Breast, Colorectal, and Pancreatic Cancer Mortality With Pathogenic Variants in ATM, CHEK2, or PALB2 - PubMed (original) (raw)

Breast, Colorectal, and Pancreatic Cancer Mortality With Pathogenic Variants in ATM, CHEK2, or PALB2

Christine M Veenstra et al. J Clin Oncol. 2025 May.

Abstract

Purpose: Oncologists encounter patients with pathogenic variants (PVs) in ATM, CHEK2, or PALB2, but little is known about their cancer mortality.

Methods: Patients who were 20 years or older, diagnosed in 2013-2019 with breast, colorectal, or pancreatic cancer, and reported to SEER registries in California and Georgia were linked to germline genetic testing results from four clinical laboratories and followed through 2021. Multivariable models of cancer mortality were fit; for each cancer, the reference group was the average hazard across all genetically tested patients with that diagnosis. Each cancer was modeled separately, followed by a single model that interacted the cancer type with all covariates. In addition to fixed effects models, random effects models were used as a regularization approach to reduce overfitting.

Results: A total of 70,272 tested patients with breast (48,473 estrogen receptor-/progesterone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative; 9,957 HER2-positive; 11,842 triple-negative) cancer, 5,822 with colorectal cancer, and 1,861 with pancreatic cancer were analyzed; the mean follow-up was 3.9 years. Patients with ATM, CHEK2, or PALB2 PVs had no differences in breast, colorectal, or pancreatic cancer mortality. Patients with ATM PVs in triple-negative breast cancer appeared to have higher mortality in fixed effects models (hazard ratio [HR], 3.7 [95% CI, 1.8 to 7.8]), but not in random effects models (HR, 1.2 [95% CI, 0.8 to 1.6]) that reduce overfitting. Patients with BRCA1/2 PVs had lower triple-negative breast cancer mortality in both models (fixed HR, 0.6 [95% CI, 0.5 to 0.9], random HR, 0.7 [95% CI, 0.6 to 0.8]). Patients with Lynch syndrome gene PVs had lower colorectal cancer mortality in both models (fixed HR, 0.5 [95% CI, 0.4 to 0.8], random HR, 0.7 [95% CI, 0.5 to 0.9]).

Conclusion: Patients with ATM, CHEK2, or PALB2 PVs had similar breast, colorectal, and pancreatic cancer mortality to the average genetically tested patient with their cancer type.

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Conflict of interest statement

Conflict of Interest Disclosures: The authors have no conflicts of interest to disclose.

Figures

Figure 1.

Figure 1.. Hazard ratios for cancer-specific mortality by genetic testing results.

Separate models were run for each cancer type (breast cancer: triple-negative, HER2-positive, and estrogen receptor (ER) and/or progesterone receptor (PR)-positive and HER2-negative; colorectal cancer; and pancreatic cancer). Genetic testing results were 1) pathogenic variants (PVs) in ATM, CHEK2, PALB2, BRCA1, BRCA2 (BRCA1/2), Lynch Syndrome genes (MLH1, MSH2, MSH6, PMS2, EPCAM), or other tested genes; 2) variants of unknown significance (VUS) in any tested gene; or 3) no pathogenic variant or VUS in any tested gene. A gamma frailty model was used to estimate random and fixed coefficients, both of which were centered around zero; hazard ratios for each cancer type represent comparison to a hypothetical person with that diagnosis and with the average hazard across all observed genetic testing results in the study population, holding other model covariates constant. For the random effects models a likelihood ratio test of whether the gene group coefficients differ overall from the average hazard for each cancer is given at the top of the figure.

References

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