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Perspectives in Targeted Therapy for Colon Cancer with Scott Paulson, MD
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Perspectives in Targeted Therapy for Colon Cancer with Scott Paulson, MD

AJMC®: Regarding left-sided versus right-sided tumors, 1 piece of data comes from a subanalysis of the CRYSTAL study, in which patients with left-sided tumors had much better response than patients with right-sided tumors. What are some possible reasons for that, and what does that say about targeting and subgrouping patients more precisely than current practice?

Paulson: You have to pay attention to it. What does it mean on a molecular level, is the key question, in my opinion. There are people who are working hard to answer those questions for us, thankfully. I think it’s an important distinction to look at, and what it tells you is that right-sided tumors just genetically tend to have more of a bad actor behind them. This does affect the sequencing of an EGFR inhibitor. It’s already a questionable piece to move immediately into the front line, and I think it’s much tougher to start off a completely wild-type patient with an EGFR inhibitor for their right-sided tumor. It’s important when making these decisions. I’d be much more interested to know what’s happening with those patients on a molecular level. Patients with left-sided tumors do exceptionally well on EGFR inhibitors. Why are they so susceptible to that? Those are the questions we want to answer. You can still have genetically right-sided tumors that appear on the left side of the colon, and vice versa. You can’t always define the tumor by drawing a line down the middle of the colon, although there is certainly a marked statistical difference.
 
AJMC®: What is the role of KRAS testing, and how early can you test a patient for KRAS so that targeted therapy can be used as soon as possible?

Paulson: I’m glad you brought that up, because I think that the landscape is continuing to change. In terms of pathology, it quite explicitly states that as soon as they have a patient’s tissue and see that it has metastatic colon cancer, the pathologist is essentially empowered to reflexively test those against an appropriate metric, such as KRASNRAS, and BRAF. The final step would be to test for microsatellite instability (MSI), because we want to try to get that information into the hands of oncologists as quickly as we can. 

MSI testing is another important piece to therapy. Those results should be considered by oncologists as they contemplate chemotherapy. It’s gotten fast enough now where you can often get those results in a timeframe that’s effective, where the patient doesn’t need to start treatment. So, if someone is profoundly systematic and has a large burden of disease that needs to start chemotherapy right away, sometimes the oncologist can’t necessarily sit back and wait for those test results or collect test results on tumor tissue that was collected too long ago, or repeat a biopsy. Sometimes you have to make the decision based on the information you have on hand. However, for the most part, our pathologists have been very engaged in that, and we’re trying to encourage our pathology departments around our state [Texas] to also be engaged on that, because knowing your RAS status, knowing your BRAF status, and knowing the microsatellite instability status and mismatch repair protein testing of your particular tumor, is critical for how you look at the global treatment of that patient. 
 
AJMC®: What are some important takeaways with regard to microsatellite instability status, and what does it affect, in terms of treatment decisions?

Paulson: For now, it is evidenced by the FDA’s approval of the use of pembrolizumab for any microsatellite-unstable cancer, which very closely follows the rapid approval in colon cancer based on a handful of patients, that if you use these drugs in MSI-high patients, they can be complete game changers.

Another important implication is that there’s a large national study currently going on for front-line MSI-high patients. The accrual in the United States has been difficult, in that most oncologists are very comfortable starting those patients on a front-line chemotherapy regimen, rather than looking at a randomized study for them. And so, there are some implications, and they’re important to look at, and it’s certainly exceptionally important to know the long-term status, even if you don’t decide to try to enroll the patient in the trial in the front line. This is because it opens up more immunotherapy options for these patients, whereas, otherwise, they would not have an option. 
 


 
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