Abstract A26: Detecting PIK3CA mutations in circulating cell-free DNA from patients with metastatic cancer: An exploratory analysis in patients with endometrial and lung cancer
Authors: Tomaso Emmanuelle di , Monk Bradley , Dy Grace , Robinson Douglas , Aimone Paola , Trandafir Lucia , Massacesi Cristian , Hirawat Samit 
Published: October 2015

Background: Personalized therapy relies on the ability to characterize the tumor at the time of treatment. Circulating cell-free DNA (cfDNA) may offer the potential for representative mutation analysis in patients with cancer irrespective of tumor tissue availability. Recent publications have started to establish the feasibility of this approach. For example, 72.5% concordance of PIK3CA mutations was reported between temporally unmatched cfDNA and archival tumor tissue from patients with metastatic breast cancer (Higgins et al. Clin Cancer Res 2012). Here, we present a retrospective analysis evaluating the reliability of detecting PIK3CA mutations in plasma samples from patients with endometrial and lung cancer – two malignancies known to harbor alterations in the PI3K pathway.

Methods: Baseline plasma DNA samples were available from 61 patients with advanced endometrial cancer (NCT01289041) and 37 patients with advanced non-small cell lung cancer (NSCLC; NCT01297491). BEAMing technology (Richardson & Iglehart. Clin Cancer Res 2012) and Sanger analysis were used in all samples. Sanger analysis was able to detect any mutation in exons 1, 5, 7, 9, and 20, whereas only selected mutations (14 in total) known to affect PI3K function in exons 1, 4, 7, 9, and 20 could be detected in cfDNA. Plasma samples were all temporally unmatched to the archival tissue specimen. Concordance analysis was performed by comparing the mutation status of samples (i.e. the proportion of samples that were detected as either wildtype or mutant consistently) between Sanger and cfDNA sequencing.

Results: 54 of 61 patients with endometrial cancer had interpretable mutation results by both Sanger and cfDNA analysis. Concordance of PIK3CA mutation was 74% between plasma and tissue. The PIK3CA mutations detected in cfDNA were distributed over exons 1, 7, 9, and 20 (29%, 19%, 33%, and 19%, respectively). Among the 37 patients with NSCLC, overall concordance was 54%. Variant distribution of PIK3CA mutations in this small number of lung tumors appeared to differ from the usual “hotspots” as two-thirds of mutations detected by Sanger analysis were not available on the BEAMing panel.

Conclusion: Concordance for PIK3CA mutation between temporally unmatched archival specimens and blood samples in this endometrial cancer patient population was in line with the published rate for metastatic breast cancer. The different mutations identified in samples from patients with NSCLC indicate a need for better understanding of the potential role of the PI3K pathway in this tumor type.

Overall these results support the feasibility of assessing PIK3CA mutations in plasma samples. The outcomes show a similar trend to multiple recent publications, thus warranting rapid further exploration of the clinical utility of cfDNA in metastatic cancer.

Citation Format: Emmanuelle di Tomaso, Bradley Monk, Grace Dy, Douglas Robinson, Paola Aimone, Lucia Trandafir, Cristian Massacesi, Samit Hirawat. Detecting PIK3CA mutations in circulating cell-free DNA from patients with metastatic cancer: An exploratory analysis in patients with endometrial and lung cancer. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr A26.