Citations 5
Abstract GS4-04: Population-based Estimates of contralateral Breast Cancer Risk among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2
Yadav, Siddhartha , Dunn, Carolyn, Holtegaard, Susan, Patel, Alpa V. , Martínez, Elena, Haiman, Christopher, Ruddy, Kathryn, Ziogas, Argyrios, Goldgar, David E. , Nathanson, Katherine L. , Yadav, Siddhartha , Nathanson, Katherine L , Boddicker, Nicholas , Na, Jie , Polley, Eric C. , Hu, Chunling , Hart, Steven N. , Gnanaolivu, Rohan , Larson, Nicole, Dunn, Carolyn, Huang, Huaizhi , Teras, Lauren R. , Lacey, James V. , Neuhausen, Susan L. , Bernstein, Leslie , Chen, Fei , Ruddy, Kathryn J. , Olson, Janet E. , John, Esther M. , Kurian, Allison W. , Sandler, Dale P. , O’Brien, Katie M. , Taylor, Jack A. , Weinberg, Clarice R. , Anton‐Culver, Hoda , Zirpoli, Gary , Domchek, Susan M. , Palmer, Julie R. , Weitzel, Jeffrey N. , Kraft, Peter , Couch, Fergus J.
Cancer Research | March 2, 2023 | Volume: 83 | Issue: 5_Supplement | Pages: GS4-04-GS4-04
10.1158/1538-7445.sabcs22-gs4-04
Abstract Purpose To estimate the risk of contralateral breast cancer (CBC) among women in the general population with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2. Methods Among 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer, a subset of 14,237 women were identified from population-based studies. The risk of CBC was estimated for PV carriers in each gene compared to women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor status. Results Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (Hazard ratio ≥ 1.9, p< 0.05) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks. In contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 15-year cumulative incidence of CBC was >20% for BRCA1, BRCA2 and CHEK2 PV carriers with breast cancer, and for PALB2 PV carriers with ER-negative breast cancer. The 15-year cumulative incidence of CBC among postmenopausal PV carriers was < 20% for PV carriers in any of the 5 genes. Conclusions Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk-reduction strategies. Citation Format: Siddhartha Yadav, Nicholas J. Boddicker, Jie Na, Eric C. Polley, Chunling Hu, Steven N. Hart, Rohan D. Gnanaolivu, Nicole Larson, Carolyn Dunn, Susan Holtegaard, Huaizhi Huang, Lauren R. Teras, Alpa V. Patel, James V. Lacey Jr., Susan Neuhausen, Leslie Bernstein, Elena Martinez, Christopher Haiman, Fei Chen, Kathryn Ruddy, Janet Olson, Esther John, Allison W. Kurian, Dale P. Sandler, Katie M. O’Brien, Jack A. Taylor, Clarice R. Weinberg, Hoda Anton-Culver, Argyrios Ziogas, Gary R. Zirpoli, David E. Goldgar, Katherine L. Nathanson, Susan Domchek, Julie R. Palmer, Jeffrey Weitzel, Peter Kraft, Fergus J. Couch. Population-based Estimates of contralateral Breast Cancer Risk among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-04.
Contralateral Breast Cancer Risk Among Carriers of Germline Pathogenic Variants in ATM , BRCA1 , BRCA2 ,
Yadav, Siddhartha , Boddicker, Nicholas , Na, Jie , Polley, Eric C. , Hart, Steven N. , Larson, Nicole L. , Holtegaard, Susan, Huang, Huaizhi , Dunn, Carolyn, Patel, Alpa V. , Martínez, Elena, Haiman, Christopher A. , Chen, Fei , Ruddy, Kathryn J. , John, Esther M. , Kurian, Allison W. , Taylor, Jack A. , Zirpoli, Gary , Goldgar, David E. , Weitzel, Jeffrey N. , Nathanson, Katherine L. , Chen, Chen , Lumby, Carolyn A. , Boddicker, Nicholas J , Hu, Chunling , Hart, Steven N , Gnanaolivu, Rohan D., Larson, Nicole , Dunn, Carolyn A, Teras, Lauren R , Neuhausen, Susan L. , Martı́nez, Marı́a Elena , Haiman, Christopher A , Chen, Fei , Ruddy, Kathryn J , John, Esther M , Kurian, Allison W , Sandler, Dale P , O'Brien, Katie M , Taylor, Jack A , Anton-Culver, Hoda , Ziogas, Argyrios , Zirpoli, Gary , Goldgar, David E , Palmer, Julie R , Domchek, Susan M , Weitzel, Jeffrey N , Nathanson, Katherine L , Kraft, Peter , Couch, Fergus J. , Chen, C , Yadav, Siddhartha , Polley, Eric C , Na, Jie , Huang, Huaizhi , Lumby, Carolyn A , Hu, Chunling , Gnanaolivu, Rohan , Teras, Lauren R. , Lacey, James V. , Olson, Janet E. , Sandler, Dale P. , O’Brien, Katie M. , Weinberg, Clarice R. , Anton‐Culver, Hoda , Ziogas, Argyrios , Palmer, Julie R. , Domchek, Susan M. , Kraft, Peter , Couch, Fergus J.
Journal of Clinical Oncology | January 9, 2023 | Volume: 41 | Issue: 9 | Pages: 1703-1713
PURPOSE To estimate the risk of contralateral breast cancer (CBC) among women with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2. METHODS The study population included 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer. The risk of CBC was estimated for PV carriers in each gene compared with women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor (ER) status. RESULTS Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (hazard ratio > 1.9) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks (hazard ratio, 2.9). By contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 10-year cumulative incidence of CBC was estimated to be 33% for BRCA1, 27% for BRCA2, and 13% for CHEK2 PV carriers with breast cancer and 35% for PALB2 PV carriers with ER-negative breast cancer. The 10-year cumulative incidence of CBC among postmenopausal PV carriers was 12% for BRCA1, 9% for BRCA2, and 4% for CHEK2. CONCLUSION Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk reduction strategies.
Abstract P2-09-01: Population-based risk estimates of clinical subtypes of breast cancer among carriers of germline pathogenic variants in cancer predisposition genes
Yadav, Siddhartha , Huang, Hongyan , Yao, Song, Vachon, Celine M. , Martínez, Elena, Lindströem, Sara, Haiman, Christopher A. , Gaudet, Mia M. , Auer, Paul, Goldgar, David E. , Nathanson, Katherine L. , Yadav, Siddhartha , Nathanson, Katherine L , Hu, Chunling , Boddicker, Nicholas , Polley, Eric C. , Hart, Steven N. , Gnanaolivu, Rohan , Na, Jie , Yao, Song , Vachon, Celine M. , Teras, Lauren R. , Taylor, Jack A. , Sandler, Dale P. , Palmer, Julie R. , Olson, Janet E. , Neuhausen, Susan L. , Marchand, Loı̈c Le , Kooperberg, Charles , Lacey, James V. , Bertrand, Kimberly A. , Bernstein, Leslie , Ambrosone, Christine B. , Weitzel, Jeffrey N. , Kraft, Peter , Domchek, Susan M. , Couch, Fergus J.
Cancer Research | March 8, 2022 | Volume: 82 | Issue: 4_Supplement | Pages: P2-09-01-P2-09-01
10.1158/1538-7445.sabcs21-p2-09-01
Abstract Introduction: The risk of specific clinical subtype of breast cancer (defined by ER and HER2 status) among women in the general population who are carriers of germline pathogenic variants (PVs) in cancer predisposition genes is not well-defined. Methods: A total of 13,153 women with breast cancer (ER+/HER2-: 9381; ER+/HER2+: 1462; ER-/HER2+: 690; and ER-/HER2-: 1620) and 25,005 unaffected women (controls) from nine studies within the CAnceR RIsk Estimates Related to Susceptibility (CARRIERS) consortium that were not enriched for family history or early onset disease were included in the present analysis. A multiplex amplicon-based panel was used to perform germline sequencing for cancer predisposition genes. Case-control associations for each of the four clinical subtype of breast cancer was performed for PVs in 5 common breast cancer predisposition genes (ATM, BRCA1, BRCA2, CHEK2 and PALB2) utilizing a logistic regression model adjusting for study, age at diagnosis, race/ethnicity and family history of breast cancer. Results: The frequency of PVs in 5 genes was 3.8% for ER+/HER2-, 6.2% for ER+/HER2+, 4.2% for ER-/HER2+ and 9.3% for ER-/HER2- subtypes. PVs in BRCA1 and BRCA2 were associated with high risk (Odds Ratio (OR) >4) for all clinical subtypes of breast cancer, but the risk was highest (OR>8) for ER-/HER2- breast cancer. PVs in PALB2 were associated with high risk (OR>4) of ER-/HER2- and ER+/HER2+ subtypes and moderate risk (OR: 2-4) of ER+/HER2- breast cancer. Irrespective of the HER2 status, PVs in ATM were associated with a moderately increased risk (OR: 2-4) of ER+ breast cancer but the risk of ER- breast cancer was not elevated. In contrast, PVs in CHEK2 were associated with high risk (OR>4) of ER+/HER2+ breast cancer and moderate risk (OR: 2-4) of ER+/HER2- and ER-/HER2+ breast cancer, but the risk of ER-/HER2- breast cancer was not elevated. Conclusions: This study provides population-based estimates of risk of specific clinical subtypes of breast cancer which will be useful for genetic counseling and targeting appropriate screening strategies in PV carriers based on subtype specific risks of breast cancer. Citation Format: Siddhartha Yadav, Chunling Hu, Nicholas J. Boddicker, Eric Polley, Steven Hart, Rohan Gnanaolivu, Jie Na, Hongyan Huang, Song Yao, Celine M. Vachon, Lauren Teras, Jack A. Taylor, Dale P. Sandler, Julie R. Palmer, Janet E. Olson, Susan Neuhausen, Elena Martinez, Sara Lindstroem, Loic Le Marchand, Charles Kooperberg, Christopher Haiman, Mia M. Gaudet, James V. Lacey, Kimberly A. Bertrand, Leslie Bernstein, Paul W. Auer, Christine Ambrosone, Jeffrey N. Weitzel, Peter Kraft, David E. Goldgar, Katherine L. Nathanson, Susan M. Domchek, Fergus J. Couch, CARRIERS Consortium. Population-based risk estimates of clinical subtypes of breast cancer among carriers of germline pathogenic variants in cancer predisposition genes [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-09-01.
Breast Cancer Screening Strategies for Women With ATM, CHEK2, and PALB2 Pathogenic Variants
Lowry, Kathryn P. , Geuzinge, H. Amarens , Stout, Natasha K. , Alagöz, Oğuzhan , Hampton, John M. , Koning, Harry J. de , Miglioretti, Diana L. , Ravesteyn, Nicolien T. van , Sprague, Brian L. , Tosteson, Anna N.A. , Weaver, Donald L. , Yaffe, Martin J. , Mandelblatt, Jeanne S. , Kurian, Allison W. , Auer, Paul L. , Berstein, Leslie, Carter, Brian D., Gaudet, Mia M. , Haiman, Christopher, Jacobs, Eric J. , John, Esther M. , Lindström, Sara , Martínez, Elena, Patel, Alpa V. , Reid, Sonya , Taylor, Jack A. , Teras, Lauren R., Vachon, Celine M. , Yao, Song, Ziogas, Argyrios, Goldgar, David E. , Chen, Chen , Chen, C , Miglioretti, Diana L , John, Esther M , Taylor, Jack A , de Koning, Harry J , Kurian, Allison W , Kerlikowske, Karla , Schechter, Clyde B. , Trentham‐Dietz, Amy , Yeh, Jennifer M. , Couch, Fergus J. , Hu, Chunling , Kraft, Peter , Polley, Eric C. , Robson, Mark E. , Hart, Steven N. , Nathanson, Katherine L. , Domchek, Susan M. , Ambrosone, Christine B. , Anton‐Culver, Hoda , Bandera, Elisa V. , Bertrand, Kimberly A. , Burnside, Elizabeth S. , Eliassen, A. Heather , Hodge, James M. , Hunter, David J. , Kooperberg, Charles , Lacey, James V. , Marchand, Loı̈c Le , Ma, Huiyan , Neuhausen, Susan L. , Newcomb, Polly A. , O’Brien, Katie M. , Olson, Janet E. , Ong, Irene M. , Pal, Tuya , Palmer, Julie R. , Rosenberg, Lynn A. , Sandler, Dale P. , Tamimi, Rulla M. , Teras, Lauren R. , Vachon, Celine M. , Weinberg, Clarice R. , Yadav, Siddhartha , Yao, Song , Weitzel, Jeffrey N.
JAMA Oncology | February 17, 2022 | Volume: 8 | Issue: 4 | Pages: 587
Risk of Late-Onset Breast Cancer in Genetically Predisposed Women
Boddicker, Nicholas , Weitzel, Jeffrey N. , Kraft, Peter , Nathanson, Katherine L. , Goldgar, David E. , Na, Jie , Huang, Hongyan , Larson, Nicole L. , Yussuf, Amal , Vachon, Celine M. , Taylor, Jack A. , Scott, Christopher E., Pesaran, Tina , Patel, Alpa V. , Ong, Irene M. , Martínez, Elena, Ma, Huiyan , Lindström, Sara , Hodge, James M. , Haiman, Christopher A. , Gaudet, Mia M. , Gao, Chi , LaDuca, Holly , Dolinsky, Jill S. , Carter, Brian D., Auer, Paul, Yadav, Siddhartha , Chen, Chen , Boddicker, Nicholas J , Hu, Chunling , Weitzel, Jeffrey N , Kraft, Peter , Nathanson, Katherine L , Goldgar, David E , Na, Jie , Gnanaolivu, Rohan D., Yussuf, Amal , Yao, Song , Vachon, Celine M. , Trentham-Dietz, Amy , Teras, Lauren R , Taylor, Jack A , Sandler, Dale P , Pesaran, Tina , Palmer, Julie R , Ong, Irene M , Neuhausen, Susan L. , Martı́nez, Marı́a Elena , Karam, Rachid , Hodge, James M , Gaudet, Mia M , Gao, Chi , LaDuca, Holly , Dolinsky, Jill S , Burnside, Elizabeth S , Bertrand, Kimberly A , Bernstein, Leslie , Ambrosone, Christine B , Yadav, Siddhartha , Hart, Steven N , Polley, Eric C , Domchek, Susan M , Couch, Fergus J. , Chen, C , Hu, Chunling , Gnanaolivu, Rohan , Yao, Song , Trentham‐Dietz, Amy , Teras, Lauren R. , Sandler, Dale P. , Palmer, Julie R. , Olson, Janet E. , O’Brien, Katie M. , Marchand, Loı̈c Le , Kooperberg, Charles , Karam, Rachid , Hunter, David J. , Lacey, James V. , Chao, Elizabeth , Burnside, Elizabeth S. , Bertrand, Kimberly A. , Bernstein, Leslie , Ambrosone, Christine B. , Hart, Steven N. , Polley, Eric C. , Domchek, Susan M. , Couch, Fergus J.
Journal of Clinical Oncology | July 22, 2021 | Volume: 39 | Issue: 31 | Pages: 3430-3440
PURPOSE The prevalence of germline pathogenic variants (PVs) in established breast cancer predisposition genes in women in the general population over age 65 years is not well-defined. However, testing guidelines suggest that women diagnosed with breast cancer over age 65 years might have < 2.5% likelihood of a PV in a high-penetrance gene. This study aimed to establish the frequency of PVs and remaining risks of breast cancer for each gene in women over age 65 years. METHODS A total of 26,707 women over age 65 years from population-based studies (51.5% with breast cancer and 48.5% unaffected) were tested for PVs in germline predisposition gene. Frequencies of PVs and associations between PVs in each gene and breast cancer were assessed, and remaining lifetime breast cancer risks were estimated for non-Hispanic White women with PVs. RESULTS The frequency of PVs in predisposition genes was 3.18% for women with breast cancer and 1.48% for unaffected women over age 65 years. PVs in BRCA1, BRCA2, and PALB2 were found in 3.42% of women diagnosed with estrogen receptor (ER)–negative, 1.0% with ER-positive, and 3.01% with triple-negative breast cancer. Frequencies of PVs were lower among women with no first-degree relatives with breast cancer. PVs in CHEK2, PALB2, BRCA2, and BRCA1 were associated with increased risks (odds ratio = 2.9-4.0) of breast cancer. Remaining lifetime risks of breast cancer were ≥ 15% for those with PVs in BRCA1, BRCA2, and PALB2. CONCLUSION This study suggests that all women diagnosed with triple-negative breast cancer or ER-negative breast cancer should receive genetic testing and that women over age 65 years with BRCA1 and BRCA2 PVs and perhaps with PALB2 and CHEK2 PVs should be considered for magnetic resonance imaging screening.