and signal transducer and activator of transcription (STAT) pathways. MET alterations occur as a result of three different genomic alterations: amplifications, mutations and fusions. These can be primary or secondary which can be de-novo or acquired following selective pressure of other TKIs. In malignancies, increased MET activity promotes anti-apoptotic and pro-migratory signals. MET alterations can be detected with the use of NGS, PCR or FISH. Currently, MET amplification is defined as MET gene copy number >5. Other cutoffs like >6 or >15 are also followed according to various studies., In GI malignancies, MET alterations are seen between 6 and 17% depending on the type of method used. It is seen in around 4-10% of upper GI malignancies, while it is rare in colon cancers. MET pathway can be targeted with the use of antibodies/ADCs against MET or HGF and selective MET TKIs.
In gastric cancer, phase III randomized control trials (RCTs) of MET inhibitors, rilotumumab and ornatuzumab in combination with chemotherapy have failed to show benefit as compared to chemotherapy alone., Similarly, in metastatic CRC, rilotumumab as well as ornatuzumab had failed to benefit in survival. TKIs targeting MET amplification or mutations, e.g., Capmatinib, Tepotinib and Savolitinib, are under clinical trial.,
Isocitrate dehydrogenase (IDH1) mutations were first identified in integrated genomic analysis of human glioblastomas. In GI malignancies, the highest incidence is seen with CCA (20%) while rarely seen in CRC (1.19%) and pancreatic cancer (0.43%). These mutations are less common in eCCA (0-7.4%) and GBC (1.5%). Mutated IDH1 leads to accumulation of 2-hydroxyglutarate (2-HG) which divers tumorigenesis. IDH1 mutations can be detected by use of next-generation sequencing or targeted PCR for hotspot codon 132 mutations on biopsy samples. Ivosedinib is an oral, small-molecule inhibitor of mutant IDH protein which was tried in phase III randomized ClarIDHy trial in mIDH1 BTCs, who had progressed on 1 or 2 prior lines of therapy. Ivosedinib improved PFS) from 1.4 to 2.4 months which was statistically significant. It is seen in cell models that 2-HG accumulation also affects homologous recombination pathways and makes cells sensitive to PARP inhibitors. A trial with olaparib in mIDH1 CCA is currently underway.
FGFR pathway aberrations
The FGFR family is characterized by seven receptors encoded by four FGFR genes. These are a class of receptor tyrosine kinases which need appropriate ligands for dimerization leading to activation of downstream signaling pathways such as PI3K-AKT pathway and Raf-MEK-ERK pathway. The downstream signaling regulates mesenchymal, antiapoptotic and mitogenic responses in cells. Till now, different aberrations leading to activation of the FGFR pathway have been identified which include 1. FGFR fusions 2. FGFR amplifications 3. FGFR mutations 4. Alternate splicing. Of all GI malignancies, FGFR pathway aberrations specifically affecting FGFR2 are most commonly seen in ICCA (11-45%). FGFR2 amplifications are also commonly reported from GC with frequencies ranging from 2 to 9% according to cohort studied, while these are rare (0.5-1.5%) in PDA and carcinoma colon. Similarly, FGFR4 is also overexpressed in 38-44% of gastric cancers as has been associated with poor prognosis. FGFR pathway aberration which include amplifications, mutations, fusion as well as splicing alterations can be collectively detected by use of NGS, while fusions and amplifications can be detected with the use of FISH.
There has been a growing interest in targeting these FGFR aberrations, especially in CCA. FIGHT-202 is a phase 2 trial of pemgatinib which is a selective oral inhibitor of FGFR1, 2 and 3 in previously treated CCA. The most common fusion partners seen in CCA were BicC family RNA binding protein 1 (BICC1) followed by KIAA1217 genes. Median OS in patients with FGFR fusions was 21.1 months, while it was 6.7 months in the other types of FGFR alterations as compared to 4 months in the comparator arm. Similarly, FGFR signaling pathway has been targeted in GC with the use of various drugs like anti-FGFR monoclonal antibodies, FGF traps, selective and non-selective tyrosine kinase inhibitors, summarized in [Table 5].
Tissue agnostic biomarkers
Tissue agnostic approach is a highly personalized approach to cancer treatment emphasizing on detection of particular molecular alteration regardless of tumor type. FDA has given tumor agnostic approval for pembrolizumab and neurotrophic receptor tyrosine kinase (NTRK) inhibitors if a specific biomarker is present.
NTRK gene fusions involving NTRK1/2/3 are oncogenic drivers in various pediatric as well as adult tumors. These are proto-oncogenes which when constitutively activate drive oncogenesis. The most common mechanism by which this occurs is NTRK fusions, while other mechanisms like alternate splicing, overexpression and mutations are also reported. Some malignancies are specially enriched in NTRK fusions such as secretory breast carcinoma, congenital mesoblastic nephroma and infantile fibrosarcomas with a prevalence of >90%., While these are rarely (<5%) seen in GI malignancies, available targeted therapies make them important. NTRK alterations can be detected by multiple ways, e.g., IHC, PCR, FISH and NGS. Most of the clinical trials have used NGS-based techniques for detection. It is important to note that even advanced DNA-based NGS assays miss some of the NTRK fusions specially involving NTRK2 and NTRK3, which can be identified with RNA NGS. Targeted RNA sequencing in companion with DNA-based NGS is the most effective way of identifying NTRK fusions. FISH and RT-PCR are also acceptable alternatives, especially in tumors known to be rich in NTRK fusions. IHC using pan-TRK antibody for TRK overexpression is another surrogate of NTRK fusion, with specificity of 98% and sensitivity of 97%. In resource-limited settings, it can be used as an initial screening following which positive results need to be confirmed with NGS.
Various multi-kinase inhibitors like crizotinib, ponatinib, nintedanib and nintedanib have activity against TRK receptors, while Larotrectinib and Entrectinib are selective 1st generation TRK inhibitors and furthest along clinical development. Both have shown response rates of 75% in heavily pretreated patients regardless of tumor histology and are FDA approved.,
Microsatellite unstable phenotype is the result of defective DNA mismatch repair (MMR) system leading to accumulation of mutations in DNA. This can be seen due to germline mutation in MLH1, MSH2, MSH6 or PMS2 or due to somatic mutations in these genes. Most common somatic as well as genetic mechanism is promoter hypermethylation of MLH1 leading to silencing. It can be assessed with IHC or sequencing by PCR or NGS. As compared to PCR, IHC has a sensitivity of 90% and specificity of 99%. In GI cancers, percentage of MSI phenotype is – EC (1.5%), GC (22%), CCA (1.5%), pancreatic cancer (1.5%) and colon cancer (20%).
As somatic mutations have a chance of coding “non-self” immunogenic antigen, tumors with large numbers of somatic mutations as seen with MSI phenotype have a chance of responding to immunotherapy. Based on the results of five multicenter single-arm studies (Keynote-016, -164, -012, -028, -158) in patients with metastatic MSI-H tumors, pembrolizumab was approved by FDA as “first tissue agnostic approval.” It had shown overall response rates of 39.6% with median duration of response ranging from 1.6 to 22.7 months.,,
Tumor mutational burden (TMB)
TMB is defined as the number of nonsynonymous somatic mutations per megabase in the coding region of DNA. High TMB as a result of higher number of somatic mutations has the possibility of responding to immune checkpoint inhibitors (ICI). Keynote-158, tested pembrolizumab in a cohort of high TMB (defined as >10 mutations/megabase), which showed RR of 29% and median survival of 11.7 months. Based on this, pembrolizumab was given tissue agnostic indication by FDA in high TMB tumors. Testing for TMB is currently done by using NGS for either whole-genome sequencing or whole-exome sequencing. Most of the clinical trials have utilized whole-genome sequencing. FDA has currently approved Foundation One CDx and MSK-IMPACT as companion diagnostic tests for detection of TMB.
| Conclusion and Future Directions|| |
Human genomic, transcriptional, proteomic and epigenetic details have been readily available in the past few decades, owing to evolving sequencing technologies. With the use of newer sequencing and molecular techniques, newer oncogenic driver pathways as well as resistance mechanisms to chemotherapy/targeted therapy are being elucidated. While the role of drugs targeting EGFR, Her2, BRAF or antiangiogenic pathways is already established with evidence from large clinical trials, there have been few clinical trials with drugs targeting alternative pathways like insulin like growth factor receptor (IGF-R), WNT, TGF-beta, NOTCH and Sonic Hedgehog (SHH). There is a large cross-talk between these pathways and the drugs targeting single molecular target have been largely unsuccessful.
While addition of targeted therapy is associated with improved outcomes there are also important drawbacks: 1. While there is improvement in response rates as well as PFS, very few agents have shown improvement in OS which is one of the important oncological end-point. 2. The cost effectiveness remains questionable as drugs are costly, need additional molecular/genetic testing and are not curative. 3. Additional targeted therapy can cause extra adverse events, some of which may be life threatening. 4. Efficacy is different among different people and currently there is a lack of good predictive marker to better select patient population. 5. As there is cross-talk between various pathways and existence of bypass mechanisms, emergence of drug resistance is inevitable for which cost=-effective solutions are not yet available. Even with the above challenges, addition of targeted therapy has improved outcomes in metastatic gastrointestinal malignancies. While newer targeted agents are being used in advanced settings either alone or in combination with existing therapies, trials are currently investigating the efficacy of established therapy in the front line and adjuvant curative setting.
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Conflicts of interest
There are no conflicts of interest.
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Department of Medical Oncology, Dr. B. R. A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]