Citations 70
MRI Surveillance and Breast Cancer Mortality in Women With BRCA1 and BRCA2 Sequence Variations
Møller, Pål , Eisen, Andrea , Peck, Larissa , Bordeleau, Louise , Zakalik, Dana , Stempa, Klaudia , Dungan, J.S., Cullinane, Carey A., Olopade, Olufunmilayo I. , Metcalfe, Kelly , Sun, Ping , Narod, Steven A. , Sweet, Kevin , Velsher, Lea, McCuaig, Jeanna , Panchal, Seema, Poll, Aletta, Lemire, Edmond G., Serfas, Kim, Costalas, Josephine Wagner, Blum, Joanne L. , Olopade, Olufunmilayo I , Metcalfe, Kelly A , Eisen, Andrea , Bordeleau, Louise , Lubiński, Jan , Kotsopoulos, Joanne , Pal, Tuya , Karlan, Beth Y. , Aeilts, Amber M. , Eng, Charis , Foulkes, William D. , Tung, Nadine , Couch, Fergus J. , Fruscio, Robert , Cajal, Teresa Ramón y , Singer, Christian F. , Neuhausen, Susan L. , Cybulski, Cezary , Gronwald, Jacek , Huzarski, Tomasz , Senter, Leigha , Saal, Howard M. , Armel, Susan Randall , Reilly, Richard B. , Cohen, Stephanie A.
JAMA Oncology | February 29, 2024 | Volume: 10 | Issue: 4 | Pages: 493
Importance Magnetic resonance imaging (MRI) surveillance is offered to women with a pathogenic variant in the BRCA1 or BRCA2 gene who face a high lifetime risk of breast cancer. Surveillance with MRI is effective in downstaging breast cancers, but the association of MRI surveillance with mortality risk has not been well defined. Objective To compare breast cancer mortality rates in women with a BRCA1 or BRCA2 sequence variation who entered an MRI surveillance program with those who did not. Design, Setting, and Participants Women with a BRCA1 or BRCA2 sequence variation were identified from 59 participating centers in 11 countries. Participants completed a baseline questionnaire between 1995 and 2015 and a follow-up questionnaire every 2 years to document screening histories, incident cancers, and vital status. Women who had breast cancer, a screening MRI examination, or bilateral mastectomy prior to enrollment were excluded. Participants were followed up from age 30 years (or the date of the baseline questionnaire, whichever was later) until age 75 years, the last follow-up, or death from breast cancer. Data were analyzed from January 1 to July 31, 2023. Exposures Entrance into an MRI surveillance program. Main Outcomes and Measures Cox proportional hazards modeling was used to estimate the hazard ratios (HRs) and 95% CIs for breast cancer mortality associated with MRI surveillance compared with no MRI surveillance using a time-dependent analysis. Results A total of 2488 women (mean [range] age at study entry 41.2 [30-69] years), with a sequence variation in the BRCA1 (n = 2004) or BRCA2 (n = 484) genes were included in the analysis. Of these participants, 1756 (70.6%) had at least 1 screening MRI examination and 732 women (29.4%) did not. After a mean follow-up of 9.2 years, 344 women (13.8%) developed breast cancer and 35 women (1.4%) died of breast cancer. The age-adjusted HRs for breast cancer mortality associated with entering an MRI surveillance program were 0.20 (95% CI, 0.10-0.43; P < .001) for women with BRCA1 sequence variations and 0.87 (95% CI, 0.10-17.25; P = .93) for women with BRCA2 sequence variations. Conclusion and Relevance Results of this cohort study suggest that among women with a BRCA1 sequence variation, MRI surveillance was associated with a significant reduction in breast cancer mortality compared with no MRI surveillance. Further studies of women with BRCA2 sequence variations are needed to ascertain these women obtain the same benefits associated with MRI surveillance.
A Likelihood Ratio Approach for Utilizing Case-Control Data in the Clinical Classification of Rare Sequence Variants: Application to BRCA1 and BRCA2
Zanti, Maria , O'Mahony, Denise G , Li, Hongyan , Aittomäkkiki, Kristiina, Andrulis, Irene L. , Aronson, Kristan J. , Bolla, Manjeet K. , Brenner, Hermann , Caputo, Sandrine M. , Chang‐Claude, Jenny , Collaborators, GC-HBOC study, Daly, Mary B., Nicolo, Arcangela De , Eccles, Diana M., Engel, Christoph , Evans, D. Gareth , Fasching, Peter A. , Giele, Willemina R. R. Geurts -, Glendon, Gord , Goldberg, Mark S. , Gómez, E. , Güendert, Melanie, Hahnen, Eric , Haiman, Christopher A. , Hamann, Ute, Harkness, Elaine F. , Hogervorst, Frans B.L., Hoppe, Reiner , Houdayer, Claude , Houlston, Richard S. , Howell, Anthony , Investigators, ABCTB, Jakimovska, Milena , John, Esther M. , Kristensen, Vessela N. , Lambrechts, Diether , Léone, Mélanie, Lindblom, Annika , Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush , Menon, Usha , Offit, Kenneth, Park, Sue K. , Peto, Julian , Plaseska‐Karanfilska, Dijana , Romero, Atocha , Schmutzler, Rita K. , Stone, Jennifer , Tapper, William , Teo, Soo‐Hwang , Thomassen, Mads , Vachon, Celine M. , Vega, Ana , Wang, Qin , Wappenschmidt, Barbara , Zheng, Wei , Easton, Douglas F. , Goldgar, David E., Eccles, Diana , Lambrechts, Diether , Houdayer, Claude , Lambrechts, Diether , Teo, Soo H , Eccles, Diana , Menon, Usha , Houlston, Richard S , Vega, Ana , Evans, D Gareth , John, Esther M , Lambrechts, Diether , Brenner, Hermann , Romero, Atocha , Engel, Christoph , Zheng, Wei , Stone, Jennifer , Gómez-García, Encarna B , De Nicolo, Arcangela , Manoukian, Siranoush , Lindblom, Annika , Plaseska-Karanfilska, Dijana , Parsons, Michael T. , Dennis, Joe , Anton‐Culver, Hoda , Augustinsson, Annelie , Becher, Heiko , Bojesen, Stig E. , Brown, Melissa A. , Buys, Saundra S. , Canzian, Federico , Castelao, Jose E. , Czene, Kamila , Devilee, Peter , Dörk, Thilo , Dunning, Alison M. , Dwek, Miriam , Gago-Domínguez, Manuela , García‐Closas, Montserrat , García-Sáenz, José Á. , Gentry‐Maharaj, Aleksandra , Geurts-Giele, Willemina R.R. , Giles, Graham G. , Guénel, Pascal , Hall, Per N , Hollestelle, Antoinette , Hopper, John L. , Jakubowska, Anna , Jernström, Helena , Kaaks, Rudolf , Kitahara, Cari M. , Koutros, Stella , Kraft, Peter , Lacey, James V. , Léoné, Mélanie, Lubiński, Jan , Lush, Michael J. , Mannermaa, Arto, Margolin, Sara , Martı́nez, Marı́a Elena , Milne, Roger L. , Monteiro, Álvaro N.A. , Murphy, Rachel A. , Neuhausen, Susan L. , Nevanlinna, Heli , Newman, William G. , James, Paul A. , Peterlongo, Paolo , Punie, Kevin , Radice, Paolo , Rashid, Muhammad Usman , Rennert, Gad , Rosenberg, Efraim H. , Saloustros, Emmanouil , Sandler, Dale P. , Schmidt, Marjanka K. , Shu, Xiao‐Ou , Simard, Jacques , Southey, Melissa C. , Stoppa‐Lyonnet, Dominique , Tamimi, Rulla M. , Taylor, Jack A. , Teras, Lauren R. , Terry, Mary Beth , Troester, Melissa A. , Vachon, Celine M. , Vreeswijk, Maaike P.G. , Weinberg, Clarice R. , Wolk, Alicja , Feng, Bing , Couch, Fergus J. , Spurdle, Amanda B. , Michailidou, Kyriaki
Human Mutation | September 15, 2023 | Volume: 2023 | Issue: No issue available | Pages: 1-17
A large number of variants identified through clinical genetic testing in disease susceptibility genes are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion) can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analysis of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC) and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity—findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared with classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and preformatted Excel calculators for implementation of the method for rare variants in BRCA1, BRCA2, and other high-risk genes with known penetrance.
ENIGMA CHEK2 gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk
Stolařová, Lenka , Kleiblová, Petra , Šťastná, Barbora , Janatová, Markéta , Soukupová, Jana , Achatz, Maria Isabel , Ambrosone, Christine B. , Apostolou, Paraskevi , Arun, Banu , Auer, Paul L. , Bertelsen, Birgitte , Japan, Biobank, Kamatani, Yoichiro, Morisaki, Takayuki , Nagai, Akiko , Muto, Kaori , Murakami, Yoshinori , Furukawa, Yoichi , Yamanashi, Yuji , Nakamura, Yusuke , Momozawa, Yukihide , Ohnishi, Yozo, Kubo, Michiaki , Higashiue, Shinichi , Kobayashi, Shuzo , Minami, Shiro, Yamaguhci, Hiroki, Arai, Hajime , Yamaji, Ken , Asai, Satoshi , Fujioka, Tomoaki, Obara, Wataru , Mori, Seijiro, Murayama, Shigeo , Miki, Yoshio , Masumoto, Akihide, Yamada, Akira , Nishizawa, Yasuko, Higashiyama, Masahiko, Kutsumi, Hiromu, Koretsune, Yukihiro , Blok, Marinus J. , Brunet, Joan , Calvello, Mariarosaria , Chen, Fei , Cortesi, Laura , Crujeiras-González, Ana , Černá, Marta , Hovhannisyan, Milena, Jelínková, Sandra , Nehasil, Petr , Macháčková, Eva , Krutilkova, Vera, Tavandzis, Spiros , Cerna, Leona, Chvojka, Štěpán, Koudová, Monika , Puchmajerová, Alena, Novotný, Jan , Veselá, Kamila , Hrušková, Lucie , Michalovska, Renata, Schwetzova, Denisa, Vlčková, Zdeňka, Černá, Monika, Hejnalová, Markéta, Jedlickova, Nikol, Šubrt, Ivan , Zavoral, Tomas, Kosařová, Marcela, Vacínová, Gabriela, Janíková, Mária , Kratochvílová, Romana , Curtisová, Václava , Vrtěl, Radek , Scheinost, Ondřej, Duskova, Petra, Putter, Robin De , Efremidis, Anna , Engel, Christoph , Evans, D. Gareth , Feliubadaló, Lídia , Fuentes-Ríos, Olivia , Gómez, E. , Haiman, Christopher A. , Hansen, Thomas van Overeem , Hodge, James M. , Huang, Hongyan , Ishak, Nur Diana Binte , Iwasaki, Yusuke , Konstantopoulou, Irene , Li, Na , Lindström, Sara , Lori, Adriana , Martinez, Elana, Martins, Alexandra , McInerny, Simone , Montagna, Marco , Mori, Luigi , Nathanson, Katherine L. , Patel, Alpa V. , Poppe, Bruce , Rosseel, Toon , Ruddy, Kathryn J. , Santos, Elizabeth Santana Dos , Vachon, Celine M. , Volk, Alexander E. , Weber‐Lassalle, Nana , Weitzel, Jeffrey N. , Yadav, Siddhartha , Zethoven, Magnus, Zhang, Ze Wen, Vega, Ana , Rossing, Maria , Valle, Jesús Del , Nicolo, Arcangela De , Hahnen, Eric , Ngeow, Joanne , Kleibl, Zdeněk , Chen, Chen , Zemankova, Petra , Stastna, Barbora , Janatova, Marketa , Soukupova, Jana , Achatz, M I , Ambrosone, Christine B , Apostolou, Paraskevi , Arun, Banu , Auer, Paul , Barnard, Mollie , Bertelsen, Birgitte , Blok, Marinus J , Boddicker, Nicholas J , Brunet, Joan , Burnside, Elizabeth S , Calvello, Mariarosaria , Campbell, Ian G , Chan, Sock Hoai , Chen, Fei , Chiang, Jian Bang , Coppa, Anna , Cortesi, Laura , Crujeiras-González, Ana , De Leeneer, Kim , de Putter, Robin , DePersia, Allison , Devereux, Lisa , Domchek, Susan M , Efremidis, Anna , Engel, Christoph , Ernst, Corinna , Evans, D Gareth , Feliubadaló, Lidia , Fostira, Florentia , Fuentes-Ríos, Olivia , Gómez-García, Encarna B , González, Sara , Haiman, Christopher A , Hansen, Thomas van Overeem , Hauke, Jan , Hodge, James M , Hu, Chunling , Huang, Hongyan , Ishak, Nur Diana Binte , Iwasaki, Yusuke , Konstantopoulou, Irene , Kraft, Peter , Lacey, James V. , Lazaro, Conxi , Li, Na , Lim, Weng Khong , Lindstrom, Sara , Lori, Adriana , Martı́nez, Marı́a Elena , Martins, Alexandra , Matsuda, Koichi , Matullo, Giuseppe , McInerny, Simone , Michailidou, Kyriaki , Montagna, Marco , Monteiro, Alvaro N , Mori, Luigi , Nathanson, Katherine L , Neuhausen, Susan L. , Nevanlinna, H , Olson, Janet E , Palmer, Julie R , Pasini, Barbara , Patel, Alpa V , Piane, Maria , Poppe, Bruce , Radice, Paolo , Renieri, Alessandra , Resta, Nicoletta , Richardson, Marcy E , Rosseel, Toon , Ruddy, Kathryn J , Santamariña, Marta , Dos Santos, Elizabeth Santana , Teras, Lauren R , Toland, Amanda Ewart , Trentham-Dietz, Amy , Vachon, Celine M. , Volk, Alexander E , Weber-Lassalle, Nana , Weitzel, Jeffrey N , Wiesmuller, Lisa , Winham, Stacey J , Yadav, Siddhartha , Yannoukakos, Drakoulis , Yao, Song , Zampiga, Valentina , Zethoven, Magnus , Zhang, Ze Wen , Zima, Tomas , Spurdle, Amanda B , Vega, Ana , Rossing, Maria , Del Valle, Jesús , De Nicolo, Arcangela , Hahnen, Eric , Claes, Kathleen B M , Ngeow, Joanne , Momozawa, Yukihide , James, Paul , Couch, Fergus J. , Macurek, Libor , Kleibl, Zdenek , Chen, C , Japan, Biobank, Kamatani, Yoichiro, Mushiroda, Taisei , Tanaka, Toshihiro , Yamaguhci, Hiroki, Okazaki, Yasushi , Takahashi, Yasuo , Nagayama, Satoshi , Yoshiyama, Takashi , Boddicker, Nicholas , Burnside, Elizabeth S. , Campbell, Ian , Borecká, Marianna , Foretová, Lenka , Havránek, Ondřej , Vočka, Michal , Michalovska, Renata, Schwetzova, Denisa, Jedlickova, Nikol, Zavoral, Tomáš, Duskova, Petra, Stránecký, Viktor , Leeneer, Kim De , Domchek, Susan M. , González, Sara , Hauke, Jan , Hu, Chunling , Kraft, Peter , Lázaro, Conxi , Matullo, Giuseppe , Michailidou, Kyriaki , Monteiro, Álvaro N.A. , Nevanlinna, Heli , Olson, Janet E. , Palmer, Julie R. , Pasini, Barbara , Radice, Paolo , Renieri, Alessandra , Santamariña, Marta , Teras, Lauren R. , Trentham‐Dietz, Amy , Wiesmüller, Lisa , Winham, Stacey J. , Yannoukakos, Drakoulis , Yao, Song , Zampiga, Valentina , Spurdle, Amanda B. , Claes, Kathleen , James, Paul A. , Couch, Fergus J.
Clinical Cancer Research | July 14, 2023 | Volume: 29 | Issue: 16 | Pages: 3037-3050
Abstract Purpose: Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testing (GGT). Experimental Design: We collected 460 CHEK2 missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1–CHEK2-knockout cells. Concordant results in both functional assays were used to categorize CHEK2 VUS from 12 ENIGMA case–control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls. Results: A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired (N = 102), functionally intermediate (N = 12), or functionally wild-type (WT)–like (N = 226). We then examined their association with breast cancer risk in the case–control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35–3.41), 1.57 (95% CI, 1.41–1.75), and 1.19 (95% CI, 1.08–1.31), respectively. The meta-analysis of population-specific datasets showed similar results. Conclusions: We determined the functional consequences for the majority of CHEK2 missense VUS found in patients with breast cancer (3,660/4,436; 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating CHEK2 variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers.
Functional and Clinical Characterization of Variants of Uncertain Significance Identifies a Hotspot for Inactivating Missense Variants in RAD51C
Nagaraj, Anil Belur , Shimelis, Hermela , Montalban, Gemma , Lee, Kun Y. , Huang, Huaizhi , Lumby, Carolyn A. , Na, Jie , Susswein, Lisa R. , Marshall, Megan L. , Hiraki, Susan , LaDuca, Holly , Yussuf, Amal , Pesaran, Tina , Haiman, Christopher A. , Lindström, Sara , Vachon, Celine M. , Ong, Irene M. , Nathanson, Katherine L. , Mer, Georges , Yadav, Siddhartha , Hruska, Kathleen S. , Dolinsky, Jill S. , Weroha, S. John , Simard, Jacques , Pang, Yuan‐Ping , Chen, Chen , Hu, Chunling , Nagaraj, Anil Belur , Shimelis, Hermela , Montalban, Gemma , Lee, Kun Y , Huang, Huaizhi , Lumby, Carolyn A , Na, Jie , Susswein, Lisa R , Roberts, Maegan E , Marshall, Megan L , Hiraki, Susan , LaDuca, Holly , Chao, Elizabeth , Yussuf, Amal , Pesaran, Tina , Neuhausen, Susan L. , Haiman, Christopher A , Kraft, Peter , Lindstrom, Sara , Palmer, Julie R , Teras, Lauren R , Vachon, Celine M. , Yao, Song , Ong, Irene M , Nathanson, Katherine L , Weitzel, Jeffrey N , Boddicker, Nicholas J , Gnanaolivu, Rohan , Polley, Eric C , Mer, Georges , Cui, Gaofeng , Karam, Rachid , Richardson, Marcy E , Domchek, Susan M , Yadav, Siddhartha , Hruska, Kathleen S , Dolinsky, Jill S , Weroha, S John , Hart, Steven N , Simard, Jacques , Masson, Jean Yves , Pang, Yuan-Ping , Couch, Fergus J. , Chen, C , Hu, Chunling , Roberts, Maegan E. , Kraft, Peter , Palmer, Julie R. , Teras, Lauren R. , Yao, Song , Weitzel, Jeffrey N. , Boddicker, Nicholas , Gnanaolivu, Rohan , Polley, Eric C. , Cui, Gaofeng , Karam, Rachid , Domchek, Susan M. , Hart, Steven N. , Masson, Jean‐Yves , Couch, Fergus J.
Cancer Research | May 30, 2023 | Volume: 83 | Issue: 15 | Pages: 2557-2571
Abstract Pathogenic protein-truncating variants of RAD51C, which plays an integral role in promoting DNA damage repair, increase the risk of breast and ovarian cancer. A large number of RAD51C missense variants of uncertain significance (VUS) have been identified, but the effects of the majority of these variants on RAD51C function and cancer predisposition have not been established. Here, analysis of 173 missense variants by a homology-directed repair (HDR) assay in reconstituted RAD51C−/− cells identified 30 nonfunctional (deleterious) variants, including 18 in a hotspot within the ATP-binding region. The deleterious variants conferred sensitivity to cisplatin and olaparib and disrupted formation of RAD51C/XRCC3 and RAD51B/RAD51C/RAD51D/XRCC2 complexes. Computational analysis indicated the deleterious variant effects were consistent with structural effects on ATP-binding to RAD51C. A subset of the variants displayed similar effects on RAD51C activity in reconstituted human RAD51C-depleted cancer cells. Case–control association studies of deleterious variants in women with breast and ovarian cancer and noncancer controls showed associations with moderate breast cancer risk [OR, 3.92; 95% confidence interval (95% CI), 2.18–7.59] and high ovarian cancer risk (OR, 14.8; 95% CI, 7.71–30.36), similar to protein-truncating variants. This functional data supports the clinical classification of inactivating RAD51C missense variants as pathogenic or likely pathogenic, which may improve the clinical management of variant carriers. Significance: Functional analysis of the impact of a large number of missense variants on RAD51C function provides insight into RAD51C activity and information for classification of the cancer relevance of RAD51C variants.
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.
CCNE1 and survival of patients with tubo‐ovarian high‐grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study
Kang, Eunyoung , Weir, Ashley , Meagher, Nicola S. , Farrington, Kyo , Nelson, Gregg , Lee, Cheng‐Han , Riggan, Marjorie J. , Popović, Gordana , Leung, Betty, Tang, Katrina , Lambie, Neil, Millstein, Joshua , Alsop, Jennifer , Anglesio, Michael S. , Barlow, Ellen , Beckmann, Matthias W. , Berger, Jessica, Bisinotto, Christiani, Bösmüller, Hans , Boros, Jessica , Brand, Alison H. , Carney, Michael E. , Casablanca, Yovanni , Cohen, Paul A. , Coulson, Penny , Courtney‐Brooks, Madeleine , Cunningham, Julie M. , Darcy, Kathleen M. , El‐Bahrawy, Mona A., Farrell, Rhonda , Fischer, Anna , García, María J. , Gayther, Simon A. , Group, AOCS, Harnett, Paul R. , Harrington, Shariska P. , Harter, Philipp , Hartmann, Arndt , Hecht, Jonathan L. , Heikaus, Sebastian, Hendley, Joy , Polo, Susanna Hernando, Heublein, Sabine , Hirasawa, Akira , Huntsman, David G. , Jimenez‐Liñan, Mercedes , Jones, Michael E. , Kennedy, Catherine J. , Khabele, Dineo , Lambrechts, Diether , Le, Nhu D. , Lener, Marcin , Lester, Jenny , Leung, Yee , Linder, Anna , Loverix, Liselore , Madan, Rashna , Maxwell, G. Larry , Olawaiye, Alexander , Oršulić, Sandra , Palacios, José , Pearce, Celeste Leigh , Pike, Malcolm C. , Quinn, Carmel M. , Mohan, Ganendra Raj , Rodríguez‐Antona, Cristina , Ruebner, Matthias , Ryan, Andy , Salfinger, Stuart , Sasamoto, Naoko , Schildkraut, Joellen M. , Schoemaker, Minouk J. , Shah, Mitul , Sharma, Raghwa , Shvetsov, Yurii B. , Singh, Naveena , Steele, Linda , Stewart, Colin J.R. , Talhouk, Aline , Tan, Adeline , Terry, Kathryn L. , Tołoczko, Aleksandra, Aa, Maaike A. van der , Gorp, Toon Van , Nieuwenhuysen, Els Van , van‐Wagensveld, Lilian, Vergote, Ignace , Wu, Anna H. , Reis, Francisco José Cândido dos , Fasching, Peter A. , Goode, Ellen L. , Goodman, Marc T. , Kommoss, Stefan , Menon, Usha , Sinn, Hans‐Peter , Staebler, Annette , Bowtell, David D.L. , Ramus, Susan J. , Lambrechts, Diether , El‐Bahrawy, Mona , Lee, Cheng-Han , Fereday, Sian , Kennedy, Catherine J , Sasamoto, Naoko , Schildkraut, Joellen M , Talhouk, Aline , Vergote, Ignace , Köbel, Martin , Lambrechts, Diether , Ramus, Susan J , Rodríguez-Antona, Cristina , Menon, Usha , Sinn, Peter , Anglesio, Michael S , Jones, Michael E , Lambrechts, Diether , Brand, Alison H , Bowtell, David D , Nelson, Gregg S , El-Bahrawy, Mona A , Harnett, Paul R , Schoemaker, Minouk J , Goodman, Marc T , Linder, Anna , Cohen, Paul , Kang, Eun‐Young, Ghatage, Prafull , Bolithon, Adelyn , Ataseven, Beyhan , Brooks‐Wilson, Angela , Brucker, Sara Yvonne , Cazorla, Alicia , Conrads, Thomas , Cook, Linda S. , Cramer, Daniel W. , Crowe, Philip John , Cybulski, Cezary , Elishaev, Esther , Erber, Ramona , Fereday, Sián , Gentry‐Maharaj, Aleksandra , Gilks, C. Blake , Group, AOCS, Grube, Marcel , Hein, Alexander , Heitz, Florian , Hernandez, Brenda Y. , Høgdall, Estrid , Høgdall, Claus , Horlings, Hugo , Huzarski, Tomasz , Jewell, Andrea , Kaufmann, Scott H. , Kommoss, Felix , Kruitwagen, Roy F.P.M. , Lubiński, Jan , Modugno, Francesmary , Neuhausen, Susan L. , Olbrecht, Siel , Sonke, Gabe S. , Sundfeldt, Karin , Swerdlow, Anthony J. , Taylor, Sarah E. , Traficante, Nadia , Van de Vijver, Koen , Vierkant, Robert A. , Wang, Chen , Wilkens, Lynne R. , Winham, Stacey J. , Benı́tez, Javier , Berchuck, Andrew , DeFazio, Anna , Gronwald, Jacek , Karlan, Beth Y. , Brenton, James D. , Pharoah, Paul D.P. , Köbel, Martin
Cancer | December 27, 2022 | Volume: 129 | Issue: 5 | Pages: 697-713
AbstractBackgroundCyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo‐ovarian high‐grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large‐scale, histotype‐specific validation has been performed. The hypothesis was that high‐level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC.MethodsWithin the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated.ResultsHigh‐level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high‐level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08‐1.47, p = .034, and HR, 1.18; 95% CI, 1.05‐1.32, p = .015, respectively). This was also true for cases with combined high‐level amplification/overexpression (HR, 1.26; 95% CI, 1.09‐1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1‐SD increase; 95% CI, 0.94‐1.06; p = .58). CCNE1 high‐level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss.ConclusionThis study provides large‐scale validation that CCNE1 high‐level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.
The risks of cancer in older women with BRCA pathogenic variants: How far have we come?
Metcalfe, Kelly , McCuaig, Jeanna , Eisen, Andrea , Elser, Christine , Senter, Leigha , Møller, Pål , Bordeleau, Louise , Velsher, Lea, Zakalik, Dana , Olopade, Olufunmilayo I. , Cullinane, Carey A., Sun, Ping , Narod, Steven A. , Metcalfe, Kelly A , Olopade, Olufunmilayo I , Kotsopoulos, Joanne , Narod, Steven A , Senter, Leigha , Eisen, Andrea , Bordeleau, Louise , Gronwald, Jacek , Tung, Nadine , Foulkes, William D. , Neuhausen, Susan L. , Fruscio, Robert , Eng, Charis , Pal, Tuya , Couch, Fergus J. , Kotsopoulos, Joanne , Lubiński, Jan
Cancer | December 26, 2022 | Volume: 129 | Issue: 6 | Pages: 901-907
AbstractBackgroundThe purpose of this study was to estimate the cumulative risks of all cancers in women from 50 to 75 years of age with a BRCA1 or BRCA2 pathogenic variant.MethodsParticipants were women with BRCA1 or BRCA2 pathogenic variants from 85 centers in 16 countries. Women were eligible if they had no cancer before the age of 50 years. Participants completed a baseline questionnaire and follow‐up questionnaires every 2 years. Women were followed from age 50 until a diagnosis of cancer, death, age 75, or last follow‐up. The risk of all cancers combined from age 50 to 75 was estimated using the Kaplan–Meier method.ResultsThere were 2211 women included (1470 BRCA1 and 742 BRCA2). There were 379 cancers diagnosed in the cohort between 50 and 75 years. The actuarial risk of any cancer from age 50 to 75 was 49% for BRCA1 and 43% for BRCA2. Breast (n = 186) and ovarian (n = 45) were the most frequent cancers observed. For women who had both risk‐reducing mastectomy and bilateral salpingo‐oophorectomy before age 50, the risk of developing any cancer between age 50 and 75 was 9%.ConclusionWomen with a BRCA1 or BRCA2 pathogenic variant have a high risk of cancer between the ages of 50 and 75 years and should be counselled appropriately.
Bilateral Oophorectomy and the Risk of Breast Cancer in BRCA1 Mutation Carriers: A Reappraisal
Menkiszak, Janusz , McCuaig, Jeanna , Metcalfe, Kelly , Foulkes, William D. , Sun, Sophie , Karlan, Beth Y. , Eisen, Andrea , Olopade, Olufunmilayo I. , Senter, Leigha , Bordeleau, Louise , Sun, Ping , Narod, Steven A. , Kim, Raymond H. , Menkiszak, Janusz , Foulkes, William D , Karlan, Beth Y , Olopade, Olufunmilayo I , Couch, Fergus J. , Huzarski, Tomasz , Senter, Leigha , Singer, Christian F , Eng, Charis , Fruscio, Robert , Narod, Steven A , Metcalfe, Kelly A , Eisen, Andrea , Bordeleau, Louise , Kim, Raymond H , Kotsopoulos, Joanne , Lubiński, Jan , Gronwald, Jacek , Neuhausen, Susan L. , Tung, Nadine , Couch, Fergus J. , Huzarski, Tomasz , Singer, Christian F. , Eng, Charis , Fruscio, Robert , Pal, Tuya
Cancer Epidemiology, Biomarkers & Prevention | April 27, 2022 | Volume: 31 | Issue: 7 | Pages: 1351-1358
Abstract Background: The lack of consensus on whether bilateral oophorectomy impacts risk of developing breast cancer among BRCA1 mutation carriers might be attributed to various biases, specifically, cancer-induced testing bias due to inclusion of prevalent cases. We conducted two complementary matched case–control analyses to evaluate the association of oophorectomy and BRCA1 breast cancer. Methods: A research questionnaire was administered every two years to collect information on exposures and disease. In the first analysis, we limited the study to prevalent breast cancer cases (diagnosed prior to study entry; n = 2,962) who were matched to controls on year of birth and country of residence (n = 4,358). In the second approach, we limited to 330 incident cases (diagnosed in the follow-up period) and 1,548 matched controls. Conditional logistic regression was used to estimate the adjusted odds ratios (OR) and 95% confidence intervals (CI) of invasive breast cancer. Results: In the first approach, there was a significant inverse association between oophorectomy and the risk of developing breast cancer [OR = 0.43; 95% confidence interval (CI), 0.34–0.55; P < 00001]. In the second approach, there was no association between oophorectomy and risk (OR = 1.21; 95% CI, 0.87–1.70; P = 0.26). Conclusions: The inclusion of women with a personal history of breast cancer prior to ascertainment likely impacts upon the association of oophorectomy and BRCA1 breast cancer risk. Impact: Oophorectomy is unlikely a determinant of breast cancer risk in BRCA1 mutation carriers but should be offered at age 35 to reduce the risk of ovarian and fallopian tube cancer.
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.