Molecular Profiling of Lung Cancer Tumors Feasible on National Scale

By Lori Solomon, Editor, Diagnostic Testing & Emerging Technologies

Routine, nationwide molecular profiling of patients with advanced non-small cell lung cancer (NSCLC) is feasible and the screening detects actionable alterations that affect treatment decisions in half of all patients, according to a large study published April 2 in The Lancet. Those with detected molecular alterations also had a survival advantage, leading the authors to conclude that routine tumor profiling offers clinical benefit to these patients.

While molecular profiling of patients with NSCLC for oncogenic drivers (most commonly EGFR mutations and ALK rearrangements) is recommended, the longer-term effects have not previously been studied in a large study of non-selected patients.

The French researchers assessed consecutive patients with advanced NSCLC, who were mandatorily screened for EGFR mutations, ALK rearrangements, as well as HER2, KRAS, BRAF, and PIK3CA mutations (per national recommendations) by 28 certified regional genetics centers in France. (These molecular targets were selected in 2009 and do not reflect changes to assessment protocols including the discontinuation of PIK3CA evaluation and the inclusion of ROS1 assessment.) Patients were assessed over a 1-year period (April 2012 to April 2013). Laboratories used either a Sanger sequencing method or a more sensitive validated allele-specific technique (with Sanger sequencing confirmation) to assess for mutations. A certified break-apart fluorescence in situ hybridization assay was used to assess the ALK rearrangements. Feasibility and potential technical issues were initially evaluated through analysis of 346 patients screened at three certified molecular genetics centers during a 3-month period (Nov. 2011 to Jan. 2012).

In all, 18,679 molecular results from 17,664 patients (median age 64.5 years; 65 percent men) were included in the analysis. Roughly three-quarters of the patients analyzed had adenocarcinoma.

The team of researchers found that the test turnaround time was 11 days. Half of cases showed a genetic alteration—most frequently KRAS mutations (n=4,894; 29 percent), followed by EGFR mutations (11 percent), ALK rearrangements (5 percent), BRAF mutations (2 percent), PIK3CA mutations (2 percent), and HER2 mutations (1 percent). Two or more mutations were found in 1 percent of samples.

At the time of analysis, the median duration of patient follow-up was 24.9 months. The presence of a genetic alteration affected first-line treatment decisions in just over half of patients (51 percent). For 23 percent of patients the “too-long” turnaround time resulted in the local multidisciplinary tumor board’s decision to proceed with planning of treatment strategy without waiting for the results.

The presence of a genetic alteration was associated with a significant improvement in the number of patients achieving an overall response and progression-free survival with first-line and second-line treatment, compared to patients with no genetic alteration detected. However, detection of a genetic alteration did not improve the inclusion rate in clinical trials, which remained at only 3 percent of the patients.

“This national program broadly (and exhaustively) screened patients with lung cancer for genetic alterations in six genes, including four emerging genetic alterations, to identify actionable targets that improved the survival of about 50 percent of patients, although at a non-negligible financial cost,” write the authors led by Fabrice Barlesi, M.D., from the Assistance Publique Hôpitaux de Marseille. “Therefore, our results should encourage all continuing worldwide initiatives to provide patients with cancer with access to personalized treatment, and provide robust information to inform these initiatives.”

The “non-negligible” financial cost associated with this sequencing totaled €21.973 million (about $25 million) across the French centers in 2012, according to data from the French National Cancer Institute.