Precision Oncology of High-Grade Ovarian Cancer Defined through Targeted Sequencing

Abstract

Background: We examined whether molecular characterization of high-grade epithelial ovarian cancer can inform the diagnosis and/or identify potential actionable targets.

Methods: All of the consecutively sequenced high-grade ovarian tumours with consent between 2014 until 2019 were included. A total of 274 tumours underwent next generation sequencing using a targeted panel.

Results: Patients with high-grade ovarian epithelial cancer were consented to prospective molecular characterization. Clinical information was extracted from their medical record. Tumour DNA was subjected to sequencing, and selected patients received PARP inhibitor therapy.

Conclusions: Tumours from 274 women were sequenced, including high-grade serous carcinoma (n = 252), clear cell carcinoma (n = 4), carcinosarcoma (n = 9), endometrioid carcinoma (n = 3), undifferentiated carcinoma (n = 1), and mixed tumours (n = 5). Genomic profiling did not influence histologic diagnosis. Mutations were identified in TP53, BRCA1, BRCA2, as well as additional homologous recombination repair pathway genes BARD1, ATR, CHEK2, PALB2, RAD51D, RAD50, SLX4, FANCA, RAD51C, and RAD54L. In addition, mutations in PTEN and CDKN2A were identified. Several somatic mutations with implications for germline testing were identified, including RMI1, STK11, and CDH1. Germline testing identified 16 previously unknown BRCA1/2 carriers. Finally, 20 patients were treated with the PARP inhibitor olaparib based on the sequencing results.

Keywords: genetics; genomics; ovarian cancer; targeted therapy.

Figure 1

(A) Characteristics of the Karolinska cohort by histology, stage, and age. (B) Overall survival of the cohort by the BRCA1/2 pathogenic variant status (absent, germline or somatic).

Figure 2

(A) Oncoprint of genomic alterations in the cohort. The text colour of the gene reflects the availability of targeted therapy, with the green text indicating an FDA approved drug, blue text indicating a drug in clinical trials, and black text indicating a gene related to an hereditary syndrome. (B) Detailed characteristics of the TP53 loss of function mutations identified in the cohort. From left to right, these pie charts indicate (1) the mutation effect, (2) whether the point mutations are missense or nonsense, (3) whether the mutation was damaging by the SIFT analysis, and (4) the effect of the mutation on transactivation. These parameters may serve as markers of response to adavosertib, as discussed in the text.

Figure 3

(A) Clinical follow-up of the 20 patients treated with olaparib, and their BRCA1/2 mutation status as germline, somatic or unknown. (B) Overall survival of the entire cohort grouped by those that received olaparib and those that did not.