Molecular Characterization Plays Vital Role in Selecting Optimal Colon Cancer Treatment

Al B. Benson III, MD, FACP, FASCO

For patients with metastatic or advanced colorectal cancer (CRC), there are multiple treatment options available; however, every patient needs to be considered carefully to select the optimal sequential treatment regimen.

Some of the factors that need to be considered for each patient include their treatment preference, tumor characteristics, and the molecular profile of their tumor. DeterminingRAS,BRAF, microsatellite instability (MSI), andHER2status of each tumor can play an important role in selecting the best treatment option.

For example, patients who areBRAF-mutant do not respond as well to anti-EGFR drugs alone. This patient population, particularly those with aBRAFV600E mutation, can have a worse prognosis, but can be treated with FOLFIRINOX [folinic acid, fluorouracil (5-FU), irinotecan, and oxaliplatin] plus bevacizumab (Avastin). Other research supports the use of a BRAF inhibitor in combination with an anti-EGFR agent and irinotecan (Camptosar).

“We are still not curing the majority of patients. I think molecular characterization, for example, is a step forward, but there is stillmuch more work ahead of us to better select patients for treatment strategies,” said Al B. Benson III, MD, FACP, FASCO.

There are currently several ongoing trials looking at treatment options for patients withHER2mutations. In order to fully optimize these treatment strategies, however, patients need to participate in clinical trials, Benson said.

In an interview withTargeted Oncology,Benson, professor of medicine at Northwestern University, discussed the treatment landscape for advanced and metastatic CRC (mCRC) and how molecular profiling can play a vital role in selecting the optimal treatment plan for each patient. He also emphasized the importance of participation in clinical trials to further understand these patients.

TARGETED ONCOLOGY:Can you start with a general overview of the treatment landscape for advanced CRC?

Benson:I think what’s important to emphasize about treatment for advanced CRC is we now have multiple aspects to consider for each individual patient. That includes patient characteristics including comorbidities, for example. It [also] includes molecular characteristics now, and it’s critical that for each patient we understand theirRASstatus,BRAFstatus, [and] MSI status. We are also exploringHER2status, and there are ongoing trials that targetHER2for patients with mCRC.

We also need to understand the tumor characteristics, as well as patient preference in making decisions. Now we have multiple opportunities for treatment over time and it’s critical to look at what is an optimal treatment sequence for individual patients. What is informative in making these choices includes factors such as right versus left CRC location. The location of the tumor is based on important molecular characteristics. For example, for right-sided CRC location, we see more individuals withBRAFand MSI tumors, and that’s important to determine what might be an optimal treatment strategy.

For example, with theBRAFpatients, that particular molecular profile in terms of theBRAFV600E mutation carries the worst prognosis, so that has to be considered in making the treatment choice. We also feel that anti-EGFR therapies don’t work as well for that population. An initial consideration for aBRAFpatient would be FOLFOXIRI with bevacizumab, but there are also data that show that combination therapies with BRAF inhibitors, anti-EGFR drugs, and irinotecan can provide benefit for these patients. There is also work looking at combinations with anti-EGFR therapy, MEK inhibitors, as well as BRAF inhibitors. These are examples of considerations for that population.

With the increasing evidence for immunotherapy, it’s very important to check the MSI status, because these are the individuals who can respond to a single-agent drug, such as nivolumab (Opdivo) [or] pembrolizumab (Keytruda); but there are also recent data showing that a combination, for example, with nivolumab and ipilimumab (Yervoy), in patients may have further benefit. Looking at these molecular characteristics and thinking about sequential therapy is increasingly important.

TARGETED ONCOLOGY:Are there any data that has come out recently that is particularly interesting in the field?

Benson:In terms of recent data, what I mentioned aboutBRAF,and, in fact, these combinations have now been included in the NCCN guidelines. The information with MSI patients and combination immunotherapy are important data. There have been data, for example, for theHER2population. Of course, that is a small group of patients, but there are data supporting the use oftrastuzumabcombinations that can benefit that population and there are ongoing clinical trials to address this group of patients. I think it is very important that people participate in these trials so we can generate confirmatory data with the hope that aHER2strategy, just as we currently use for gastric cancer and breast cancer, be included as a standard approach for theHER2mCRC patient.

There’s also work looking at cell-free DNA (cfDNA). The presence of cfDNA, for example, for patients who have had complete resection of colon tumors may indicate that that individual has a higher risk of recurrence. There are proposals now looking, for example, with the stage II patient, analysis of cfDNA such that those individuals might be randomized to chemotherapy to determine if chemotherapy may actually reduce recurrence for those individuals. This is an important area also looking at cfDNA for mCRC patients to see if there is a benefit with looking at particular treatment strategies.

TARGETED ONCOLOGY:What are some of the unmet needs that still exist in this patient population?

Benson:There remain many unmet challenges here. We are still not curing the majority of patients. I think molecular characterization, for example, is a step forward, but there is stillmuch more work ahead of us to better select patients for treatment strategies. Also [we need] to look at these molecular characteristics to see if we can develop specific treatment strategies with, for example, new drugs we don’t currently have available that might better improve outcome for patients. There is no question that there is an array of immunotherapy strategies with the introduction of targeted treatments, and for select patients, the use of immunotherapy is improving outcomes; it’s just we have much more work ahead of us.

This is exactly why we need to encourage participation in clinical trials, because not only are we looking at treatment strategies, but also the collection of tissue and analysis to, we hope, further our opportunities to better understand treatment biology and to introduce new treatment strategies.

TARGETED ONCOLOGY:What advice would you give to a community oncologist treating mCRC?

Benson:What’s critical is to look carefully at characteristics I mentioned. That includes patient preference, patient characteristics, molecular characteristics, and tumor characteristics to define an optimal sequential treatment approach for each individual patient. There is growing evidence that if you look carefully at these characteristics and you integrate sequential approach, you’re going to have the best opportunity to benefit each individual patient.

Also, I would strongly encourage participation in clinical trials because, as I mentioned, that will give us the best opportunity to further advance the field. After all, all of these advances we have currently made have been because of participation in the clinical trials. We’ve had many [advances in] chemotherapy combinations, the introduction of targeted therapies, and certainly the advances that have been made in terms of immunotherapy.