Perspective from Jeffrey D. Bradley, MD
March 17, 2017
3 min read

Multiple biopsies may help identify, treat resistance in NSCLC

Perspective from Jeffrey D. Bradley, MD
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More than one in five patients with non–small cell lung cancer develop various types of genetic resistance during treatment and could benefit from additional biopsies to alter treatment, according to a study presented at the Multidisciplinary Thoracic Cancers Symposium.

“Although treatments initially yield high responses, resistance typically develops after about 9 to 13 months of treatment,” Zofia Piotrowska, MD, a thoracic oncologist at Massachusetts General Hospital Cancer Center, said during a press briefing. “As much as half the time, the dominant resistance mechanisms observed on one biopsy may no longer be relevant on a second biopsy, and a second biopsy may uncover a new potentially targetable resistance mechanism.”

Zofia Piotrowska

As many as 30% of NSCLC cases are driven by mutations in the epidermal growth factor receptor gene, and patients typically are treated with drugs that inhibit activation of the gene. However, nearly all tumors eventually develop resistance to therapeutic agents. A tumor biopsy identifies specific secondary mutations in patients; however, further biopsies are not routinely obtained during the course of treatment.

“We hope that these findings will prompt clinicians to consider repeat biopsies when selecting a new therapy for patients with EFGR–mutant lung cancer,” Piotrowska said. “We now feel that this binary positive–negative classification may underestimate the true heterogeneity of resistance cancers and, in fact, in some cases, may prevent patients from accessing potentially effective treatment strategies.”

Piotrowska and colleagues retrospectively analyzed 355 biopsies of NSCLC tumors obtained from 221 patients (69% women; median age, 59 years; range, 28-88) from 2008 to 2016 who had EGFR exon 19 deletion (64%), L858R (33%) or other activating mutations (3%).

After patients showed resistance to first-line EGFR inhibitor therapy, researchers examined tumor samples for various genetic causes of resistance, including T790M, the most common secondary mutation.

All patients received at least one biopsy at first resistance to EGFR inhibitors.

Nineteen percent of the biopsies showed more than one resistance mechanism simultaneously. As expected, the T790M mutation was found in 61% of patients. Further, 18% of patients had EGFR amplification, 5% had amplification of the MET gene, 3% transformed from NSCLC to small cell disease, 2% acquired PIK3CA mutations and 1% acquired BRAF mutations.

Overall, 37% of patients (n = 83) underwent two subsequent biopsies during treatment after developing EGFR resistance. Resistance mechanisms varied between biopsies for 49% of these patients, including 20% who gained the T790M mutation and 11% who lost it. Three of the 17 patients who lost T790M demonstrated a new resistance mechanism on the second biopsy.


Researchers also evaluated the safety and feasibility of multiple biopsies. Two of 307 biopsies (0.7%) resulted in clinically significant complications. Additionally, 13% (n = 28) of patients were able to undergo three or more postresistance biopsies.

“We were surprised to find that, among these 83 patients [who underwent two post-resistance biopsies], nearly half had variations in their resistance mechanisms observed between biopsies one and two,” Piotrowska said. “Of 17 patients who lost T790M between biopsy one and two, three were found to have a new resistance mechanism on second biopsy.”

Piotrowska described the heterogeneity of tumor resistance as “quite complex” and noted further study is needed for researchers to fully understand the various time points of resistance.

“Clearly, the idea that things are static and that one dominant resistance mechanism is at play is probably oversimplifying reality, and we need to learn much more,” Piotrowska said. “The heterogeneity of resistance cancer likely has many different components. On a practical level, for clinicians, when a patient is treated with a first-line EGFR inhibitor and the tumor progresses, there are many different technologies now. I’ve heard many clinicians say they reach first for a liquid biopsy to look for T790M because in the current era that’s where we have an FDA–approved second-line targeted therapy available.” – by Chuck Gormley


Piotrowska Z, et al. Abstract 1. Presented at: Multidisciplinary Thoracic Cancers Symposium; March 16-18, San Francisco.

Disclosure: Piotrowska reports consultant roles with AstraZeneca and Boehringer Ingelheim. Please see the abstract for a list of all other researchers’ relevant financial disclosures.