PIK3CA, KRAS, and BRAF mutations in patients with advanced cancers treated with PI3K/AKT/mTOR axis inhibitors.

Abstract

2583 Background: Activating mutations of the p110α subunit of phosphatidylinositol 3-kinase (PI3K) (PIK3CA) have been identified in various tumors, and preclinical data suggest that these mutations may predict for response to PI3K/AKT/mTOR inhibitors, but that concomitant KRAS or BRAF mutations may mediate resistance. Methods: Tumors from patients (pts) referred to the Phase I Program for targeted therapy from 10/08 to 11/09 were analyzed for PIK3CA mutations using PCR-based DNA sequencing of exon 9 (helical domain) and exon 20 (kinase domain). Consecutive pts with any tumor type and PIK3CA mutation were treated whenever possible with agents targeting the PI3K/AKT/mTOR signaling pathway. Results: Overall, 316 patients were analyzed and 36 (11%) had a PIK3CA mutation (exon 9, n=17; exon 20, n=19). In tumor types with > 5 pts tested, PIK3CA mutations were most frequent in squamous cervical cancer (33%, 3/9 pts), endometrial (29%, 5/17), breast (24%, 5/21), squamous head and neck (19%, 3/16), colorectal (16%, 12/74), ovarian (14%, 6/42), pancreatic (12.5%, 1/8), and non-small cell lung cancer (12.5%, 1/8). Of the 36 pts with PIK3CA mutations, 24 (median number of prior therapies, 4) were treated on a protocol that included a PI3K/AKT/mTOR pathway inhibitor. Of 24 pts, 6 (25%) had a PR (2/5 endometrial; 2/6 ovarian; 1/3 breast, 1/3 squamous cervical) and 4 (17%) had stable disease (SD) for ≥ 4 months. Of these 24 pts, 8 (33%) had coexisting KRAS and/or BRAF mutations. Of these 8 pts (colorectal 4, gynecologic cancers 4), 1 (12.5%) had SD for ≥ 4 months (colorectal) and 2 (25%) pts (both ovarian) had a PR. Of these 24 pts, when 4 pts with colorectal cancer and KRAS and/or BRAF mutations were excluded, the rates of PR and SD for ≥- 4 months were 30% (6/20) and 20% (4/20), respectively. Conclusions: PIK3CA mutations were detected in 11% of pts with various solid tumors. Ten pts (42%) had a PR (25%) or SD ≥ 4 months (17%). These preliminary results with PI3K/AKT/mTOR axis inhibitors are encouraging and although the number of pts is small, they suggest that coexisting KRAS and/or BRAF mutations may be associated with resistance to PI3K/AKT/mTOR axis inhibitors in colorectal cancer, but not in gynecologic cancers. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Centocor, Johnson & Johnson, Maxygen, Merck & Co. Amgen, AstraZeneca, Center for Biomedical Continuing Education, Genentech, Enzon, IDSC, ImClone Systems, Johnson & Johnson, Maxygen, Merck, Pharmion, Roche Abraxis, Amgen, AmpliMed, Antigenics, AstraZeneca, Bayer, BMS, Callisto, Celgene, Centocor, Concordia, Curagen, Eisai, Eli Lilly, EMD Serono, Enzon, Exelixis, Genentech, GlaxoSmithKline, Globomax, Hoffman- La Roche, Kinex, Merck, Metastatix, MGI Pharmaceuticals, Millennium, Myriad, Novartis, Oncothyreon, Pfizer, Pharmacyclics, Pharmion, Phoenix Biotech, Reata, Taiho, Vioquest, Ziopharm