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Wash U Reports Challenges and Successes in First NSCLC Patients to Receive Targeted Sequencing

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NEW YORK (GenomeWeb) — Researchers from Washington University in St. Louis have published a report detailing the results and initial impacts of their clinical targeted cancer sequencing program in about 400 of the first non-small cell lung cancer patients to receive the service.

The data, published online this week in Cancer show that the lab was successful in sequencing patients about half the time, and identified actionable mutations in about half of those successfully sequenced. Physicians then treated their patients with targeted drugs based on the NGS results in 11 percent of the sequenced cases.

According to the authors, the data offers a clear picture of both the successes and challenges of NGS in the setting of a truly routine clinical practice than what has been seen in some previous publications.

"We are showing here … perhaps for the first time systematically how often we succeed in getting sequencing results from samples obtained from routine biopsies in the clinic," Ramaswamy Govindan, the study's senior author told CSN in an email.

"This truly reflects what happens in a real-life scenario [as opposed to] when samples are sent away to a third-party commercial entity for sequencing … with the likely underrepresentation of true failures," he added.

Lung cancer, Govindan wrote, is the largest cancer subgroup Wash U has sequenced through its clinical genomics program, so provided a promising subject for a review of the center's real-world results.

Among the 381 first NSCLC cases with archived tissue referred for sequencing by the Wash U Genomics and Pathology Services — a consecutive cohort of patients seen from the initiation of the test in March 2012 through October 2013 — only 55 percent could be successfully sequenced.

In the study, the Wash U team also broke down their sequencing success rates for different sample types, highlighting important considerations for more efficient and effective clinical use of sequencing moving forward.

Primary lung tumor tissue excision specimens led to successful sequencing 97 percent of the time, while endoscopic biopsies were successful only half the time, and core biopsies only about 30 percent of the time, the team reported.

Median turnaround time was about 21 days over this time frame, improving as the lab changed from the Illumina HiSeq 2000 to the HiSeq 2500.

Of the 209 samples the lab successfully sequenced, 46 percent had at least one actionable mutation — either a level-one variant, which include those recognized by the program's clinical genomicist as either prognostic or predictive of therapeutic response in NSCLC specifically, or a level-two variant: mainly variants considered either prognostic or predictive in other tumor types.

Ian Hagemann, the study's first author, told CSN in an email that Wash U's protocol for defining actionable mutations is comparatively stringent, requiring clinical-grade evidence, specifically from a study performed in humans and classified in Medline as a clinical trial.

"Some mutations are common [and] are pathogenetically important, but are neither predictive nor strongly prognostic —TP53 nonsense mutations come to mind, in lung cancer. These were not considered actionable in our study. What would the action be?" he wrote.

According to the authors, based on the presence of variants that met this actionability threshold, physicians initiated a targeted therapy for their patient in accordance with sequencing results in 11 percent of the cases who were successfully sequenced, and six percent of the referred cohort overall.

Wash U researchers reported this January in more detail about one case in which sequencing led successfully to targeted treatment, a woman with a metastatic thymic carcinoma who had failed standard therapy and was able to receive successful treatment with a tyrosine kinase inhibitor based on the discovery of an activating KIT mutation.

According to the study authors, an overall 11 percent targeted treatment rate is lower than what has been seen in some other cancer mutation programs, such as the Lung Cancer Mutation Consortium, or LCMC. But these have predominantly been efforts designed to rapidly direct patients to readily available clinical trials rather than reflective of everyday clinical practice.

Hagemann also noted that the group's report reflects an earlier version of Wash U's cancer sequencing panel that did not allow, as the current version does, the detection of structural variants. During the study period, the lab performed adjunct FISH testing for relevant rearrangements in ALK, MET, ROS, and other genes, and based on these results another eight patients were placed on genomically matched therapy. "Today, those patients would not necessarily need separate FISH testing," Hagemann wrote.

Overall, Wash U increased its sequencing panel from 25 to 40 genes as of late 2013.

One lingering question for the group, and for other clinical genomics programs, is whether the use of NGS can be shown to not just impact physician decision making and the choice of cancer therapy, but to also translate to better patient outcomes down the line.

"In the long run, the NGS community clearly needs to show that NGS testing is cost-effective," Hagemann wrote. "To do this we will need to document not just placement on a matched therapy, but also improved survival as a result of NGS testing — which we do not do here."

While some efforts, like the LCMC, have hinted at a survival benefit, this has yet to be replicated definitively across studies and clinical sequencing efforts.

"We also plan to study clinical outcomes in our patients," Hagemann said, "because those data may teach us how to select the best candidates for NGS testing, and may help us to balance the costs of the testing against its benefits."

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