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Certain BRAF Mutations May Indicate Tumors More Likely to Respond to Anti-EGFR Therapy

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NEW YORK – Cancer patients with certain BRAF mutations might be more likely to respond to anti-EGFR therapy, potentially allowing clinicians to more precisely target their tumors.

Scientists have recently grouped BRAF mutations into three classes, each of which may be susceptible to different treatment approaches, though researchers are still investigating.

Researchers from the US and Japan conducted a retrospective analysis of metastatic colorectal cancer patients with non-V600 BRAF mutations who had received anti-EGFR antibody treatment. Between 22 percent and 30 percent of BRAF mutations in colorectal cancer are non-V600 mutations.

As they reported in Clinical Cancer Research this month, Memorial Sloan Kettering Cancer Center's Rona Yaeger and her colleagues found that 78 percent of patients with a certain kind of non-V600 BRAF mutation responded to anti-EGFR therapy in a first- or second-line setting, while patients with another type of non-V600 BRAF mutation were less likely to respond.

"We see that not every mutation is the same, not every mutation in BRAF is the same," Yaeger, the first author of the study and a medical oncologist at MSKCC, said. "And so that can have therapeutic differences."

Colorectal cancer isn't the only cancer in which BRAF mutations occur. They also crop up in, for instance, in lung cancer and melanoma. These findings from Yaeger and her colleagues suggest that anti-EGFR therapy could possibly work in those instances as well, but more data is needed.

Only recently have researchers begun to explore these non-V600 BRAF mutations. As David Santamaría, a group leader at European Institute of Chemistry and Biology, noted, that was due to a focus on the activating V600E BRAF mutations that are common in melanoma. Many custom panels used in the clinic to genotype patients did not even consider these non-V600 mutants, he added.

But work within the past few years has pointed to the existence of three classes of BRAF mutations. Class 1 mutations consist of those BRAF V600 mutations that are independent of upstream RAS and signal as monomers.

Classes 2 and 3 encompass the non-BRAF V600 mutations. Class 2 includes activating mutations that are RAS independent, as they dimerize and signal without RAS activation. And, even though class 3 mutations are inactivating mutations, they activate the MAPK pathway through increased RAS binding and RAS-dependent CRAF activation.

Current RAF inhibitors target BRAF monomers, like those in class 1 tumors, but not dimers, like those in class 2 and 3 tumors. It's been suspected that these classes of tumors might instead be susceptible to other treatment approaches, such as MEK inhibition, or for class 3 a receptor tyrosine kinase inhibitor — like an EGFR inhibitor — since it needs RTK-dependent RAS signaling.

But, it's been unclear whether that is the case. In 2017, researchers conducting the Biomarker Research for anti-EGFR monoclonal Antibodies by Comprehensive Cancer genomics (BREAC) study reported in the British Journal of Cancer that patients with metastatic colorectal cancer with non-V600 BRAF mutations had a low response rate to EGFR-based treatment. But, as April Rose, a medical oncology resident at the University of Toronto, noted, the BREAC study didn't sub-classify the non-V600 BRAF mutations into class 2 or class 3 mutations.

Clinicians who see non-V600 BRAF mutations are "like, 'Oh, is this the same as V600? Is it different?'" Yaeger said. "And so that's part of a point here to say, 'Well, let's see. Does it matter?'"

What mutations mean

In their new study, Yaeger and her colleagues amassed data on metastatic colorectal cancer patients with non-V600 BRAF mutations from the US and Japan. They had noted in patient-derived xenograft models of colorectal cancer that mice with tumors derived from patients with class 2 mutants were resistant to treatment with the EGFR inhibitor cetuximab (Eli Lilly's Erbitux), while two of the three mice with tumors from patients with class 3 mutations were responsive.

Through their search, they identified 153 metastatic colorectal patients with non-V600 BRAF mutations. In all, their cohort included 32 metastatic colorectal cancer patients with class 2 BRAF mutations, 72 with class 3 BRAF mutations, 13 uncharacterized ones, and one BRAF mutant with no effect on ERK signaling.

In their cohort, metastatic colorectal cancer patients with class 3 BRAF mutations had a much higher response rate to anti-EGFR therapy, 50 percent, than did patients with class 2 BRAF mutations, who had an 8 percent response rate.

"It's gratifying because [it's] a little bit of a proof of principle that they really are RTK driven," Yaeger said of the findings.

When they analyzed the data based on treatment line, Yaeger and her colleagues found that 78 percent of patients with class 3 BRAF mutations who received an anti-EGFR antibody treatment as a first- or second-line therapy responded to it.

That is a high response rate, Rose said. She noted that it is higher than what some clinical trials, such as the FIRE-3 study, have found for first-line therapies. "It is a pretty impressive response rate," she said, noting that it is especially so as the data includes second-line treatments. She cautioned, though, that it is based on a small sample size. Only nine patients with class 3 BRAF mutations received an anti-EGFR antibody treatment in a first- or second-line setting.

Yaeger and her colleagues also reported that one patient with a class 2 BRAF mutation responded to anti-EGFR treatment. This, Santamaría noted, is not expected based on the biology, and, especially as it is just one patient, could be the result of a mischaracterized mutation or another mutation in that patient's tumor that drives the effect. Rose similarly said the finding could even be because patients in the analysis were often given chemotherapy plus an EGFR inhibitor and the response could just be due to the chemotherapy.

Still, Yeager and her colleagues' findings hint that some patients might benefit from anti-EGFR treatments.

If a clinician has patients with non-V600 mutations — especially class 3 mutations — Rose said they might want to consider EGFR inhibitor therapy. "I think a good thing to take away from this paper for clinicians who are considering whether or not to add an EGFR inhibitor to, for example, chemotherapy or to give an EGFR inhibitor alone, there's no strong data suggesting that you should not," she said.

BRAF mutations crop up in other tumor types beyond colorectal cancer. They are also frequent in melanoma, non-small cell lung cancer, and some thyroid cancers. One estimate suggests that between half and 80 percent of BRAF mutations in non-small cell lung cancer are non-V600 mutations. One recent study even uncovered a class three BRAF mutation in a tumor that metastasized to the ovaries.

"In theory, any epithelial tumor might … benefit from having a class 3 BRAF mutant as a signal amplifier," Santamaría said.

Targeting these class 3 mutations is particularly intriguing for lung cancer, Rose said, as it typically has an active EGFR pathway. However, she pointed out that monoclonal anti-EGFR antibodies are not the standard of care for lung cancer, but that these findings could instead provide a preclinical rationale for exploring that treatment approach in a clinical trial.

"If I was treating a lung cancer patient who had a class 3 [BRAF mutation], I wouldn't offer an EGFR monoclonal antibody based on these data," she said. "But, certainly, I think it's hypothesis generating."

Even among the metastatic colorectal cancer patients in Yaeger and colleagues' study, not all of those with class 3 BRAF mutations responded to anti-EGFR therapy. That's what Yaeger is interested in digging into next.

"What else is going on? Are there other RTKs one can identify? Are there other strategies that we could use more broadly that would inhibit upstream signaling?" she asked. "The future for us is really thinking, 'Are there other things we can do to extend the responses?'"

Other clinical trials, such as one at Princess Margaret Cancer Center that Rose is part of, are also looking into ways to target these tumors. At Princess Margaret, researchers are examining whether melanoma patients with non-V600 BRAF mutations respond to a combination therapy of BRAF and MEK inhibitors. A similar study is also underway, led by Yaeger, at MSKCC.

For BRAF V600E mutations, the ANCHOR-CRC study, which includes investigators from the US and Europe, is evaluating whether metastatic colorectal cancer patients with those cancers respond to a triple combination of BRAF, MEK, and EGFR inhibitors.

Rose added that while that trial is focused on BRAF V600E mutated cancers, there is some evidence indicating that non-V600 BRAF mutated cancers might respond to BRAF and MEK inhibitors. She said it would be interesting to know if non-V600 BRAF mutated cancers are susceptible to that combination of BRAF, MEK, and EGFR inhibitors. The BIG BANG study out of Japan is currently examining this combination of BRAF, MEK, and EGFR inhibitors in metastatic colorectal cancer patients with non-V600 BRAF mutations.

"I think that will be very informative," Rose said.