Christine M Veenstra, Paul Abrahamse, Ann S Hamilton, Kevin C Ward, Scarlett L Gomez, Lihua Liu, Steven J Katz, Timothy P Hofer, Allison W Kurian
{"title":"与ATM、CHEK2或PALB2致病变异有关的乳腺癌、结直肠癌和胰腺癌死亡率。","authors":"Christine M Veenstra, Paul Abrahamse, Ann S Hamilton, Kevin C Ward, Scarlett L Gomez, Lihua Liu, Steven J Katz, Timothy P Hofer, Allison W Kurian","doi":"10.1200/JCO-24-02442","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>Oncologists encounter patients with pathogenic variants (PVs) in <i>ATM</i>, <i>CHEK2</i>, or <i>PALB2</i>, but little is known about their cancer mortality.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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 <i>ATM</i>, <i>CHEK2</i>, or <i>PALB2</i> PVs had no differences in breast, colorectal, or pancreatic cancer mortality. Patients with <i>ATM</i> 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 <i>BRCA1</i>/<i>2</i> 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]).</p><p><strong>Conclusion: </strong>Patients with <i>ATM</i>, <i>CHEK2</i>, or <i>PALB2</i> PVs had similar breast, colorectal, and pancreatic cancer mortality to the average genetically tested patient with their cancer type.</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":" ","pages":"1587-1596"},"PeriodicalIF":42.1000,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12037317/pdf/","citationCount":"0","resultStr":"{\"title\":\"Breast, Colorectal, and Pancreatic Cancer Mortality With Pathogenic Variants in <i>ATM</i>, <i>CHEK2</i>, or <i>PALB2</i>.\",\"authors\":\"Christine M Veenstra, Paul Abrahamse, Ann S Hamilton, Kevin C Ward, Scarlett L Gomez, Lihua Liu, Steven J Katz, Timothy P Hofer, Allison W Kurian\",\"doi\":\"10.1200/JCO-24-02442\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>Oncologists encounter patients with pathogenic variants (PVs) in <i>ATM</i>, <i>CHEK2</i>, or <i>PALB2</i>, but little is known about their cancer mortality.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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 <i>ATM</i>, <i>CHEK2</i>, or <i>PALB2</i> PVs had no differences in breast, colorectal, or pancreatic cancer mortality. Patients with <i>ATM</i> 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 <i>BRCA1</i>/<i>2</i> 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]).</p><p><strong>Conclusion: </strong>Patients with <i>ATM</i>, <i>CHEK2</i>, or <i>PALB2</i> PVs had similar breast, colorectal, and pancreatic cancer mortality to the average genetically tested patient with their cancer type.</p>\",\"PeriodicalId\":15384,\"journal\":{\"name\":\"Journal of Clinical Oncology\",\"volume\":\" \",\"pages\":\"1587-1596\"},\"PeriodicalIF\":42.1000,\"publicationDate\":\"2025-05-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12037317/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Clinical Oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1200/JCO-24-02442\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/2/28 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Clinical Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1200/JCO-24-02442","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/2/28 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
Breast, Colorectal, and Pancreatic Cancer Mortality With Pathogenic Variants in ATM, CHEK2, or PALB2.
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.
期刊介绍：
The Journal of Clinical Oncology serves its readers as the single most credible, authoritative resource for disseminating significant clinical oncology research. In print and in electronic format, JCO strives to publish the highest quality articles dedicated to clinical research. Original Reports remain the focus of JCO, but this scientific communication is enhanced by appropriately selected Editorials, Commentaries, Reviews, and other work that relate to the care of patients with cancer.
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