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Management of Metastatic CRC Rooted in Molecular Subsets

Caroline Seymour
Published: Tuesday, Mar 05, 2019

John L. Marshall, MD
John L. Marshall, MD
Treating patients with newly diagnosed metastatic colorectal cancer (mCRC) requires great foresight, explained John L. Marshall, MD.

“The oncologist is the quarterback of the team and makes the decisions, so the oncologist has to know all the plays in the playbook and know when to call the right play,” said Marshall.

Some of those “plays” include the use of molecular profiling at diagnosis to establish the tumor origin and the presence or absence of microsatellite instability (MSI) and alterations in RAS, BRAF, HER2, and NTRK.

Based on these results, physicians can then cultivate an appropriate treatment plan for their patients. For example, if a patient has left-sided RAS wild-type/BRAF wild-type CRC, physicians should opt for an EGFR-directed therapy as it has shown a clear survival benefit in that subset of patients. Moreover, if a patient has a MSI-high (MSI-H) tumor, he/she may benefit from immunotherapy.

Although HER2 amplification has not been as potent of a target as some of the other established alterations, preliminary data with trastuzumab (Herceptin) and lapatinib (Tykerb) have shown potential, and, as such, warrant its incorporation into broad molecular panels.

The oncologist may lead the team, but multidisciplinary management will ensure that the best outcomes are delivered to patients, according to Marshall.

“New discoveries in other diseases and in gastrointestinal cancers will help push the bar forward, as well as the increased recognition that the optimum management of colon cancer—particularly stage IV colon cancer—is a multidisciplinary team sport,” he said.

In an interview during the 2019 OncLive® State of the Science Summit™ on Gastrointestinal Cancers, Marshall, chief, Division of Hematology/Oncology, Medstar Georgetown University Hospital director, Otto J. Ruesch Center for the Cure of Gastrointestinal Cancer, Georgetown-Lombardi Comprehensive Cancer Center, discussed the current and future scope of mCRC.

OncLive: What is the importance of molecular profiling in patients with newly diagnosed mCRC?

Marshall: Molecular profiling is critical in frontline metastatic colon cancer. You need to know that right from the beginning. You have to know MSI, RAS, BRAF, HER2, and NTRK. Most physicians are doing broad molecular profiling. [In my presentation tonight], I also made the point of [differentiating between] left- versus right-sided tumors. In right-sided colon cancer, EGFR therapies don't seem to work as well. In left-sided colon cancers, it’s really important to know all of the molecular testing. If your patient is in that left-sided RAS wild-type, BRAF wild-type group, there are retrospective data looking at EGFR-targeted therapy. In that 20% of patients, the data suggest that there may be a benefit to using those drugs in that space. In the rest of patients, it probably doesn't matter. You can give everyone FOLFOX and bevacizumab (Avastin), but in that group you need to think twice about EGFR therapy.

Should HER2 amplification be accounted for on molecular profiling panels?

HER2 is a critical thing to look for in CRC, and how one measures it probably matters. Certainly, the higher the gene amplification, the more responsive [the patient will be to therapy]. Most physicians use immunohistochemistry. Those patients with high [HER2] expression seem to be the ones who benefit.

Let's face it: this is not as potent of a target as it is in breast cancer, where it totally transforms the disease. It helps. It's generally a refractory question, not one you would bring into first- or second-line settings—at least in today's world. [We’re] trying to take these subsets of patients and [add more data to the mix]. Some of the data with trastuzumab and lapatinib look promising. If you don't look, you won't find [these alterations]. Most people would say it's somewhere around 3% to 5% of patients with colon cancer who have HER2 expression. You have to look for it.

What has been the impact of immunotherapy in patients with MSI-H as well as microsatellite stable tumors?

You have to know the MSI status of every patient with colon cancer, regardless of stage. Most of us test this using immunohistochemistry first, but you can do this with next-generation testing. Tumor mutational burden helps confirm that. You need that signal in colon cancer for immunotherapy to even be in play. It's not common, so you have to keep looking to find it. Most of your patients will not have that.

View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Oncology Briefings™: Individualizing Treatment After Second-Line Therapy for Patients With mCRCAug 29, 20191.0
Community Practice Connections™: Navigating New Sequencing Challenges for the Treatment of Hepatocellular CarcinomaAug 30, 20191.5
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