BRCA mutations in metastatic colorectal cancer (mCRC) and response to chemotherapy.
Bibliographic record
Abstract
235 Background: Mutations in BRCA 1/2 are typically associated with breast, ovarian, pancreatic and prostate cancers. BRCA mutations have been reported in colorectal cancer in sporadic case series. Unlike other cancers, the significance of BRCA mutations in mCRC is not known. We report the prevalence and molecular characteristics associated with BRCA 1/2 mutations in mCRC, and investigate the impact of these mutations on chemotherapy response since both oxaliplatin (OX) and irinotecan (IRI) interfere with DNA repair pathways. Methods: The Ontario-wide Cancer Targeted Nucleic Acid Evaluation (OCTANE) database was queried to identify mCRC patients (pts) harbouring BRCA 1/2 mutations. BRCA 1/2 mutations were detected using panel-based next generation sequencing (NGS) on archival tumour tissue. Clinical and molecular variables were collected, together with treatment outcomes. Results: Of 279 mCRC pts within the OCTANE database as of March 2019, 9 pts with BRCA 1/2 mutations were identified (3.2%): 4 BRCA 1 and 5 BRCA 2 mutations. Each patient had a unique variant with 8/9 missense mutations and 1/9 splicing error. Allele frequency ranged from 0.11 to 0.57. RAS or BRAF mutations were present in 67%. Common co-mutations included TP53 (56%), APC (56%), TSC1 (44%), ROS1 (33%) and ATM(33%). 2 pts were mismatch repair deficient. Median age was 48.5 years (range: 31-69 years), 56% males. 5 pts presented with de novo metastatic disease. First line OX-containing chemotherapy was administered to 4 pts, and IRI to 3 pts. 2 pts did not receive chemotherapy (1 had surgery only post-adjuvant OX, and 1 immunotherapy). Overall response rate (ORR) was 71%, with all pts achieving a partial response or stable disease. The median progression-free survival was 7.5 months (range: 1.8- 31.7 months) and median overall survival 68.5 months (range: 10.5- 68.5 months) respectively. Conclusions: BRCA 1/2 mutations are present in a small subset of mCRC pts. Pts with these mutations tend to be younger at diagnosis. BRCA 1/2 mutations are associated with favourable response to first line chemotherapy. Targeting BRCA 1/2 mutations may broaden treatment options for these patients.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".