Monitoring Resistance, Recurrence in NSCLC

Two presentations at the Multidisciplinary Thoracic Cancers Symposium in San Francisco, CA, March 16–18, indicate the importance of serial biopsies, whether tissue- or liquid-based, in monitoring patients with non–small cell lung cancer (NSCLC). One study analyzed acquired resistance among patients with EGFR-mutant disease; another explored using circulating tumor cells (CTC) to predict the recurrence of locally advanced NSCLC.

Zofia Piotrowska, MD, of Massachusetts General Hospital Cancer Center in Boston, and her colleagues retrospectively examined tissue biopsies from 221 patients, obtained after they stopped responding to first-line EGFR inhibitor therapy. Unsurprisingly, the T790M resistance mutation, typically the first to emerge in these patients, was found in 61% of them. “We also found that 1 in 5 patients harbored more than one resistance mechanism simultaneously,” Piotrowska said—for instance, PIK3CA alterations alongside MET amplification. In 3% of cases, histologic transformation to small cell lung cancer was observed.

Among 83 patients who had two biopsies, the investigators reported that 49% had different resistance mechanisms between the first and second evaluations. “Our findings point to the heterogeneity of acquired resistance to EGFR therapy, which may have been underestimated until now,” Piotrowska said. “As much as half of the time, the dominant mechanism observed in one biopsy may no longer be relevant in the second biopsy.” Serial tumor assessments—which this study determined to be generally safe and practicable, with clinically significant complications arising in only 0.7% of patients—are therefore warranted to guide individual treatment decisions, she added.

“Repeat biopsies are clearly feasible,” agreed Max Diehn, MD, PhD, of Stanford University School of Medicine in Stanford, CA. However, “noninvasive methods will be more readily applicable and likely more cost-effective.”

When it comes to using CTCs to monitor patients with locally advanced NSCLC, the data are still sparse, noted Chimbu Chinniah of the University of Pennsylvania's Perelman School of Medicine in Philadelphia. “Ours is the largest prospective study evaluating CTCs as a potential biomarker in this population,” he said—to date, the utility of liquid biopsies has mainly been assessed in metastatic NSCLC.

Chinniah and his colleagues enrolled 48 patients, all of whom received concurrent chemotherapy and radiation. Blood tests were done before, during, and after treatment, along with PET/CT imaging at 3-month intervals. Analyzing 15 patients whose disease recurred, the investigators noted that their CTC counts were initially negative following treatment, then rose in subsequent tests. In 10 cases, this increase was detectable an average of 6 months before radiographic evidence of recurrence.

The team's method to identify and count CTCs—a GFP-tagged adenoviral probe that binds to telomerase, high levels of which are found within cancer cells—“may be more sensitive and specific than other techniques that look at cell-surface markers,” Chinniah added.

Among patients with localized disease, “identifying recurrence is complicated by normal tissue changes caused by chemotherapy and radiation,” Diehn noted, so CTCs are potentially an improvement over tissue biopsy. Circulating tumor DNA analyses may be still more sensitive, he added, and “ultimately, clinical trials are needed to test if early treatment of recurrence, based on a blood assay, improves overall survival.” –Alissa Poh