CRC Biomarkers Exert Growing Influence on Prognosis and Treatment

Christina Loguidice
Published: Friday, Sep 02, 2016
John L. Marshall, MD

John L. Marshall, MD

Molecular testing for colorectal cancer continues to evolve at a rapid pace. Biomarkers already have the potential to predict outcomes and better target therapies, with the eventual goal to completely personalize treatments based on the patient’s individual biomarker profile and other tumor markers. However, knowing which molecular testing to perform or how to interpret the results can be challenging, particularly as new discoveries continue to be made.

During a recent OncLive Peer Exchange panel titled “Optimizing Systemic Therapy in Advanced Colorectal Cancer,” the panelists provided an overview of how they are using molecular markers in their practice to help with risk stratification and guide treatment. They also reviewed new advances in molecular testing and discussed the impact of tumor location (left- vs right-sided) on prognosis and treatment, the latter of which was a major finding unveiled at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting.

Defining the Essential Molecular Tests

With regard to molecular tests, “it seems every year the story changes,” said moderator John L. Marshall, MD, as he first addressed the panel. Based on currently available data, the panelists agreed that all patients with newly diagnosed metastatic colon cancer should receive KRAS, RAS (extended analysis), and BRAF testing and also be assessed for microsatellite instability (MSI). The panel suggested that upfront testing for HER2 could also be considered, but is not regarded as mandatory yet.

KRAS and RAS results

impact treatment decisions, and an extended RAS analysis should be performed even in the setting of KRAS wild-type tumors, the panel noted. “[With this testing], you’ll identify at least an additional 13% to 16% of extended RAS mutations that could impact your treatment despite being KRAS wild-type,” said Cathy Eng, MD. She recommended clinicians send out for extended RAS testing if their centers are not routinely performing it.

Cathy Eng, MD

Cathy Eng, MD

Although BRAF testing does not direct therapy, it should be assessed because it is a poor prognostic indicator. “The patient with a BRAF mutation probably has a survival of 1 year, or a little more,” said Daniel G. Haller, MD. However, many good clinical trials are ongoing for patients with BRAF-mutant metastatic colorectal cancer, offering hope to these patients, noted Eng.

  MSI testing assesses tumors for mutations in DNA mismatch repair genes, such as MLH1, MSH2, or MSH6, which cause repair errors in repetitive sequences and, subsequently, MSI of tumors. In the past, MSI testing was only done for stage II cancers to determine if patients would benefit from 5-fluorouracil (5-FU). “Now, in stage IV, we realize if patients’ MSI is high, they’ll benefit from a checkpoint inhibitor,” said Tara E. Seery, MD.

A major challenge with MSI testing is that its results are difficult to interpret, particularly because not all results are actionable. In January 2015, ASCO started tumor oncology boards ( to help clinicians get a better handle on tumor molecular profiling tests and studies, noted Haller, who is involved with the initiative.

HER2 testing for colon cancer is still largely experimental. Although it can be considered because a clinical trial will be investigating trastuzumab (Herceptin) for colorectal cancer, data on HER2 testing in this tumor type are not sufficient to give it high-priority status or to support repeat HER2 testing, as is currently the standard of care for breast cancer, noted Tanios Bekaii-Saab, MD. In contrast, Eng was more supportive of HER2 testing. “Less than 10% of patients are going to be HER2/neu positive, but I still think we need to educate people [since we’re now going to have trials for them],” she said.

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