Abstract B001: Identification of monoallelic <i>ATM</i> loss-of-function and homologous recombination deficiency (HRD) in high-grade ovarian tumor with prolonged response to camonsertib and low-dose gemcitabine combination therapy
Bibliographic record
Abstract
Abstract Intra-tumor heterogeneity and the prevalent loss-of-function mutations within DNA damage repair (DDR) genes constitute salient hallmarks of high-grade ovarian malignancies. However, the etiological drivers beyond BRCA1/2 mutations, as well as the chronology of tumor evolutionary processes, remain enigmatic. Here, we present the case of a 60-year-old female with high-grade serous ovarian cancer, initially treated with primary debulking surgery followed by 6 cycles of adjuvant intraperitoneal cisplatin and paclitaxel. After a 16-month platinum-free interval, the patient (pt) developed recurrent disease and subsequently received 5 weeks of neoadjuvant olaparib followed by secondary debulking surgery and adjuvant carboplatin as part of a clinical trial (NCT02489006). The pt became platinum refractory after 4 cycles of carboplatin, then received weekly paclitaxel and biweekly bevacizumab with stable disease as best response and eventual progression after 17 cycles. Molecular profiling of the metastatic biopsies at the time of initial recurrence identified a pathogenic ATM (c.4910-1G>A) alteration for which the pt was then enrolled onto the Phase Ib TRESR trial (NCT04497116). The trial enrolled pts ≥18 years, ECOG PS 0-1, with advanced solid tumors with deleterious DDR alterations. The pt received a starting dose of 1000mg/m2 gemcitabine (gem) with 80mg of the ATR inhibitor camonsertib (cam; 3 days [d] on/4d off) on a 21d cycle (2 weeks [w] on/2w off). The pt had a partial RECIST 1.1 response at 4 months (mo) and remains on treatment after 18mo. Due to toxicities (primarily neutropenia) the pt had a series of dose reductions to 200mg/m2 gem with 50mg cam (2d on/5d off) on a 28d cycle (1w on/1w off). Circulating tumor fraction (TF), measured by methylation-based profiling, remained at or below the limit of quantitation of the assay through 11mo (0.01% TF, testing of later timepoints ongoing). At 13mo, the target lesions began increasing in size (-50% to -43%) prompting a dose increase of cam to 80mg (same gem dose), after which the target lesions decreased to nadir (-52%) at 76w with concomitant CA-125 decrease. Retrospective whole-genome sequencing (WGS) of the secondary debulking surgery specimen as well as targeted sequencing (SyNthetic lethal Interactions for Precision Diagnostics [SNiPDx]) and immunohistochemistry of the metastatic biopsy revealed ATM protein loss only in a portion of the tumor and a monoallelic ATM mutation. Genomic signature analysis of WGS indicated presence of single-base substitution signatures 3+8 (HRD-related) and HRD positivity (BRCA1-type; CHORD algorithm). In contrast, while HRD+ was also detected in the primary tumor sample, the ATM alteration was absent and ATM protein expression was uniform, suggesting that ATM loss was a late event in tumor evolution. This case highlights the complexity of intra-tumor heterogeneity and clonal evolution in ovarian tumors and importance of “functional” HRD as no apparent mutational driver was identified. Citation Format: Stephanie Lheureux, Joseph D. Schonhoft, Ian M. Silverman, Julia Yang, Adrienne Johnson, Brooke Grant, Alexander Fortuna, Trevor J. Pugh, Parham Nejad, Bernard Lam, Sahaj Arora, Ashley Adile, Stephenie D. Prokopec, Jeffrey Bruce, Danielle Ulanet, Maria Koehler, Ezra Rosen, Victoria Rimkunas. Identification of monoallelic ATM loss-of-function and homologous recombination deficiency (HRD) in high-grade ovarian tumor with prolonged response to camonsertib and low-dose gemcitabine combination therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr B001.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".