Biomarkers in the Management of Metastatic Colorectal Cancer- a Mini Review

Colorectal cancer is the third most common cancer detected in both men and women in the United States. As per American Cancer Society, 101,420 new cases of colon and 44,180 new cases of rectal cancer are expected in the United States, for the year 2019. The lifetime risk of developing CRC is expected to be 1 out of 22 (4.49%) for men and 1 out of 24 (4.15%) for women. In terms of mortality, CRC is the second leading cause of cancer related mortality in both men and women, accounting for 51,020 deaths in 2019 [1,2]. Historically, 5-fluorouracil (5-FU) has been the standard of care for metastatic CRC (mCRC) but following the approval of cytotoxic agents and several targeted therapies in the last two decades, the landscape of treatment of mCRC has changed, leading to increased tumor response and patient survival rates [3]. Cytotoxic agents have been combined with biologic agents in the current standard of care for mCRC. A total of ten different classes of drugs (three classes of cytotoxic agents, six classes of biologic agents, namely anti EGFR, anti-VEGF, multitargeted tyrosine kinase inhibitors, NTRK inhibitors, BRAF inhibitors, MEK inhibitors and one class of immunotherapy) are currently being used for the treatment of mCRC. An overview of all the different drugs that have been approved by the US Food and Drug Administration (USFDA) for use in the management of mCRC, with their mechanism of action and adverse effect profile has been described in Table 1 [4-6]. Received: October 09, 2019 Published: October 18, 2019


Introduction
Colorectal cancer is the third most common cancer detected in both men and women in the United States. As per American Cancer Society, 101,420 new cases of colon and 44,180 new cases of rectal cancer are expected in the United States, for the year 2019. The lifetime risk of developing CRC is expected to be 1 out of 22 (4.49%) for men and 1 out of 24 (4.15%) for women. In terms of mortality, CRC is the second leading cause of cancer related mortality in both men and women, accounting for 51,020 deaths in 2019 [1,2].
Historically, 5-fluorouracil (5-FU) has been the standard of care for metastatic CRC (mCRC) but following the approval of cytotoxic agents and several targeted therapies in the last two decades, the landscape of treatment of mCRC has changed, leading to increased tumor response and patient survival rates [3]. Cytotoxic agents have been combined with biologic agents in the current standard of care for mCRC. A total of ten different classes of drugs (three classes of cytotoxic agents, six classes of biologic agents, namely anti EGFR, anti-VEGF, multitargeted tyrosine kinase inhibitors, NTRK inhibitors, BRAF inhibitors, MEK inhibitors and one class of immunotherapy) are currently being used for the treatment of mCRC. An overview of all the different drugs that have been approved by the US Food and Drug Administration (USFDA) for use in the management of mCRC, with their mechanism of action and adverse effect profile has been described in Table 1 [4][5][6]. Tipiracil)   A combination of  nucleoside analog,  and, a thymidine  phosphorylase  inhibitor   inhibition of thymidylate  synthase by the  nucleoside analog and  prevents degradation of  trifluridine via thymidine  phosphorylase   third-or fourth-line treatment  for metastatic colorectal cancer   combination severe myelosuppression,  loss of appetite, diarrhea, nausea, vomiting,  fatigue, fever, rashes, itchiness, mouth  sores, dizziness, confusion,

Cytotoxic Agents
We have seen minimal improvements in the biomarkers driven cytotoxic strategies in the past decade. Most known predictive biomarkers for cytotoxic agents are as follows. allele. A study demonstrated that patients with homozygous and to some extent, heterozygous for allele UGT1A1*28 developed more severe toxicities with irinotecan therapy. However, it also showed that these patients have better response rates and PFS compared with another allele UGT1A*1 [22].

ABCC5 and ABCG1 Polymorphisms -Irinotecan Toxicity:
Polymorphism in the ATP-binding cassette (ABC) genes that participate in the pharmacokinetics of irinotecan were studied.
It was observed that the polymorphic transporter genes ABCG1 and ABCC5 were associated with increased risk of developing neutropenia and diarrhea, respectively, in patients treated with irinotecan. This biomarker can potentially further personalize the FOLFIRI treatment of mCRC patients [23].

Topoisomerase 1 Copy Number Alterations: It is known
that FOLFIRI and FOLFOX are considered as equally valid as first-line therapy in the mCRC. However, clinicians choose one from their experience or one that they are comfortable managing their toxicities. It has been observed in a study that there is a significant association between the increasing copy number (CN) of topoisomerase 1 (TOP1) and response to irinotecan monotherapy [24] thus suggesting FOLFIRI over FOLFOX in these patients.

Mutations in RAS
Epidermal Growth Factor (EGF) binding the EGF receptor to be harmful when combined with oxaliplatin [25,26]. Therefore, it is recommended that panitumumab and cetuximab (monoclonal antibodies against EGFR) are utilized only in patients with wild type RAS (wt RAS). Results from the PRIME study demonstrated that not only the exon 2 (codon 12 and 13) with seven specific mutations that account for over 90% of KRAS mutations but also KRAS exon 3 (codon 61) and exon 4 (codon 117 and 146), and NRAS mutations also predict for nonresponse to EGFR inhibitor therapy [27]. In addition, it was observed that some patients with wt RAS also did not benefit from anti-EGFR therapy. On further studies, patients with wt KRAS, some miRNAs predicted response to anti-EGFR treatment. Low expression of miR-1881a has been associated with unfavorable outcomes [28][29]. to chemotherapy alone [30][31]. Based on these results, EGFR inhibitors are not recommended in BRAF mutant patients.

PTPRT and PTPRD:
It is observed in a study that deleterious mutation in receptor-type tyrosine-protein phosphatase T (PT-PRT), a phosphatase involved in JAK/STAT signaling pathway and its related gene PTPRD correlated with the resistance towards bevacizumab therapy [32]. However, the study involved a tiny sample; hence, more extensive studies must be done to establish the observed effect.

Prognostic Markers
Prognostic markers are biomarkers that give overall progress of a disease in a patient population. Previously, the classical prognostic markers in oncology include the size of the tumor, stage, and presence of metastasis. With the advent of modern molecular techniques and genomic sequencing technology, molecular biomarkers are being discovered which can establish some prognostic value. Table 2 lists out some of the prognostic markers that have been studied and can potentially be used in the clinical practice.

Conclusion
Although many potential predictive and prognostic biomarkers are being reported in various studies, very few of them are used in the clinical practice due to varying reasons. More clinical studies must be done to identify newer potential biomarkers and to establish the clinical validity of some know biomarkers so that they can be used in clinical practice to individualized treatment options and predict the outcomes.