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Review Identifies Potential Predictive Biomarkers in Colorectal Cancer

David Bai, PharmD
A recent review outlined a vast array of biomarkers that may have clinical implications on the treatment and prognosis of colorectal cancer (CRC).
A recent review outlined a vast array of biomarkers that may have clinical implications on the treatment and prognosis of colorectal cancer (CRC).

The 5-year survival for metastatic CRC (mCRC) has been significantly low, at 13.8%, since clinicians started treating their patients with 5-flurorouracil (5-FU) and leucovorin combined with irinotecan, oxaliplatin, and a monoclonal antibody (cetuximab, panitumumab, bevacizumab). Because of the lack of survival improvements in this patient population, investigators are turning to precision medicine for effective therapies that may reshape treatment and increase survival. With the advent of new-generation sequencing, many new biomarkers across several cancer types have been identified that may allow for better precision medicine. In a contemporary review, investigators focused on analyzing these biomarkers and summarizing the key clinical implications they may have in the treatment and prognosis of CRC.

Investigators have been aware of the predictive and prognostic values of RAS for some time now. Mutations in the KRAS gene result in a loss of response to EGFR inhibitors and have been an independent predictor for worse overall survival in patients undergoing mastectomy in hepatic disease. The prevalence of the KRAS mutation is approximately 40% in patients with mCRC, and the National Comprehensive Cancer Network recommends extended RAS genomic testing to identify potential treatment options.

Mutations in BRAF, MEK, and HER2 have also started receiving attention as potential predictive biomarkers. Patients with BRAF-mutated melanoma have been treated successfully with BRAF inhibitors (eg, dabrafenib); however, for patients with BRAF-mutated mCRC, BRAF inhibitors have induced very poor response rates. The predictive value of HER2 and MEK has yet to be determined, and multiple trials have begun targeting these patient subgroups. For MEK involvement, triple therapy with a BRAF inhibitor, a MEK inhibitor (eg, trametinib), and an EGFR inhibitor has shown to have improved clinical response, whereas patients with CRC and HER2 amplification may benefit from dual HER2 inhibition.

Other potential biomarkers of interest in CRC include microsatellite instability (MSI)/deficient mismatch repair (dMMR), PIK3CA, tumor-infiltrating lymphocytes (TILs), and POLE. dMMR has been shown to increase the response for immunotherapy. In patients with dMMR or high MSI, investigators have observed higher response rates and disease control. Two PD-1 inhibitors, pembrolizumab and nivolumab, are both FDA approved for use in dMMR/MSI-high–expressing mCRC. PIK3CA, TIL, and POLE are all biomarkers for CRC that have no current treatment recommendations. For TIL, results of some studies have indicated that a higher quantity of lymphocytes leads to improved prognosis. Patients with POLE mutation may have a greater immunotherapeutic response, and PIK3CA has also demonstrated predictive value when aspirin use post surgery led to better outcomes.

Germline pharmacogenomic biomarkers that are drug targets have also been investigated for potential predictive and/or prognostic value. Polymorphisms of DPYD, TYMS, and MTHFR that result in reduced activity or expression may increase the toxicity of 5-FU. Polymorphisms of UGT1A1 that reduce activity significantly increased the risk of irinotecan-related toxicity. Other enzymes such as ERCC, a nucleotide excision repair enzyme, may cause tumors to be more sensitive to platinum therapies, and reduced expression of VEGFA may improve bevacizumab response.

Prognostic and predictive biomarkers are a prominent part of advancing personized therapy. As these biomarkers are evaluated in larger studies, their uses may reshape the treatment regimens and processes in CRC.

Reference

Patel JN, Fong MK, Jagosky M. Colorectal cancer biomarkers in the era of personalized medicine. J Pers Med. 2019;9(1):E3. doi: 10.3390/jpm9010003.

 
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