Ailith Ewing

Molecular Profiling and Tumor Biomarker Analysis of GOG281/LOGS: A Positive Late-Phase Trial of Trametinib for Recurrent/Persistent Low-Grade Serous Ovarian Carcinoma

Abstract Purpose: Low-grade serous ovarian carcinoma (LGSOC) is a distinct form of ovarian cancer characterized by younger patient age and relative chemoresistance. The GOG281/LOGS trial (NCT02101788) investigated the efficacy of the MEK inhibitor trametinib compared with physician’s choice standard-of-care (SOC) in patients with LGSOC with persistent/recurrent disease. The study demonstrated significantly improved progression-free survival (PFS) in the trametinib-treated arm. Experimental Design: Two hundred and sixty patients with recurrent/persistent LGSOC were enrolled and randomly assigned in GOG281. We performed molecular analysis of 170 patients with available tumor specimens, comprising whole-exome sequencing and phospho-ERK (pERK) IHC, to identify biomarkers of clinical benefit from trametinib. The demographics of the translational cohort (n = 170) were comparable with those of the total trial cohort. Results: High tumor pERK expression (greater than the median histoscore of 140) was associated with significantly prolonged PFS with trametinib treatment versus SOC (median 20.1 vs. 5.6 months, log-rank P < 0.0001; test for interaction P = 0.023). Tumors harboring canonical RAS–RAF–MAPK mutations (KRAS/BRAF/NRAS: 44/134, 32.8% of cases) had a higher response rate to trametinib (50.0% vs. 8.3%; Barnard’s P = 0.0004; test for interaction P = 0.054), but KRAS/BRAF/NRAS status was not predictive of prolonged PFS (test for interaction P = 0.719). KRAS amplification (n = 5 without KRAS/NRAS/BRAF mutation) and mutation of MAPK-associated genes (n = 25 without KRAS/NRAS/BRAF mutation or KRAS copy number gain) expanded the number of cases with identifiable MAPK defects to 55.2%, but consideration of these events did not improve the discrimination of trametinib responders. Chr1p loss (49% of cases) was associated with lower pERK expression (P = 0.021). Conclusions: This exploratory analysis suggests that pERK expression and mutation of KRAS/BRAF/NRAS are candidate biomarkers of improved PFS and response to trametinib, respectively.

Structural Variants at the BRCA1/2 Loci are a Common Source of Homologous Repair Deficiency in High-grade Serous Ovarian Carcinoma

Abstract Purpose: The abundance and effects of structural variation at BRCA1/2 in tumors are not well understood. In particular, the impact of these events on homologous recombination repair deficiency (HRD) has yet to be demonstrated. Experimental Design: Exploiting a large collection of whole-genome sequencing data from high-grade serous ovarian carcinoma (N = 205) together with matched RNA sequencing for the majority of tumors (N = 150), we have comprehensively characterized mutation and expression at BRCA1/2. Results: In addition to the known spectrum of short somatic mutations (SSM), we discovered that multi-megabase structural variants (SV) were a frequent, unappreciated source of BRCA1/2 disruption in these tumors, and we found a genome-wide enrichment for large deletions at the BRCA1/2 loci across the cohort. These SVs independently affected a substantial proportion of patients (16%) in addition to those affected by SSMs (24%), conferring HRD and impacting patient survival. We also detail compound deficiencies involving SSMs and SVs at both loci, demonstrating that the strongest risk of HRD emerges from combined SVs at both BRCA1 and BRCA2 in the absence of SSMs. Furthermore, these SVs are abundant and disruptive in other cancer types. Conclusions: These results extend our understanding of the mutational landscape underlying HRD, increase the number of patients predicted to benefit from therapies exploiting HRD, and suggest there is currently untapped potential in SV detection for patient stratification.

Divergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancer

Abstract Deciphering the structural variation across tumour genomes is crucial to determine the events driving tumour progression and better understand tumour adaptation and evolution. High grade serous ovarian cancer (HGSOC) is an exemplar tumour type showing extreme, but poorly characterised structural diversity. Here, we comprehensively describe the mutational landscape driving HGSOC, exploiting a large (N = 324), deeply whole genome sequenced dataset. We reveal two divergent evolutionary trajectories, affecting patient survival and involving differing genomic environments. One involves homologous recombination repair deficiency (HRD) while the other is dominated by whole genome duplication (WGD) with frequent chromothripsis, breakage-fusion-bridges and extra-chromosomal DNA. These trajectories contribute to structural variation hotspots, containing candidate driver genes with significantly altered expression. While structural variation predominantly drives tumorigenesis, we find high mtDNA mutation loads associated with shorter patient survival. We show that a combination of mutations in the mitochondrial and nuclear genomes impact prognosis, suggesting strategies for patient stratification.

Somatic BRCA1/2 mutations are associated with a similar survival advantage to their germline counterparts in tubo-ovarian high grade serous carcinoma

Half of high grade serous tubo-ovarian carcinomas (HGSOC) demonstrate homologous recombination repair (HRR) deficiency, most commonly through germline or somatic pathogenic variants in BRCA1/2 (gBRCA1/2 or sBRCA1/2). gBRCA1/2 is associated with favourable survival, greater response rate to platinum-based chemotherapy, and marked sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. sBRCA1/2 has been assumed to confer a similar clinical phenotype; however, few studies have specifically investigated sBRCA1/2 versus gBRCA1/2 to demonstrate their equivalence. We investigated the association of gBRCA1/2, sBRCA1/2 and non-BRCA HRR gene mutations with HGSOC patient survival using two patient cohorts (cohort 1, n = 174 matched FFPE tumour and normal with panel-based sequencing; cohort 2, n = 279 matched fresh tumour and normal with whole genome sequencing). TCGA-OV samples (n = 316) were used for external validation. Patients with HRR-mutant tumours (BRCA1, BRCA2, non-BRCA HRR-mutant) demonstrated prolonged survival across both cohorts (cohort 1: multivariable hazard ratio [multiHR] 0.53 [0.32-0.87]; cohort 2: multiHR 0.36 [0.25-0.51]). gBRCA1/2 and sBRCA1/2 were associated with a similar survival benefit compared to the HRR-wildtype group in the combined cohort (cohort 1 +2) (gBRCA1/2: multiHR 0.50 [0.34-0.71]; sBRCA1/2: multiHR 0.41 [0.25-0.68]). These findings were recapitulated using the TCGA-OV dataset (gBRCA1/2: multiHR 0.56 [0.34-0.91]; sBRCA1/2: multiHR 0.48 [0.25-0.92]). Non-BRCA HRR mutations were associated with marked survival advantage (multiHR vs HRR-wildtype 0.22 [0.11-0.45]). The survival advantage in BRCA1-mutant cases (germline or somatic) was less marked (multiHR for non-BRCA HRR-mutant vs BRCA1-mutant 0.41 [0.19-0.90]). gBRCA1/2, sBRCA1/2 and non-BRCA HRR mutations were all associated with high HRDetect scores measuring HRR deficiency (median 1.00 versus 0.56 in HRR-wildtype, P < 0.01). gBRCA1/2 and sBRCA1/2 are equivalent in their association with prolonged survival. Non-BRCA HRR gene mutations may be associated with markedly favourable survival in HGSOC.