Results from a first population-based cohort of cancer mortality in patients with ATM, CHEK2, or PALB2 pathogenic variants (PVs) across breast, colorectal, and pancreatic cancers, suggest that people with ATM, CHEK2, or PALB2 PVs have similar breast, colorectal, and pancreatic cancer mortality hazard when compared with the overall hazard for patients with those cancer types.
The results may reassure patients and inform clinical discussions about prognosis according to Dr. Allison W. Kurian of the Departments of Medicine and Epidemiology and Population Health, Stanford University School of Medicine in Stanford, CA, US and colleagues, who published the findings on 28 February 2025 in the JCO.
Inherited PVs inform cancer treatment, surveillance, and testing of relatives. Three genes in which PVs are often detected are ATM, increasing risk of breast, pancreatic, and potentially colorectal cancers; CHEK2, increasing risk of breast and potentially other cancers; and PALB2, increasing risks of breast, pancreatic, and potentially other cancers. While CHEK2 PVs were associated with colorectal cancer risk in previous studies, recent studies have questioned this association and consensus is lacking.
ATM, CHEK2, or PALB2 PVs account for approximately 3% of breast cancer cases, representing nearly half of clinically meaningful PVs detected on germline testing. Yet, little is known about cancer mortality with these PVs. Although previous studies demonstrated lower breast, ovarian, and pancreatic cancer mortality with BRCA1/2 PVs and lower colorectal cancer mortality with Lynch syndrome gene PVs, studies of CHEK2 PV-associated breast cancer mortality had mixed results.
In this study, the authors investigated cancer-specific mortality in a population-based cohort of all adults diagnosed in a period from 2013 to 2019 with breast, colorectal, or pancreatic cancer in Georgia and California who had germline testing results from one of four participating laboratories. The hypothesis was that patients with ATM, CHEK2, or PALB2 PVs have no difference in cancer-specific mortality compared with the average risk for genetically tested patients with same cancer type.
Patients who were 20 years or older, reported to the US National Cancer Institute’s (NCI’s) Surveillance, Epidemiology and End Results (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 modelled 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 regularisation approach to reduce overfitting.
A total of 70272 tested patients with breast (of whom 48473 with oestrogen receptor-/progesterone receptor-positive, HER2-negative; 9957 with HER2-positive; 11842 with triple-negative) cancer, 5822 with colorectal cancer, and 1861 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% confidence interval [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).
The authors commented that as in all studies of gene-outcome relationships, there are potential selection effects in terms of who received genetic testing. Genetic testing rates vary by cancer type, race, and ethnicity. The current results are predictive comparisons that apply to the tested population, and one should be cautious in generalising beyond that population or if the tested population changes substantially.
However, the study limitations are counterbalanced by considerable strengths: a diverse, contemporary, population-based sample representing a catchment area of 50 million people and the most complete population-based sample of genetically tested patients that exists to date; lifetime passive and active follow-up by SEER registries; and genetic data directly from testing laboratories. Therefore, these results may reassure patients and inform clinical discussions about prognosis according to the authors.
The study was supported by grants from the NCI. The collection of cancer incidence data used in this study was supported by the California Department of Public Health, Centers for Disease Control and Prevention's (CDC) National Program of Cancer Registries, and the NCI's SEER Program. The collection of cancer incidence data in Georgia was supported by NCI and CDC.
Reference
Veenstra CM, Abrahamse P, Hamilton AS, et al. Breast, Colorectal, and Pancreatic Cancer Mortality With Pathogenic Variants in ATM, CHEK2, or PALB2. JCO; Published online 28 February 2025. DOI: https://doi.org/10.1200/JCO-24-02442