Abstract 3707
Background
Although rare, the incidence of BM is increasing due to the improvement in metastatic CRC treatment and longer survival. Genomic analyses of small series revealed that BM can harbor potentially unique driver mutations. We aimed to comprehensively characterize the molecular profile of BM and explore the differences between BM vs other distant metastases (OM) and primary tumors (PT) in CRC.
Methods
Tumor samples from BM (n = 81), PT (n = 6898) and OM (n = 5918) were analyzed using NGS (TruSEQ on 45 genes or NextSEQ on 592 genes), in situ hybridization and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci.
Results
The most frequently mutated genes in BM were TP53 (80%), APC (73%), KRAS (68%), ARID1A (18%), PIK3CA (13%) and FBXW7 (9%). The most prevalent copy number increase was seen in CDX2 (20%), CCND2 (7%), FLT1 (7%), FLT3 (7%) and FOXO1 (7%). When compared to OM and PT, mutations in KRAS (BM: 68%, OM: 49%, PT: 48%), CDKN2A (5%, 1%, 1%), ERCC2 (2%, 0, 0) and HRAS (1%, 0, 0) were significantly higher in BM (P<.05); BRCA1 was significantly higher in BM vs OM (3 vs 1%, P=.025). Conversely, BRAF mutations trended to be lower in BM vs PT (4 vs 10%, P=.059). Overall, copy number alterations (CNA) were significantly higher in BM vs PT and OM, including CDX2, CCND2, FLT1, FOXO1, ERC1, FGF23, KDM5A, NSD3, FGFR1 (P<.05). HER2 overexpression showed a non-statistically significant trend to be higher in BM compared to PT and OM (7%, 2%, 3%, P=.064). Significantly lower rates of TMB-high (>17mut/MB) and MSI-high were seen in BM vs PT (2 vs 9% and 1 vs 8%, P=.049 and .031, respectively) but not compared to OM. No RSPO3 nor NTRK1 fusions were seen in BM (n = 5). Female gender was associated with younger age in BM (53.5 vs 62 yr, P=.0014) and OM (58.8 vs 60.2 yr, P<.0001), not seen in PT.
Conclusions
This is the largest and most extensive profiling study to investigate the molecular makeup of BM and the differences with PT and OM in CRC. Our data show distinct mutations and CNA characterizing BM and lower expression of immune related markers, supporting the rationale to develop tailored approaches to the treatment of this metastatic site.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
National Cancer Institute grant number P30CA014089, Gloria Borges WunderGlo Foundation-The Wunder Project, Dhont Family Foundation, San Pedro Peninsula Cancer Guild, Daniel Butler Research Fund, Call to Cure Research Fund and Fong Research Project.
Disclosure
J. Xiu: Full / Part-time employment: Caris Life Sciences. Y. Baca: Full / Part-time employment: Caris Life Sciences. R.M. Goldberg: Research grant / Funding (self), Travel / Accommodation / Expenses: Caris Life Sciences. A. Grothey: Travel / Accommodation / Expenses: Caris Life Sciences. A.F. Shields: Research grant / Funding (self), Travel / Accommodation / Expenses: Caris Life Sciences. A. Seeber: Advisory / Consultancy: Caris Life Sciences. M.E. Salem: Travel / Accommodation / Expenses: Caris Life Sciences. P.A. Philip: Travel / Accommodation / Expenses: Caris Life Sciences. J.L. Marshall: Advisory / Consultancy: Caris Life Sciences. W..M. Korn: Full / Part-time employment: Caris Life Sciences. H.J. Lenz: Travel / Accommodation / Expenses: Caris Life Sciences. All other authors have declared no conflicts of interest.
Resources from the same session
1433 - Comprehensive pan-cancer analysis of KRAS genomic alterations (GA) including potentially targetable subsets
Presenter: Sai-Hong Ou
Session: Poster Discussion 2 – Translational research
Resources:
Abstract
4105 - Genetic variants in the one-carbon metabolism pathway to predict outcome in patients with metastatic colorectal cancer (mCRC): data from TRIBE and FIRE-3 phase III trials.
Presenter: Alberto Puccini
Session: Poster Discussion 2 – Translational research
Resources:
Abstract
2381 - Oral Intestinal Alkaline Phosphatase Improves Efficacy of 5-FU in a Colorectal Cancer Mouse Model
Presenter: Christian Furlan Freguia
Session: Poster Discussion 2 – Translational research
Resources:
Abstract
1699 - Pan-cancer analysis of clinical acquired resistance (AR) in BRAF-driven real-world cases
Presenter: Filippo Pietrantonio
Session: Poster Discussion 2 – Translational research
Resources:
Abstract
3025 - Primary ovarian carcinomas arising in BRCA1 mutation carriers contain a small fraction of BRCA1-proficient cells, which rapidly repopulate tumor mass during neoadjuvant chemotherapy but become outgrown by BRCA1-deficient clones during platinum-free intervals
Presenter: Evgeny Imyanitov
Session: Poster Discussion 2 – Translational research
Resources:
Abstract
4924 - Analysis of the Androgen Receptor status in liquid biopsy to predict the outcome to abiraterone and enzalutamide in CRPC patients
Presenter: Marzia Del Re
Session: Poster Discussion 2 – Translational research
Resources:
Abstract
Poster Discussion 2 – Translational research - Invited Discussant 92PD, 1880PD and 1881PD
Presenter: Alberto Bardelli
Session: Poster Discussion 2 – Translational research
Resources:
Slides
Webcast
Poster Discussion 2 – Translational research - Invited Discussant 93PD and 1882PD
Presenter: Dennis (Yuk-Ming) Lo
Session: Poster Discussion 2 – Translational research
Resources:
Slides
Webcast