1. Samson, Kurt

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SAN FRANCISCO-Acquired genetic mutations in treatment-resistant non-small cell lung cancer (NSCLC) can fluctuate with time, and multiple changes can occur simultaneously, according to a study presented at the 2017 Multidisciplinary Thoracic Cancers Symposium (Abstract 1).

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Investigators at Massachusetts General Hospital (MGH) Cancer Center, Boston, found that in almost half of the patients they studied the dominant resistance mutation on first biopsy was no longer pertinent on second biopsy. Moreover, new and potentially targetable resistance mechanisms were found on second biopsy.


"Our data suggests that heterogeneity plays a key role in the evolution of acquired resistance over time, and assumptions based on prior biopsies may not hold after subsequent therapies. Therefore, repeat biopsies should be considered to guide treatment," lead author Zofia Piotrowska, MD, a thoracic oncologist at MGH, told a press briefing.


"Until recently, resistance mechanisms were usually thought of as static, but the study demonstrates that a binary designation of resistance may oversimplify cancer's true biology. These genetic mutations can fluctuate over time, and some patients can harbor more than one mutation," she explained. "As a field, we need to know how to take this and integrate it into practice."


The retrospective study was based on analysis of 335 biopsied tumors from 223 patients with acquired resistance to epidermal growth factor receptor (EGFR) inhibitors-the most common targeted therapy for NSCLC. The investigators found that nearly one in five patients had more than one type of resistance mutation.


Between 10 percent and 30 percent of NSCLC cases are driven by mutations in the EGFR gene, Piotrowska noted. Such patients are typically treated with drugs to inhibit activation of the gene, but most tumors eventually develop resistance to the inhibitors.


Patients who acquire resistance usually undergo a tumor biopsy and are designated as being either positive or negative for specific secondary mutations, but recent studies indicate resistance in EGFR can make permanent designations based on a single biopsy insufficient.


"In an era where cancer treatment is increasingly personalized to the biology of each individual patient, our findings highlight the importance of molecular testing, and the need for improved, noninvasive methods for serial testing," she explained. "The picture is quite complex and needs more study."


Examining Genetic Mutations

Piotrowska and her colleagues retrospectively evaluated at least one biopsy per patient taken at first sign of resistance. They searched for several different genetic mutations, including T790M, the most common secondary mutation in NSCLC. T790M results in an amino acid substitution and is present in about half of patients with EGFR-resistance.


Simultaneous resistance mechanisms were discovered in almost 19 percent of the patients including the T790M mutation, which was found in 61 percent of patients.


Eighty-three patients (37%) underwent two biopsies and, in 49 percent of these, mutations varied between biopsies. Changes included both gain and loss of the T790M mutation (20% and 11% of patients, respectively). In addition, three patients had a new resistance mechanism on the second biopsy.


Between one and four biopsies were evaluated for each patient. 18 percent of patients had EGFR amplification, 2 percent acquired PIK3CA mutations, 5 percent had amplification of the MET gene, 3 percent had non-small cell cancer transformed into small cell disease, and 1 percent acquired BRAF mutations.


The rate of complications was low, Piotrowska noted, with just two in 304 biopsies resulting in a clinically-significant complication.


"We hope that these findings will prompt clinicians to consider rebiopsy when selecting a new therapy," she said. "While we observed that biopsies were generally safe and feasible, noninvasive testing methods, such as liquid biopsies that analyze tumor DNA circulating in the patient's blood, may provide another method to more easily characterize resistance over time."


Practice Implications

The biggest message from the study is that cancer is very heterogeneous, especially lung cancer, said briefing moderator Ravi Salgia, MD, PhD, Professor and Chair of Medical Oncology and Therapeutics Research at City of Hope Comprehensive Cancer Center, in Duarte, Calif.


"We can see how complex resistance has become," he told Oncology Times. "In the old days, there was chemoradiation, but with targeted therapies there are different mechanisms involved and that there are changes with changes in therapy as well as temporal and spacial considerations that come into play with acquired resistance mutations."


Testing for changes in mutations as resistance develops can be done today with additional biopsies, but as the study indicates, one biopsy is often not enough, Salgia noted. "This recognition is part of the ongoing paradigm shift toward precision therapeutics as we move toward a common standard of treatment."


It is also important to remember immunotherapy only works in a subset of these patients, he said. "Today. we can use targeted immunotherapy in around 20 percent, but that means that for 80 percent have to use a different strategy," he concluded.


Kurt Samson is a contributing writer.