Looking for Zebras in Metastatic Colorectal Cancer

Christina T. Loguidice
Published: Friday, Jan 04, 2019
John L. Marshall, MD

John L. Marshall, MD

When you hear hoofbeats, think of horses not zebras.” The idea behind this medical adage is that horses are more common than zebras, so if you hear hoofbeats, they are much more likely to come from a horse than a zebra. However, colorectal cancer (CRC) requires more careful analysis. Although it’s one of the most commonly diagnosed cancers in the United States,1 and researchers’ understanding of the biology and pathophysiology of CRC has grown, its many variations require that each case be diagnosed with care.

During a recent OncLive Peer Exchange®, a panel of CRC experts discussed the heterogeneity of metastatic CRC (mCRC) and the need to identify patient subsets within this disease to enable a precision medicine approach. They also shared their insights on some immunotherapies that are in development.

Importance of Next-Generation Sequencing

Next-generation sequencing (NGS) has revolutionized cancer care, enabling researchers to better understand the complicated molecular mechanisms of oncogenesis and identify treatment targets to improve patient care and outcomes. Yet not all patients with mCRC are receiving NGS.

“I see lots of patients with colon cancer with zero molecular testing when we start out,” John L. Marshall, MD, said. In recent years, researchers have identified several mutations in patients with mCRC that can help with prognostication and guide treatment decision making, which makes these tests essential to optimizing care.

“I think, off the bat, you should have patients’ RAS status—KRAS and NRAS. You should probably know their RAF status up front—BRAF. We should definitely know their MSI [microsatellite instability] status,” panelist Bert H. O’Neil, MD, said. The panelists suggested that large CRC centers are increasingly moving toward earlier testing with comprehensive panels that assess for these and other genomic alterations, rather than using a variety of tests throughout the treatment course to assess for defects in a single gene or small set of genes.

A comprehensive panel mentioned was the FoundationOne CDx, which evaluates all guideline-recommended genes in solid tumors and provides information on MSI status and tumor mutational burden.2 A 2017 study coauthored by panelist Marwan G. Fakih, MD, puts in perspective how comprehensive genomic testing can uncover not only well-characterized alterations, which were mentioned by O’Neil, but also rarer alterations that might open the door to new treatment approaches for smaller subsets of patients with mCRC, some of whom might have few treatment options.3 For example, although ERBB2 (HER2)-amplified tumors, which do not respond to EGFR antagonists, were identified in only 5.1% of the 138 patients included in Fakih’s single-institution study, those patients could now be considered for HER2-directed treatments, the viability of which was demonstrated by the HERACLES trial results.3,4 In HERACLES, 10 of 33 patients (30.3%) with HER2-amplified, treatment-refractory mCRC achieved an objective response with dual HER2 blockade (trastuzumab [Herceptin] plus lapatinib [Tykerb]), with 2 patients achieving complete responses (CRs).4 At the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, the HERACLES investigators recommended a cutoff of 3 copies of ERBB2 in plasma to select patients who are most likely to benefit from HER2 blockade.5

Of all known actionable mutations in mCRC, RAS is the most common. In Fakih’s study, it was present in 51.4% of the patients.3 In contrast, RAF mutations were significantly less common, observed in 7.2% of patients. The frequencies of both mutations were reported to be concordant with those historically reported in mCRC.3 During the Peer Exchange, the panel noted that RAS and RAF mutations are associated with resistance to anti-EGFR therapies; thus, these treatments should be avoided in these patients. However, because it can take 10 to 14 days to receive NGS results, the panel also discussed how to proceed with treatment before a patient’s RAS and RAF statuses are known.


View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: 2nd Annual International Congress on Oncology Pathology™Aug 31, 20191.5
Community Practice Connections™: 2nd Annual School of Nursing Oncology™Sep 28, 20191.5
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