Abstract 99P
Background
KRASm are common oncogenic drivers and covalent G12C inhibitors are in clinical trials. We examined the landscape of KRASm in ctDNA and concordance between matched tissue and ctDNA.
Methods
Hybrid capture-based comprehensive genomic profiling (CGP) was performed on pan-tumor tissue (n = 325,433) or ctDNA (n = 28,748) during clinical care. Maximum somatic allele frequency (MSAF) was used to estimate presence of ctDNA; MSAF = 0 samples were excluded.
Results
3,947 (21%) of 19,032 ctDNA samples were positive for KRASm (base substitution or indel). KRASm were detected most frequently in ctDNA of pancreatic ductal adenocarcinoma (PDAC; 288/572, 50%), colorectal (CRC; 462/1,075, 43%), and non-squamous non-small cell lung cancer (non-SqCC NSCLC; 1,122/5,710, 20%). G12C was most frequent in non-SqCC NSCLC (36% of KRASm), whereas KRASm in PDAC and CRC were predominantly G12D (44% and 25%) and G12V (27% and 19%). Co-alterations in TP53 and STK11 and were found in 65% and 5.5% of KRASm pan-tumor ctDNA, and 57% and 12% of KRAS G12C+ non-SqCC NSCLC. In 491 paired tissue and ctDNA cases with ≥1 sample harboring a KRASm, positive percent agreement (PPA) to tissue and liquid was 73% and 88%, respectively. Mean MSAF for ctDNA with KRASm present vs absent was 15% vs 7.2% (p = 5.7e-13). 187 pairs were temporally matched ( ≤60 days apart, median 20 days) and the remaining 304 pairs were collected 63-5,374 days apart (median 405 days). In 5.3% of cases (16/304), KRASm was present only in the second sample and co-occurred with another known driver, and therefore may represent acquired resistance. Among temporally matched pairs, PPA was 82% for all KRASm (n=187) and 80% for G12C (n = 35). PPA to tissue for temporally vs non-temporally matched non-SqCC NSCLC, CRC, and PDAC pairs was 80% vs 69%, 86% vs 84%, and 85% vs 67%.
Conclusions
KRASm were detected in ctDNA from diverse cancers, and frequencies were similar to those reported in tissue (Ou et al. ESMO 2019 Abstract 92PD), with some differences presumed due to assay selection bias. For tissue-ctDNA pairs collected ≤60 days apart, PPA to tissue was 82% for cases with evidence of ctDNA. This suggests clinical utility of ctDNA CGP as a complementary approach to tissue CGP.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Foundation Medicine.
Funding
Foundation Medicine.
Disclosure
J. Lee: Full/Part-time employment: Foundation Medicine, Inc.; Shareholder/Stockholder/Stock options: Roche. J.H. Chung: Full/Part-time employment: Foundation Medicine; Shareholder/Stockholder/Stock options: Roche. J. Venstrom: Leadership role, Travel/Accommodation/Expenses, Full/Part-time employment: Foundation Medicine; Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options: Roche; Advisory/Consultancy: Synkrino. B. Alexander: Leadership role, Full/Part-time employment: Foundation Medicine; Shareholder/Stockholder/Stock options: Roche; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Puma Biotechnology; Research grant/Funding (institution): Celgene. A.B. Schrock: Full/Part-time employment: Foundation Medicine; Shareholder/Stockholder/Stock options: Roche. S-H.I. Ou: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Roche; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): AstraZeneca; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Takeda; Advisory/Consultancy: TP Therapeutics; Honoraria (self), Speaker Bureau/Expert testimony: Genentech; Shareholder/Stockholder/Stock options: Turning Point Therapeutics; Honoraria (self): Foundation Medicine; Honoraria (self): Merck; Honoraria (self), Research grant/Funding (institution): ARIAD; Research grant/Funding (institution): Ignyta; Research grant/Funding (institution): Astellas Pharma; Research grant/Funding (institution): Chugai Pharma; Research grant/Funding (institution): Revolution Medicines.