Abstract PR09: Frequency and etiology of ctDNA-positive metastatic prostate cancer with BRCA2, ATM, or CDK12 mutations
Bibliographic record
Abstract
Abstract Recent sequencing efforts have shown that genomic alterations within DNA damage repair (DDR) pathways are relatively common in metastatic prostate cancer (mPCa). Patients harboring DDR gene aberrations can respond poorly to standard-of-care androgen receptor (AR)-targeted therapy, potentially because defective DNA repair enables rapid tumor evolution. Research has shown that DDR-deficient mPCa is often genetically unstable due to its high mutation frequency; however, the specific differences in mutations and copy number alterations between DDR mutant and nonmutant tumors have not been established. We performed targeted next-generation sequencing on 1,214 cell-free DNA samples from 718 patients with mPCa. In 30 patients with disruption of BRCA2, ATM, or CDK12, we also sequenced archival primary tumor tissue. 118 patients had a deleterious germline or somatic mutation in at least one of the 22 DDR genes on our targeted panel. The most commonly altered were BRCA2 (n=41), ATM (n=20), and CDK12 (n=21), together present in ~14% of patients. Disruption of the intact second allele was detected in 96%, 82%, and 84% of patients with mutations in BRCA2, ATM, and CDK12, respectively. Patients with a mutation in any one of these genes had fewer mutations in TP53 than a control cohort of DDR-intact patients (p<0.05). However, BRCA2-defective patients had frequent compound deletions of tumor-suppressor genes (TP53, PTEN, RB1). In patients with CDK12 mutations, PTEN or RB1 deletion was rare and samples instead exhibited copy number gains of MDM2 and/or CCND1. ATM-deficient cases did not demonstrate the same degree of genomic instability as either BRCA2- or CDK12-defective disease. In summary, patients with BRCA2, ATM, or CDK12 gene disruption possess distinct patterns of genomic alterations. These findings might help clarify why some DDR-deficient mPCa cases represent a more aggressive disease subtype with a poor response to AR-targeted therapy. This abstract is also being presented as Poster A36. Citation Format: Evan Warner, Steven Yip, Matti Annala, Gang Wang, Arkhjamil Angeles, Arshia Beigi, Elena Schönlau, Amanda Wong, Sinja Taavitsainen, Gillian Vandekerkhove, Kevin Beja, Matti Nykter, Daniel Khalaf, Kim Chi, Alexander Wyatt. Frequency and etiology of ctDNA-positive metastatic prostate cancer with BRCA2, ATM, or CDK12 mutations [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr PR09.
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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 | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.006 | 0.001 |
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".