Liquid biopsy improves detection of targetable mutations in non-small cell lung cancer - Healio

Erica L. Carpenter

The addition of plasma next-generation sequencing to solid tissue biopsy improved detection of therapeutically targetable mutations in patients with stage IV non-small cell lung cancer, according to results of a prospective cohort study.

“This study looked at real-world, in-clinic applicability of plasma next-generation sequencing,” Erica L. Carpenter, MBA, PhD, research assistant professor of medicine at Perelman School of Medicine at University of Pennsylvania and director of the Abramson Cancer Center’s Circulating Tumor Material Center, told HemOnc Today. “Ordering plasma next-generation sequencing almost doubled the yield of targetable mutations that were detected by tissue next-generation sequencing alone.”

The study included 323 patients (60.1% women; median age, 65 years, range, 33-93) with metastatic NSCLC who underwent plasma next-generation sequencing using a 73-gene commercial platform (Guardant360, Guardant Health). The researchers assessed 166 patients at initial diagnosis and 157 upon disease progression, according to Carpenter. The majority of the patients (85.4%) had adenocarcinoma.

“Fifteen patients with squamous histology were included based on physician ordering preference,” Carpenter said.

More than one-third of the patients (35%) had targetable mutations in EGFR, ALK, MET, BRCA1, ROS1, RET, ERBB2 or BRAF.

Tissue next-generation sequencing was not possible for 31% (n = 101) of the patients, either due to insufficient DNA quality or quantity (n = 79) or because tissue biopsy was considered unsafe or not technically feasible (n = 22). Another 94 patients (29.1%) underwent liquid biopsy alone, either due to the physician’s recommendation or patient’s preference.

Median follow-up was 7 months (range, 1-21).

Among those who underwent both types of next-generation sequencing or were unable to have tissue sequencing (n = 229), therapeutically targetable mutations were found in 47 patients (20.5%) with tissue biopsy alone and 82 patients (35.8%) with the addition of liquid biopsy.

Liquid biopsy detected targetable mutations in one-third of patients (n = 33) who opted for that test alone.

“Importantly, when we measured the response to therapy for patients treated based on the plasma result alone, the overall response rate to targeted therapy was 86%,” Carpenter said. Those included complete or partial responses or stable disease.

Other findings showed no correlation between plasma-based targeted mutation allelic fraction and depth of Response Evaluation Criteria in Solid Tumors response (r = –0.121).

“As recently as 3 or 4 years ago, the mutations found in plasma but not in matched tissue would have been considered false positives,” Carpenter said. “We now know that they can be clinically actionable. While a tissue biopsy remains essential for initial cancer diagnosis, in the setting of inadequate tissue DNA for next-generation sequencing, our results show that plasma next-generation sequencing can be an adequate surrogate for molecular profiling. Our results add to the evidence that plasma next-generation sequencing is specific, so that if a mutation is found, it should be acted upon — leading to a real-time clinical implication of plasma NGS.”

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Aggarwal added that patients with limited disease burden do not have adequate shed DNA.

“We acknowledge that our study was conducted among physicians who were comfortable ordering and interpreting the plasma next-generation sequencing assay,” she said. “This user experience bias probably enriched for a population of patients likely to have targetable mutations. But, this is also a real-world clinical experience in more than 300 patients, where about a third of the patients did not undergo tissue biopsy due to patient or provider preference, so there is real value there.”

Additional study on whether next-generation sequencing is ready for routine clinical use is warranted, Bishal Gyawali, MD, PhD, of Brigham and Women’s Hospital and Harvard Medical School, and Howard (Jack) West, MD, of the Swedish Cancer Institute in Seattle, wrote in an accompanying editorial.

“While broad genomic testing is appropriate when the pretest probability of identifying a clinically relevant target with effective biomarker-driven therapy is sufficiently high, the relative ease of plasma next-generation sequencing should not lower our threshold to perform next-generation sequencing as a flailing effort to find ‘some hope’ in settings in which relevant targets with associated therapies are very uncommon,” they wrote. “A shotgun approach may be appropriate if there is a sufficient chance of hitting a target suspected to be there, but we do not know exactly where; however, there are more accurate and precise weapons if we have a better idea where the true target is. If not, and if there is little reason to expect the existence of a

real target, merely having a readily available shotgun should not lead us to shoot blindly in the dark without acknowledging that we may do unexpected damage.” – by Rob Volansky

For more information:

Erica L. Carpenter, MBA, PhD, can be reached at Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, 8-104 South Pavilion, 8th Floor, 3400 Civic Center Blvd., Philadelphia, PA 19104; email: erical@upenn.edu.

Disclosures: Carpenter reports honoraria from Imedex; research funding from Janssen Pharmaceuticals and Merck; a patent, royalties or intellectual property interest from Children’s Hospital of Philadelphia; and travel, accommodations or expenses from VPS Hospitals in United Arab Emirates. Please see the study for all other authors’ relevant financial disclosures. Gyawali reports that his work at PORTAL is funded by a grant from the Laura and John Arnold Foundation. West reports no relevant financial disclosures.

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