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The Evolution of Biomarkers to Guide the Treatment of Metastatic Colorectal Cancer
Lisa E. Davis, PharmD, FCCP, BCPS, BCOP
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The Evolution of Biomarkers to Guide the Treatment of Metastatic Colorectal Cancer

Lisa E. Davis, PharmD, FCCP, BCPS, BCOP
In the United States, colon cancer is one of the leading causes of death and cancer-related death. There is a critical need to improve clinical outcomes in patients with metastatic colorectal cancer (mCRC), as current survival rates are unsatisfactory. There have been significant advances in the treatment of mCRC over the past decade. Molecular characteristics of mCRC and identification of mutations can serve predictive and prognostic indicators of disease response to treatment. These biomarkers can be incorporated into clinical decision making when developing an individualized treatment plan. Targeted therapies have improved the survival of patients with mCRC. As we learn about the various molecular alterations in this disease, additional emerging therapies can be developed to improve clinical outcomes in patients with mCRC.
Am J Manag Care. 2018;24(7):-S0
Introduction

Colorectal cancer (CRC) is the third most common type of newly diagnosed cancer and the third most common cause of cancer-related death in the United States, with 50,630 deaths due to CRC expected in 2018.1 Overall CRC incidence and death rates have been declining over the past several decades.2 The decreasing trend in CRC mortality rate is attributed to increased screening and use of colonoscopy in screening, improvements in treatment, and greater integration of continuity of care.3 Changes in patterns of lifestyle habits associated with CRC risk and increased usage of screening have contributed to a decline in the overall incidence of CRC by about 3.5% annually over a 10-year period from 2005 to 2014. However, the incidence of CRC among patients younger than 55 years has been increasing since the mid-1990s, with the most rapid increase in metastatic disease.4 This steady increase in CRC incidence among younger adults, which may be due to obesity and lifestyle factors, is a concern for the future burden of disease and colorectal cancer mortality in this population.4 Approximately 50% to 60% of patients with CRC develop metastatic CRC (mCRC), and 80% to 90% will have unresectable liver metastases.5,6

Although currently available therapies can reduce rates of disease progression and extend survival of patients with mCRC, the possibility of a cure for mCRC is limited to select individuals who are able to undergo surgical resection of metastatic disease.5 The 5-year relative survival for patients with mCRC is about 13.9%.2 Alterations in several key CRC genes are linked to prognosis and survival, but importantly also serve as biomarkers to identify tumor sensitivity and resistance patterns to targeted therapies. These statistics highlight the critical need for better therapies, as well as for biomarkers to guide treatment decisions that improve treatment outcomes for mCRC. Recent advances in biomarker research and new treatment options for this disease warrant the education of healthcare personnel treating patients with mCRC so that they can better tailor therapies for more effective management.

Genetic Biomarkers in CRC

The development of CRC is driven by molecular changes and mutations in key genes within a network of signaling pathways that influence tumorigenesis.7 Our understanding of the biology of CRC continues to improve, and efforts to develop therapeutic strategies that target some of these genetic mutations have led to advances in treatment. Genetic testing to select therapies for patients with CRC has been the focus of many recent studies and has become standard practice for the management of patients with CRC.8 With the availability of effective immunotherapy for mCRC and newer targeted therapies, there has been increased acceptance of the need for more extensive molecular testing. Given the wide array of genetic and epigenetic alterations involved in colorectal tumorigenesis, efforts to classify CRC based on distinct subtypes that represent pathologic and molecular features have been challenging.7 Most recently, however, a molecular classification for CRC that defines 4 different subtypes with implications for patient management has been reported.9 Several biomarker tests provide prognostic and/or predictive information for patients with CRC (Table 16).

Biomarkers that can predict the response to specific therapy or treatment regimens are predictive. Kirsten rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) gene status in the epidermal growth factor receptor (EGFR) signaling pathway are predictive for tumor sensitivity to monoclonal antibodies that target the EGFR. Wild-type KRAS and NRAS tumors respond to these therapies, while mutant KRAS and mutant NRAS tumors do not respond.8 DNA mismatch repair (MMR) gene status is predictive for tumor sensitivity to anti-programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) therapies.7 Mutations or epigenetic modifications of MMR genes can result in MMR protein deficiency and microsatellite instability (MSI). Depending on the extent of MSI, tumors are classified as MSI-high (MSI-H) or MSI-low (MSI-L). Tumors that are MMR protein deficient are considered MSI-H. Sufficient MMR proteins are critical for deleting DNA mismatches that occur during DNA replication; therefore, tumor cells that are MMR protein deficient accumulate thousands of mutations that can encode for mutant proteins that promote their growth. These proteins have the potential to be recognized and targeted by the immune system.

Mutations in other genes, including V-raf murine sarcoma viral oncogene homolog B1 (BRAF), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), phosphatase and tensin homolog (PTEN), overexpression of V-Erb-B2 erythroblastic leukemia viral oncogene homolog 2 (HER2), and mesenchymal-epithelial transition (MET), may also influence response to anti-EGFR monoclonal antibodies, but only BRAF testing is included in current guidelines.8

Certain molecular alterations in the tumors have significant implications for patient treatment and “personalized therapy” for CRC. However, the use of tumor-based gene mutations to guide therapy can be influenced by the source of tumor DNA, sampling sites, and temporal factors. Although the most common source of DNA for molecular profiling is isolated from formalin-fixed paraffin embedded (FFPE) tumor tissue specimens, cell-free DNA, which is believed to reflect circulating tumor DNA (ctDNA), can be isolated from whole blood, that is, “liquid biopsy.”

During the progression of mCRC, different patterns of genetic mutations may develop between DNA collected from primary tumors and sites of metastatic disease.7 For mutations in certain clinically relevant genes such as KRAS, NRAS, BRAF, PIK3CA, and mutant p53 (TP53), there is a greater than 90% concordance between primary tumors and metastatic disease.7,10 Concordance for PTEN expression by immunohistochemistry (IHC) is lower. Rates of PTEN expression vary from 47% to 98% between primary and metastatic sites, thereby reducing the utility of this biomarker in clinical practice.7,11

The American Society for Clinical Pathology, the College of American Pathologists, the Association for Molecular Pathology, and the American Society of Clinical Oncology have developed evidence-based guidelines to establish standard molecular biomarker testing to guide targeted therapies for patients with CRC.8 According to their guidelines, the evidence supports molecular testing for genes in the EGFR signaling pathway such as KRAS and NRAS. They noted that mutations in other biomarkers also have clear prognostic value. These markers include testing for the BRAF pV600, DNA MMR gene status and IHC testing for MutL homolog 1 (MLG1), MSH6 and PMS2.8 The National Comprehensive Cancer Network (NCCN) guidelines specifically recommend universal MMR or MSI testing in all patients with a personal history of colon or rectal cancer.6 The NCCN also recommends that patients with mCRC have their tumors genotyped for RAS (KRAS and NRAS) as well as the BRAF V600E mutation.6 The development of validated, robust biomarkers is essential for personalized therapy.

mCRC Molecular Subtypes

Gene expression-based subtyping is an accepted process for stratifying diseases; however, published gene-expression classifications showed a high level of heterogeneity and lack of consistency among subtypes of CRC. In 2015, the Colorectal Cancer Subtyping Consortium (CRCSC), an international consortium, was formed to resolve inconsistencies among the reported gene expression-based subtype classifications of CRC.9 They found interconnectivity among 6 different classification systems. Using this interconnectivity, they developed 4 consensus molecular subtypes (CMS) of CRC with distinguishing features (Table 27,9,12,13). Their aim was to establish a useful cancer subtyping strategy that incorporates clinical and molecular features that correlate with patient outcomes.

Implications for Therapy

These 4 consensus molecular subtypes (CMS1-4) are biologically distinct, have different clinical courses, and may predict therapy response.13 Patients with CMS1 subtype have MSI-H tumors that produce mutated proteins due to the high number of gene mutations. These mutated proteins are recognized by the immune system and result in a lymphocytic infiltrate of the tumor.6,12,14 Therefore, patients with CMS1 tumors may be excellent candidates for immune checkpoint inhibitors.12,15 A recent phase 2 clinical trial of pembrolizumab (PD-1 inhibitor) demonstrated a 40% response rate in patients with MMR-deficient mCRC. There was no response in patients with MMR-proficient tumors.12,16 Patients with tumors that are MMR protein deficient or MSI-H mCRC usually have a poor prognosis and are less responsive to conventional chemotherapy.17,18

Patients with CMS2 subtype disease do not typically harbor tumor mutations of BRAF or RAS, and are therefore likely to benefit from anti-EGFR therapies. Patients with CMS2 tumors also may benefit from oxaliplatin-containing regimens, although this observation was conducted from a retrospective analysis of patients with early stage colon cancer and requires further confirmation.19 Given frequent activation of c-MYC proto-oncogene (MYC) and WNT signaling pathways, CMS2 tumors may respond better to a number of agents under development that target these pathways, as well as inhibitors of Aurora A kinase.12,20

Patients with CMS3 subtype tumors have frequent RAS, PIK3CA, and PTEN mutations, which confer resistance to anti-EGFR therapy. However, these tumors show an increased activity in various metabolic pathways that are under investigation as new targets for agents that target tumor glycolysis, glycogen synthase kinase, and amino acid metabolic pathways.12,21-23

CMS4 tumors express genes associated with epithelial to mesenchymal transition (EMT), which appears to be higher in stromal cells as compared with tumor cells. Agents that inhibit the TGF-β signaling pathway may be useful in affecting tumor stroma. CMS4 tumors may also be sensitive to inhibitors of angiogenesis. Because they are also enriched with stem cells, CMS4 tumors appear to be particularly sensitive to combinations of irinotecan, fluorouracil, and leucovorin, such as FOLFIRI and FOLFOXIRI.12,24

 
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