|Year : 2020 | Volume
| Issue : 2 | Page : 66-71
Biomarkers in colon cancer and its clinical implications
Vijay Kumar Srinivasalu1, Keechilat Pavithran2
1 Department of Medical Oncology, Mazumdar Shaw Cancer Center, Bengaluru, Karnataka, India
2 Department of Medical Oncology, Amrita Institute of Medical Sciences and Research Center, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
|Date of Submission||19-Nov-2020|
|Date of Acceptance||19-Nov-2020|
|Date of Web Publication||31-Dec-2020|
Dr. Keechilat Pavithran
Department of Medical Oncology, Amrita Institute of Medical Sciences and Research Center, Amrita Vishwa Vidyapeetham, P.O. AIMS Ponekkara, Kochi 682 041, Kerala.
Source of Support: None, Conflict of Interest: None
Colorectal cancers have been a major burden in our society, with nearly 20,000 deaths in a year. Most of the patients are diagnosed with metastatic disease at presentation and have shorter survival despite the best effective treatment. The detection of novel targets and predictive biomarkers has changed the treatment paradigm, resulting in improved quality of life and prolonged survival in these patients. However, the identification of an ideal biomarker has been a major challenge and a quest for better biomarkers to detect premalignant lesions, early-stage cancers; to identify high-risk subsets who derive maximum benefit from adjuvant chemotherapy and minimize unnecessary chemo-toxicity; to identify newer targeted therapies in advanced stage to improve clinical responses; and to provide personalized treatments that would significantly help in improving survival outcomes. In this review article, we provide an overview of the biomarkers with clinical importance and an update on newer noninvasive, sensitive, and clinically reliable biomarkers in development.
Keywords: Biomarkers, BRAF, colon cancer, K-ras, MSI
|How to cite this article:|
Srinivasalu VK, Pavithran K. Biomarkers in colon cancer and its clinical implications. J Curr Oncol 2020;3:66-71
| Introduction|| |
Colorectal cancer is the seventh leading cancer in India, but its incidence has been extremely low compared with the western world. There are around 27,000 new cases of colorectal cancers diagnosed every year, with 19,500 deaths reported as per GLOBOCAN 2018. There is an upsurge of data indicating a 2–4 times increase in colorectal cancer incidence over the past few decades.,, The age-adjusted rates for colon cancer incidence recorded by all cancer registries in India are low compared with the western population, with an incidence rate of 0.7 to 3.7/100,000 among men and 0.4 to 3/100,000 among women. With the global burden set to increase by 60%, with more than two million new cases by 2030, and with around one million deaths, there is a need to intervene early as people develop disseminated disease.
Surgery has been the primary treatment modality in early and locally advanced colon cancer, with systemic chemotherapy as an adjuvant in patients with stage III (node-positive) and clinically high-risk stage II patients, which is still debatable. Clinical trials have shown significant benefits with fluoropyrimidines and oxaliplatin as adjuvant chemotherapy to improve overall survival and reduce the risk of relapse in patients with stage III colon cancer in the MOSAIC study. Despite undergoing surgery and chemotherapy, only 50% of stage III cancer is cured with surgery; another 20% of patients survive from receiving adjuvant chemotherapy, and nearly 30% of patients relapse within two to three years. Adding chemotherapy exposes one-third of patients (nearly 80%) to unnecessary additional toxicity with adjuvant chemotherapy.
The five-year overall survival rate for stage I, II, III, and IV is 90%,70%,58%, and less than 15%, respectively. Despite the best efforts with combined modality treatments, long-term survivors are very few; hence, there is a dire necessity to identify reliable biomarkers to help identify patients who are most likely to benefit from aggressive treatment and also help detect patients in early-stage cancers before the onset of symptoms and reduce toxicity by avoiding chemotherapy in a subset of patients with negligible benefits.
| Various Biomarkers and Their Classification|| |
Biomarkers are naturally occurring molecular patterns, genes, or characteristics found in blood, other body fluids, or tissues. They are quantifiable characteristics of biological processes and are used as a tool for early cancer detection and individualized treatment in colon cancers., They also help provide information on disease progression, recurrence, and resistance to treatment and act as personalized indicators for therapeutic effectiveness.
Classification of biomarkers
Diagnostic biomarkers help diagnose cancer early before the onset of clinical symptoms, improving survival by detecting early-stage cancers and premalignant lesions, including high-risk polyps. They behave as an initial screening tool. The sensitivity of fecal immunochemical testing (FIT) for detecting colorectal cancers was 73.8% versus 92.3% for a stool-based DNA assay that screens for KRAS, aberrant NDRG4, and BMP3 methylation. Sensitivity to detect premalignant lesions with FIT testing is 23.8% versus 42.4% for stool DNA testing. To detect polyps with high-grade dysplasia, FIT had 45.2% sensitivity, and stool DNA testing had 69.2% sensitivity. However, for serrated sessile polyps measuring >1 cm, it was 5.1% with FIT compared with 42.4% with stool DNA sampling. These findings highlight the challenges faced in establishing an ideal biomarker for screening and early detection of precancerous lesions, and it is essential to maintain a low threshold for more invasive colonoscopy in these patients.
Prognostic biomarkers provide information on patient outcomes irrespective of the treatment they receive, such as overall survival and relapse-free survival. Prognostic biomarkers help in predicting disease progression, including early recurrence and mortality. Mutations in proto-oncogene KRAS is associated with a greater risk of recurrence after curative surgery, as well as worse overall survival after liver metastasectomy., Carcinoembryonic antigen predicts early recurrences in patients who undergo surgery but it has a low sensitivity and specificity. Thus, the incorporation of prognostic markers might help identify patients who benefit from aggressive treatments.
Diagnostic biomarkers provide information on treatment response and help in deciding therapy. They are used to tailor treatments according to the molecular subtype individually. Poor response was noted with anti-EGFR receptor therapy in patients harboring KRAS mutations. As primary resistance mechanisms were noted in patients with RAS mutation, they were excluded from treatment with an anti-EGFR monoclonal antibody. Nearly 40% of metastatic colorectal cancers harbor KRAS mutations and could be spared expensive anti-EGFR treatment.
The FOLFIRI regimen, a combination of Irinotecan and 5FU, the enzyme responsible for metabolizing 5FU in more than 80% of patients, is dihydropyrimidine dehydrogenase (DPD). DYPD*2A and DPYD*13 variant alterations led to an increase in adverse events, with a 25% to 50% reduction in a dose of 5-FU resulting in decreased toxicity. Irinotecan is metabolized by diphosphate-glucuronosyltransferase 1A (UGT1A), and homozygosity in the UGT1A1*28 allele results in a dose-dependent increase in toxicity compared with the UGT1A1*1 genotype.In homozygous carriers of UGT1A1*28 or UGT1A1*6, higher incidence of Irinotecan-induced severe toxicity was noted, and a 25% to 30% dose reduction was recommended in these patients. A pre-therapeutic genotyping of UGT1A1 helps reduce costs and decrease unnecessary toxicity. These interventions help improve treatment response, decrease toxicity, and help select appropriate doses to obtain maximum benefit. As only KRAS and extended RAS (NRAS), BRAF, and MSI status are recommended by national guidelines in evaluating treatment response and predicting outcomes in metastatic colorectal cancers, there is a need to develop additional reliable biomarkers. However, a series of potential investigational biomarkers are being explored.
| Clinically Meaningful Biomarkers in Current Treatment of Colorectal Cancer|| |
Colorectal cancers are mostly sporadic (70%–80%), with approximately only 20% being hereditary. These tumors occur due to the accumulation of genetic and epigenetic alterations and are very heterogeneous. APC is the most commonly mutated gene in about 80% to 82% of cases, followed by TP53, KRAS, and PIK3CA. Testing for NRAS, KRAS, BRAF (genes involved in colorectal carcinogenesis), and MSI status (those associated with DNA mismatch repair defects) are the prerequisites before the initiation of therapy.
Fifteen percent of colorectal cancers show microsatellite instability (MSI) and are very distinct in clinical and pathological features. These are right-sided tumors, with a poorly differentiated histology and with rich lymphocyte infiltration and are diagnosed at a young age. Overall, patients with MSI-high status show a better prognosis than patients with MSI-low (MSS) status. When added to clinicopathological variables, MSI status led to significantly improved prognostic predictions in patients with colorectal cancer. This led to its inclusion in clinical ESMO and NCCN guidelines. MSI-H tumours with stage II disease had a better prognosis with no additional benefit when treated with 5-FU chemotherapy., However, in localized colorectal cancers, MSI is a valuable prognostic marker, but not a predictive biomarker.
In stage III colon cancers, the differences are minimal, and the MSI status is less informative. In stage IV, patients with MSI-H can be considered for monotherapy with pembrolizumab. Tumors with MMR defects had higher responses with checkpoint inhibitors due to their increased mutational load and immune cell infiltration. Despite the MSI-high status, responses to immunotherapy have not been consistent; given the high cost of these drugs, there is a need for predictive biomarkers to identify intrinsic and acquired resistance.
Mutations in Kirsten rat sarcoma viral oncogene
Forty-five percent of stage IV colorectal cancers harbors Kirsten rat sarcoma viral oncogene (KRAS) mutation and is very low in early-stage tumors (15%–37%). A mutation in KRAS was detected commonly on codon 12 and codon 13; both of these were associated with inferior survival in wild-type BRAF colorectal cancers. To evaluate the predictive value of KRAS mutations, five randomized trials comprising 1239 metastatic colorectal cancers were analyzed in a meta-analysis and it was found that KRAS exon 2 variants, G12V and G12D had no impact on overall survival. KRAS G12C-variant showed an inferior overall survival compared with the nonmutated tumors.
The benefit of adding an anti-EGFR drug to standard chemotherapy has been well documented, and this benefit is limited to patients only with wild-type KRAS and NRAS mutant tumors. As stage IV colorectal cancers have a high incidence of KRAS and NRAS mutations (40% and 7%), respectively, it is essential to assess the mutational status of NRAS and KRAS codons 12 and 13 of exons 2, 3, and 4 before initiation of therapy with anti-EGFR antibodies.
Interestingly, response to anti-EGFR treatment in patients with wild-type KRAS is not exclusive, and they develop resistance due to ectodomain mutations, which drives the MAP kinase activation despite EGFR inhibition. Hence, additional biomarkers are needed to identify patients with wild-type KRAS who benefit from anti-EGFR therapy.
Mutations in BRAF
BRAF mutations are detected in 10% of colorectal cancers, and they occur on codon 600 (BRAF V600E), which constitutes almost 90% of all BRAF mutations. BRAF is mutually exclusive with other RAS mutations. BRAF-V600E-mutated tumors are clinicopathologically unique, as they possess high-grade histology, extensive nodal metastasis (four or more positive lymph nodes), MSI-high status, and increased prevalence in females; they are often located in the right side of the colon. In contrast, BRAF wild-type tumors have no such preferences and can be found in any part of the colon. Patients harboring BRAF mutations have inferior survival in stage III and IV colon cancers, but not in stage II. As per the BEACON study, testing for BRAF V600 mutation in stage III–IV colorectal cancers had minimal impact on therapy decision and was exclusively a prognostic marker.
BRAF mutant tumors (RAS wild-type that benefit from anti-EGFR therapy) predict a lack of response to anti-EGFR treatment in colorectal cancer. Meta-analyses suggested an inferior outcome with anti-EGFR antibodies in patients with KRAS wild-type BRAF mutant metastatic colorectal cancer, and there are conflicting data regarding the response to EGFR-targeting agents in BRAF-mutant colorectal cancers.
Treatment of BRAF-V600E mutant stage IV disease showed benefit with encorafenib (BRAF inhibitor) and cetuximab doublet or three-drug combinations of binimetinib (MEK inhibitor), cetuximab, and encorafenib in the second- or third-line setting in the BEACON study. This chemotherapy-free targeting combination approved by the FDA is a significant breakthrough in a difficult-to-treat subpopulation of patients with metastatic colorectal cancer. However, this trial is highly debatable due to an inferior control arm. Importantly, as there is a significant overlap of MSI with BRAF V600E mutations, checkpoint inhibitors may play a pivotal role. The NCCN guidelines recommend testing BRAF mutational status in patients with metastatic colorectal cancer for the reasons mentioned earlier.
| Future Promising Biomarkers|| |
Liquid biopsy: ctDNA and tumor mutational burden
Collection and analysis of circulating tumor cells or cell-free nucleic acids, and tumor-derived exosomal vesicles shed into the bloodstream or other fluids from the primary or the metastatic tumor is done by a liquid biopsy. The ctDNA is usually either not detectable or less than 1% in early cancers, increasing up to 50% in patients with metastatic disease. Of late, ctDNA helps assess residual disease burden, monitoring disease progression, or detects early recurrences, selects patients who derive maximum benefits from targeted therapy, and helps in the assessment of response to systemic treatments.
In the IDEA-FRANCE trial, positive ctDNA at four weeks after surgery was associated with inferior outcomes compared with ctDNA-negative patients who received adjuvant treatment for three months. So ctDNA can be useful as an independent prognostic marker. The ctDNA can assess the tumor mutational burden, identifying patients who respond to checkpoint inhibitors. However, TMB, as an independent prognostic factor, is still not well established, with recent evidence suggesting that MSI combined with ctDNA and TMB could increase the checkpoint blockade therapy efficacy.
NTRK, ALK, and ROS alterations
Gene fusion is detected in only 0.5% to 2% of patients with colorectal cancer. However, its prognostic or predictive value is unclear. In patients with metastatic colorectal cancers with LMNA-NTRK1, CAD-ALK, and STRN-ALK fusions, treatment with entrectinib showed significant responses in the STARTRK study. Entrectinib is a small molecule that inhibits ALK, ROS1, and TrkA-B-C. The FDA has approved it for treating all cancer types, including colon cancer harboring NTRK-fusion mutation.
Cell proliferation and apoptosis is inhibited by HER2 (Errb2) receptor activation. Overexpression of HER2 is due to either amplification or somatic mutation activation seen in 5% of colorectal cancers. MyPathway study (a combination of trastuzumab and pertuzumab) and HERACLES study (trastuzumab combined with lapatinib) showed promising benefits in HER2-amplified metastatic colon cancers. Data from recent studies show the acquired amplification of HER2 to be associated with resistance to anti-EGFR therapy, and they serve as a predictive marker for EGFR-targeted treatment.
This gene mutation is noticed in around 14% to 18% of patients with colorectal cancer and detected on exons 9 and 20. PIK3CA mutation on exon 20 is linked to resistance with therapy (anti-EGFR therapies and first-line chemotherapy). It is challenging to assess the predictive value of PIK3CA as a biomarker, as it mostly coexists with other RAS and BRAF mutations, and meta-analysis failed to show the significance of PIK3CA mutation as a prognostic biomarker in colorectal cancer.
Right-sided colon cancers have inferior outcomes and lack benefit with anti-EGFR therapy for KRAS wild-type tumors compared with left-sided colon cancers., Right-sided colon cancers with metastasis respond better to immunotherapy, as they possess a high antigenic load in comparison with patients with left-sided KRAS wild-type tumors who derive maximum benefit with anti-EGFR therapy.
CpG island methylator phenotype
Methylation of genes in CpG islands leads to malignant transformation and CpG island methylator phenotype (CIMP). Three studies (two retrospective studies and one post hoc analysis) suggested CIMP-positive tumors to have inferior survival compared with CIMP-negative tumors. However, clinical validity as an independent prognostic biomarker is still awaited.
MicroRNAs (miRNAs) help in inhibiting translation by binding to the 31 of mRNA and consist of 8–25bp ribonucleotides, which regulate gene expression. Low miR-31-3p expression correlated with superior progression-free survival, and in KRAS wild-type colon cancers receiving adjuvant chemotherapy, it serves as a promising predictive biomarker for anti-EGFR therapy.
CDX2 and MYO5B expression
These biomarkers have been extensively evaluated in early-stage colon cancer. These genes are involved predominantly in the differentiation of epithelial cells. Lower expression of MYO5B correlates with inferior overall survival and disease-free survival rates, with an excellent prognostic value in patients with stage II colon cancer. However, the assessment of CDX2 as a prognostic marker is still not clinically indicated and needs further investigation.
Plasmacytoma variant translocation 1 (PVT1)
It is a long coding RNA present on chromosome 8 and undergoes dependent transcription. In colorectal cell lines, increased PVT1 expression correlated with inferior survival. Similarly, a meta-analysis of 39 studies concluded that an increase in PVT1 expression is associated with reduced overall survival, and its role as a potential diagnostic marker is also being evaluated.
Tests based on gene expression
To identify patients with high-risk features in early-stage colon cancers, various single and multiple gene expression signatures are identified. The most commonly preferred are OncotypeDx and ColoPrint. Although they are commercially available, they have not been recommended for clinical use.
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Conflicts of interest
There are no conflicts of interest.
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