Abstract 474P
Background
PM are the third most frequent site of metastasis (mets) in mCRC but there are limited data regarding molecular characterization. Our aim was to evaluate clinical and genomic alterations associated with PM and survival outcomes.
Methods
The AACR GENIE Biopharma Collaborative is a registry of clinical and genomic data from pts with CRC who had tumor sequencing (55-500 genes) from 2015-2017 at three academic centers. Imaging reports and medical oncologists’ clinical notes were retrospectively curated. Association between variables and PM were analyzed using Mann-Whitney U and Fisher’s exact test. Kaplan–Meier method was used to estimate the median overall survival (OS). Hazard ratio (HR) and 95% confidence intervals (95% CI) were calculated using the Cox Proportional-Hazards Model. Both estimates of time-to-event endpoints were adjusted to left truncation bias introduced by the inclusion criteria for this project.
Results
A total of 703 pts with mCRC at diagnosis were analyzed, including 150 (21%) with PM. PM were associated with female sex (57% vs 43%; p<0.01) and histological grade (Grade 3-4 42% vs 22%; p<0.01). PM were less frequent in rectal tumors (15% vs 34%; p<0.01). The only genomic alteration associated with PM was MED12 mutation (mt) (13% vs 3%) after correction for multiple testing (q=0.01). APC mt occurred less often in pts with PM (60% vs 80%; q<0.01). Mismatch repair deficiency (dMMR) was more frequent in PM (7% vs 3%; p=0.02). OS was worse for pts with PM versus non-PM (median 21 months (m) vs 28.3m, p<0.01). PM was a prognostic factor for OS in multivariable analysis (HR 1.6; 95% CI 1.2-2.1) adjusted by age, tumor side, RAS/BRAF mt and liver or lung mets. Among subgroups by RAS/BRAF status, pts with RAS/BRAF mt with PM and other mets had the poorest OS. Table: 474P
| Median OS (m) (95% CI) | p-value | |
| RAS/BRAF mt and only PM | 28.9 (19.8-44) | 0.09 |
| RAS/BRAF wild type (wt) and only PM | 36.4 (26.6-NA) | |
| RAS/BRAF mt with PM and other mets | 12.2 (1.2-22.7) | 0.11 |
| RAS/BRAF wt with PM and other mets | 27.6 (21.7-38.5) | |
| RAS/BRAF mt and without PM | 22.7 (19.8-27.2) | <0.01 |
| RAS/BRAF wt and without PM | 40 (32.9-45.5) |
Conclusions
PM at diagnosis in mCRC was associated with female sex, high grade, non-rectal primary, dMMR, and MED12 mt. PM was an independent negative prognostic factor for OS.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
American Association of Cancer Research (AACR).
Funding
AACR Project GENIE receives funding from Amgen, Inc.; Bristol-Myers Squibb Company; Merck Sharp & Dohme Corp.; AstraZeneca UK Limited; Genentech; Novartis; Pfizer, Inc.; Bayer Healthcare Pharmaceuticals, Inc.; Boehringer Ingelheim; and Janssen Pharmaceuticals Inc.
Disclosure
G.J. Riely: Financial Interests, Institutional, Sponsor/Funding: Novartis; Roche/Genentech; GlaxoSmithKline; Pfizer; Infinity Pharmaceuticals; Mirati Therapeutics; Merck; Takeda; Financial Interests, Institutional, Royalties: Patent application submitted covering pulsatile use of erlotinib to treat or prevent brain metastases; Financial Interests, Personal, Other, Travel Expenses: Merck Sharp and Dhome; Financial Interests, Personal, Other: Pfizer; Roche/Genentech; Takeda. E.M. Lepisto: Non-Financial Interests, Personal, Full or part-time Employment, An Immediate Family Member: Kiniksa Pharmaceuticals; Financial Interests, Personal, Stocks/Shares, An Immediate Family Member: Kiniksa Pharmaceuticals. M.L. LeNoue-Newton: Financial Interests, Personal, Research Grant: AACR GENIE Project; GE Healthcare. J.L. Warner: Financial Interests, Personal, Member of the Board of Directors: HemOnc.org LLC; Financial Interests, Personal, Stocks/Shares: HemOnc.org LLC; Equity; Financial Interests, Personal, Advisory Role: IBM Watson Oncology; Westat; Financial Interests, Personal, Research Grant: NIH; AACR. S.M. Sweeney: Financial Interests, Personal, Full or part-time Employment, An Immediate Family Member: Concert AI; Financial Interests, Personal, Sponsor/Funding: Amgen; AstraZeneca; : Bristol-Myers Squibb; Genentech; Bayer; Boehringer Ingelheim; Janssen; Merck; Novartis; Analysis Group. D. Schrag: Financial Interests, Personal, Other, Editorial Services: JAMA; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Funding: AACR; Financial Interests, Personal, Principal Investigator: Grail. P. Bedard: Financial Interests, Personal, Advisory Role: Seattle Genetics; Lilly; Amgen; Merck; BMS; Pfizer; Financial Interests, Institutional, Principal Investigator: Bristol-Myers Squibb; Sanofi; AstraZeneca; Genentech/Roche; Servier; GlaxoSmithKline; Novartis; PTC Therapeutics; Nektar; Merck; Seattle Genetics; Mersana; Immunomedics; Lilly; Amgen; Bicara. All other authors have declared no conflicts of interest.