Purpose: Despite major progress in the molecular characterization of ovarian cancers (OC), women with recurrent, advanced stage OC continue to be treated with cytotoxic chemotherapy agents that have poor overall response rates. This contrasts with the treatment paradigm for other cancers, where outcomes have been improved by selecting treatment based upon “actionable” genomic alteration(s) that are in drug-targetable pathways. There is a need to determine if molecular profiling for OC patients can improve treatment outcomes. Such a profile should comprehensively identify “actionable” genetic aberrations as well as measure expression levels of proteins that are drug targets/response biomarkers.
Methods: The presence of mutations or alterations [e.g., copy number (CN)] in ~200 genes was determined using a validated exon-capture sequencing platform (Foundation Medicine, Inc) and protein levels of ERBB2, EGFR, ESR1, cMET, PTEN, RB1, and p16 were measured by IHC (Caris Life Sciences and Clarient, Inc). Formalin-fixed, paraffin-embedded tumor blocks were obtained following informed patient consent. Results were provided to the patient and medical team to enable informed decisions regarding subsequent treatment. The effectiveness of targeted therapies was assessed by CA125 levels and/or diagnostic imaging scans; clinical data were captured in an encrypted and privacy-protected database.
Results: 88 tumor specimens (20 primary, 68 recurrent) were analyzed from 85 patients, most diagnosed with stage III/IV OC [60 high grade serous (HGS) or mixed histology, 3 LG serous, 4 SB, 4 MMMT, 5 CC, 4 E, 1 M, 4 NOS]. A median of 3 (range 0-6) “actionable” alterations were detected/tumor with TP53 the most frequently altered (77%, 90% in HGS). Genes in key targetable pathways were altered: PI3K-AKT-mTOR (34%), RAS-MAPK (35%), HR DNA repair (31%; 20%: BRCA1/2), cell cycle (36%), GF receptor TK (23%), and MYC (22%). CN changes for PIK3CA, AKT3, and KRAS were common in HGS, while mutations were common in non-HGS. PTEN, RB1, and p16 protein loss were primarily detected in non-HGS tumors. Most genetic alterations in CDKN2A, RB1, and PTEN correlated with protein levels. Profile-directed treatment options were pursued for at least ten patients, who received PARP inhibitor olaparib (somatic BRCA2 MUT), mTOR inhibitors everolimus (PIK3CA MUT; TSC1 DEL; NF1 MUT/PTEN loss) or temsirolimus (NF1 MUT), MEK inhibitor trametinib (KRAS MUT), MET/ALK inhibitor crizotinib (high cMET), combination PI3K GDC-0941 and MEK inhibitor GDC-0973 (PIK3CA MUT /KRAS MUT), hedgehog inhibitor vismodegib (PTCH1 MUT), FGFR inhibitor JNJ-42756493 (FGFR1 AMP) and elicited 3 partial responses and 2 extended remissions with 2 patients still on treatment.
Conclusion: Comprehensive tumor molecular profiling approaches that measure protein, as well as DNA mutations and copy number alterations in targetable pathways are needed to identify drugs that are appropriate for each patient’s tumor profile. Early evidence suggests that advanced stage OC patients may benefit from targeted drugs and additional work is needed to understand if profile-directed treatment will provide benefit beyond currently available chemotherapy options.
Citation Format: D. A. Zajchowski, PhD, M. Whitlow, PhD, K. M. Zajchowski, L. K. Shawver, PhD. Genomic profiles inform treatment decisions and enable future drug/biomarker discovery [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-TECH-1127.