Abstract 844P
Background
Inhibitors of KRAS mutant (mt) disease have shown efficacy in non-small cell lung, pancreas and colon cancers. Data about KRAS mts in ovarian cancer for targeted therapy are lacking.
Methods
The Caris Database of 7325 EOC (with various histologies) were queried for presence of actionable mutations. Next-generation sequencing results of 592 genes were available. Comparison was done using Fisher-Exact/ChiSquare (p values) and adjusted for multiple tests by Benjamini-Hochberg (q).
Results
a. KRAS mts in EOC: KRAS mts are seen in 8.2% (606/7325) EOC analyzed. Of 606 KRAS mts, subtypes G12D = 221 (36.5%), G12V = 217 (35.8%) were the most common; G12C = 51 (8.4%), other G12 mts such as A, F, I, L, R, S = 55 (9%). Pathogenic mts at codons 13, 61 and others were seen in 62 tumors (10.2%). Remaining EOCs were wt = 6719 (91.7%). b. KRAS mts infrequently co-occur with BRCA1/2 mutations: BRCA mts are significantly less prevalent in KRAS mt EOC compared to wt (BRCA1: 0.9% vs 9.2%; BRCA2: 1.3% vs 6.1% wt, q<0.05), and G12C-mt tumors show the highest co-occurrence with BRCA1 (4.6%) and BRCA2 (2.3%) among all KRAS mts. c. KRAS mts infrequently overlap with other oncogenic drivers: Mts in HRAS (0.3% vs 0.1% wt, p>0.05), MEK1 (0.3% vs 0.1% wt, p>0.05) do not overlap with KRAS mt while GNAS is higher in KRAS mt tumors (1.2% vs 0.1% wt, q<0.05). Enhancer mutations of the PI3K pathway are significantly higher in KRAS mt tumors. In KRAS mt vs wt, PTEN were 7.3% vs 3.4%, PIK3CA 17.2% vs 7.8% (both q<0.05) and PIK3R1 2.1% vs 1.0% (p<0.05). d. Known biomarkers of immunotherapy response occur at low frequency in both KRAS mt and wt: MSI-H and TMB-H (>17 mt/MB) were seen 1.6% and 3.1% in the KRAS mt and 1% and 2.2% in wt, respectively (p>0.05). STK11 mts were 0.5% KRAS mt and 0.1% wt (p<0.05). e. Differences in markers of genomic integrity: Tumors with KRAS mts had lower rates of p53 mts than KRAS wt (29.6% vs 80% of wt, q<0.05), but higher rates of ARID1A mts (49.7% vs 29.1%, q<0.05). ATM mts were more frequent in KRAS mt disease (3.7% vs 1.6%, q<0.05).
Conclusions
KRAS mt disease represents a genomically distinct group of EOC with minimal overlap to other targeted therapy or immunotherapy options. BRCA1/2 mts were mutually exclusive from KRAS mt suggesting a separate treatment opportunity for recurrent disease or maintenance therapy.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
M. Dietrich: Advisory/Consultancy: Amgen. J. Xiu, W.M. Korn: Full/Part-time employment: Caris Life Sciences. V.B. Galvan Turner: Advisory/Consultancy: AstraZeneca. B. Erickson: Advisory/Consultancy: Boston Scientific. T. Herzog: Advisory/Consultancy: Caris Life Sciences. All other authors have declared no conflicts of interest.