Citations 14
Abstract P2-13-02: Chemotherapy-related amenorrhea (CRA) after adjuvant trastuzumab emtansine (T-DM1) compared to paclitaxel in combination with trastuzumab (TH) (TBCRC033: ATEMPT trial)
Ruddy, Kathryn J. , Trippa, Lorenzo , Hu, Jiani , Barry, William T., Dang, Chau T. , Isakoff, Steven J. , Valero, V., Faggen, Meredith, Mulvey, Therese M. , Bose, Ron , Weckstein, Douglas, Reeder‐Hayes, Katherine E. , Ramaswamy, Bhuvaneswari , Zuckerman, Dan Sayam , Hart, Lowell L., Gadi, Vijayakrishna K. , Constantine, Michael, Cheng, Kit , Briccetti, Frederick , Schneider, Bryan P. , Garrett, A. Merrill, Albain, Kathy S. , DeFusco, Patricia, Ardman, Blair, Nanda, Rita , Jankowitz, Rachel C. , DeMeo, Michelle K. , Burstein, Harold J. , Krop, Ian E. , Tolaney, Sara M. , Yardley, Denise Aysel , Wolff, Antonio C. , Rugo, Hope S. , Marcom, Paul Kelly , Tung, Nadine , Winer, Eric P. , Partridge, Ann H.
Cancer Research | March 26, 2020 | Volume: 80 | Issue: 4_Supplement | Pages: P2-13-02-P2-13-02
10.1158/1538-7445.sabcs19-p2-13-02
Abstract Background: CRA is a surrogate for ovarian toxicity and associated risk of infertility and long-term menopausal symptoms. Therefore, it is important to assess and report the rate of CRA when we study a new neoadjuvant treatment regimen. In the Adjuvant Paclitaxel and Tratuzumab (APT) trial, we found that CRA rate associated with adjuvant TH (12 weeks of paclitaxel and a year of trastuzumab) for human epidermal growth factor receptor-2 (HER2)-positive breast cancer was lower than historically seen with cyclophosphamide-based regimens. The ATEMPT trial allowed a direct comparison of the CRA rate associated with TDM1 and TH. Methods: The ATEMPT trial randomized patients (pts) with Stage I HER2+ breast cancer 3:1 to T-DM1 3.6 mg/kg IV every 3 weeks (w) x17 vs. T 80 mg/m2 IV with H qw x 12 (4 mg/kg load →2 mg/kg), followed by H (6 mg/kg q3w x 13). Participants who reported that they were premenopausal at enrollment were asked to complete menstrual surveys at baseline and every 6-12 months throughout a 36 month follow-up period. For this analysis, CRA was defined as report of no menstruation within the prior six months on a survey completed 18 months after enrollment. Results: Of 512 ATEMPT enrollees, 497 began protocol therapy, 130 (26%) were premenopausal at enrollment and answered baseline menstrual questions, 42 of these 130 were excluded from the current analyses because they did not complete the 18-month survey, and 7 of the remaining 88 had received gonadotropin-releasing hormone agonist before 18 months, leaving 81 for analysis. None had undergone hysterectomy or oophorectomy. Median age was 44 (range 23-53) among the TH patients (n=20), and 46 (range 34-54) among the T-DM1 patients (n=61). On the 18-month survey, 45% of women treated with TH reported at least one one episode of menses during the prior 6 months compared to 75% of women in the T-DM1 arm (p=0.011). Among those ≤ 40 years old, 50% of TH patients and 100% of T-DM1 patients reported menstruation at that timepoint. Please see Table for additional data in subgroups. Conclusions: In this relatively small sample, CRA at 18 months was less common after adjuvant T-DM1 than after TH (though even with TH, nearly half of women did menstruate after chemotherapy, even in the subset aged 41+). This will be reassuring to young patients with HER2-positive breast cancer who seek to maintain ovarian function. Larger studies are needed to confirm this finding and to assess a possible differential impact of these drugs on subgroups based on age, endocrine therapy, and body mass index. Additional research should also focus on menopausal symptoms and actual fertility after receipt of T-DM1. Menstruation in 61 T-DM1 arm patients with informative surveys at 18 monthsMenstruation in 20 TH arm patients with informative surveys at 18 monthsAge at study entry95% CI95% CI≤4012/12 (100%)74-100%4/8 (50%)16-84%41+34/49 (69%)55-82%5/12 (42%)15-72%BMI<3040/52 (77%)63-87%6/16 (38%)15-65%30+6/9 (67%)30-93%3/4 (75%)19-99%Endocrine therapy currentlyYes27/39 (69%)52-83%2/12 (17%)2-48%No19/22 (86%)65-97%7/9 (78%)40-97% Citation Format: Kathryn J. Ruddy, Lorenzo Trippa, Jiani Hu, William T. Barry, Chau T. Dang, Denise A. Yardley, Steven J. Isakoff, Vincente V. Valero, Meredith G. Faggen, Therese M. Mulvey, Ron Bose, Douglas J. Weckstein, Antonio C. Wolff, Katherine E. Reeder-Hayes, Hope S. Rugo, Bhuvaneswari Ramaswamy, Dan S. Zuckerman, Lowell L. Hart, Vijayakrishna K. Gadi, Michael Constantine, Kit L. Cheng, Frederick M. Briccetti, Bryan P. Schneider, A. Merrill Garrett, P. Kelly Marcom, Kathy S. Albain, Patricia A. DeFusco, Nadine M. Tung, Blair M. Ardman, Rita Nanda, Rachel C. Jankowitz, Michelle K. DeMeo, Harold J. Burstein, Eric P. Winer, Ian E. Krop, Ann H. Partridge, Sara M. Tolaney. Chemotherapy-related amenorrhea (CRA) after adjuvant trastuzumab emtansine (T-DM1) compared to paclitaxel in combination with trastuzumab (TH) (TBCRC033: ATEMPT trial) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-13-02.
Transcriptome‐wide association study of breast cancer risk by estrogen‐receptor status
Feng, Helian , Gusev, Alexander , Wu, Lang , Abu-Full, Zomoroda, Aittomäki, Kristiina, Andrulis, Irene L. , Antoniou, Antonis C. , Arason, Aðalgeir , Arndt, Volker , Aronson, Kristan J. , Asseryanis, Ella, Auer, Paul L. , Azzollini, Jacopo , Barkardóttir, Rósa B. , Barrowdale, Daniel , Beckmann, Matthias W. , Bermisheva, Marina , Białkowska, Katarzyna , Bogdanova, Natalia , Bojesen, Stig E. , Bolla, Manjeet K. , Borg, Åke , Brauch, Hiltrud , Brenner, Hermann , Brüning, Thomas , Burwinkel, Barbara , Caldés, Trinidad , Canisius, Sander , Campa, Daniele , Carter, Brian D., Castelao, Jose E. , Chang‐Claude, Jenny , Christiansen, Hans , Claes, Kathleen , Collaborators, GEMO Study, Collaborators, EMBRACE, Collaborators, GC‐HBOC study, Cox, Angela , Daly, Mary B., Leeneer, Kim De , Dörk, Thilo , Dwek, Miriam , Eccles, Diana M., Ejlertsen, Bent , Engel, Christoph , Fasching, Peter A. , Flyger, Henrik, Friedman, Eitan , Frost, Debra, Gabrielson, Marike , Ganz, Patricia A. , Gapstur, Susan M. , García‐Closas, Montserrat , Gaudet, Mia M. , Glendon, Gord , Goldberg, Mark S. , Goldgar, David E., González‐Neira, Anna , Greene, Mark H. , Guénel, Pascal , Haiman, Christopher A. , Hamann, Ute, Hake, Christopher R., He, Wei , Heyworth, Jane , Hogervorst, Frans B.L., Hooning, Maartje J. , Hoover, Robert N. , Hopper, John L. , Huang, Guanmengqian, Hulick, Peter J. , Humphreys, Keith , Imyanitov, Evgeny N., Investigators, ABCTB, Investigators, HEBON, Investigators, BCFR, Investigators, OCGN, Jakimovska, Milena , Jakubowska, Anna , James, Paul A. , Janavicius, Ramunas, Jankowitz, Rachel C. , John, Esther M. , Johnson, Nichola , Jung, Audrey , Kiiski, Johanna I. , Konstantopoulou, Irene , Kristensen, Vessela N. , Laitman, Yael , Lambrechts, Diether , Leroux, Dominique, Lester, Jenny, Lesueur, Fabienne , Lindor, Noralane M. , Lindström, Sara, Lo, Wing‐Yee, Loud, Jennifer T. , Makalic, Enes , Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush , Margolin, Sara , Matricardi, Laura , Maurer, Tabea, Mavroudis, Dimitrios, McGuffog, Lesley, Meindl, Alfons , Menon, Usha , Michailidou, Kyriaki , Kapoor, Pooja M., Montagna, Marco , Moreno, Fernando , Muranen, Taru , Nathanson, Katherine L. , Nevelsteen, Ines, Ņikitina-Zaķe, Liene , Offit, Kenneth, Oláh, Edith , Olopade, Olufunmilayo I. , Olsson, Håkan , Osório, Ana , Papp, J., Park‐Simon, Tjoung‐Won , Pedersen, Inge Søkilde , Peixoto, Ana , Peterlongo, Paolo , Peto, Julian , Phillips, Kelly‐Anne , Plaseska‐Karanfilska, Dijana , Poppe, Bruce , Pradhan, Nisha , Prajzendanc, Karolina , Punie, Kevin , Pylkäs, Katri , Rantala, Johanna, Rashid, Muhammad Usman , Rennert, Gad , Romero, Atocha , Saloustros, Emmanouil , Sandler, Dale P. , Santos, Catarina , Sawyer, Elinor J. , Schmutzler, Rita K., Schoemaker, Minouk J. , Scott, Rodney J. , Simard, Jacques , Skytte, Anne‐Bine , Soucy, Penny, Spinelli, John J. , Stone, Jennifer , Tapper, William , Taylor, Jack A. , Teixeira, Manuel R. , Terry, Mary Beth , Teulé, Àlex , Thomassen, Mads , Thöne, Kathrin , Thull, Darcy L. , Tollenaar, Rob A.�E.�M. , Torres, Diana , Vachon, Celine M. , Ouweland, Ans M.W. van den, Vega, Ana , Viel, Alessandra , Vieiro‐Balo, Paula, Wang, Qin , Wappenschmidt, Barbara , Weinberg, Clarice R. , Weitzel, Jeffrey N. , Wendt, Camilla, Winqvist, Robert , Yang, Xiaohong R., Easton, Douglas F. , Chenevix‐Trench, Georgia , Durocher, Francine , Eccles, Diana , Janavičius, Ramūnas , Khaw, Kay‐Tee , Lambrechts, Diether , Lindor, Noralane, Dörk, Thilo , Lambrechts, Diether , Hulick, Peter J , James, Paul , Lesueur, Fabienne , Peterlongo, Paolo , Rennert, Gad , Sandler, Dale P , Teixeira, Manuel R , Eccles, Diana , Menon, Usha , Vega, Ana , Weitzel, Jeffrey N , Claes, Kathleen B M , Azzollini, Jacopo , John, Esther M , Konstantopoulou, Irene , Matricardi, Laura , Olopade, Olufunmilayo I , Arndt, Volker , Jakubowska, Anna , Lambrechts, Diether , Brenner, Hermann , Cox, Angela , Guénel, Pascal , Muranen, Taru A , Romero, Atocha , Saloustros, Emmanouil , Torres, Diana , García-Closas, Montserrat , Makalic, Enes , Michailidou, Kyriaki , Bogdanova, Natalia V , Taylor, Jack A , Nathanson, Katherine L , Arason, Adalgeir , Barrowdale, Daniel , Engel, Christoph , Montagna, Marco , Viel, Alessandra , Simard, Jacques , Chenevix-Trench, Georgia , Jung, Audrey Y , Gabrielson, Marike , Stone, Jennifer , Pylkäs, Katri , Rashid, Muhammad U , De Leeneer, Kim , Manoukian, Siranoush , Bojesen, Stig E , Schoemaker, Minouk J , Weinberg, Clarice R , Phillips, Kelly-Anne , Terry, Mary Beth , Brauch, Hiltrud , Plaseska-Karanfilska, Dijana , Sawyer, Elinor J , Paşaniuc, Bogdan , Long, Jirong , Anton‐Culver, Hoda , Arun, Banu , Balmañà, Judith , Barnes, Daniel R. , Behrens, Sabine , Benı́tez, Javier , Blanco, Ana , Blomqvist, Carl , Boeckx, Bram , Bonanni, Bernardo , Borg, Åke , Briceño, Ignacio , Broeks, Annegien , Cai, Qiuyin , Caligo, Maria A. , Campbell, Ian , Carter, Jonathan , Chanock, Stephen Jacob , Chung, Wendy K. , Clarke, Christine L. , Collaborators, GEMO Study, Collaborators, EMBRACE, Collaborators, GC‐HBOC study, Couch, Fergus J. , Cross, Simon S. , Cybulski, Cezary , Czene, Kamila , Hoya, Miguel de la , Dennis, Joe , Devilee, Peter , Dı́ez, Orland , Domchek, Susan M. , dos‐Santos‐Silva, Isabel , Dunning, Alison M. , Ellberg, Carolina , Eriksson, Mikael , Fletcher, Olivia , Fostira, Florentia , Fritschi, Lin , Garber, Judy E. , García-Sáenz, José Á. , Giles, Graham G. , Godwin, Andrew K. , Goldgar, David E., Gronwald, Jacek , Hall, Per N , Hollestelle, Antoinette , Investigators, ABCTB, Investigators, HEBON, Investigators, BCFR, Investigators, OCGN, Isaacs, Claudine , Vijai, Joseph , Karlan, Beth Y. , Хуснутдинова, Э. К. , Lázaro, Conxi , Leslie, Goska , Lubiński, Jan , Mannermaa, Arto, Martens, John W.M. , Martı́nez, Marı́a Elena , Meindl, Alfons , Kapoor, Pooja M., Miller, Austin , Moserle, Lidia , Mulligan, Anna Marie , Neuhausen, Susan L. , Nevanlinna, Heli , Nielsen, Finn Cilius , Parsons, Michael T. , Pharoah, Paul D.P. , Presneau, Nadège , Radice, Paolo , Risch, Harvey A. , Robson, Mark E. , Schmidt, Marjanka K. , Schmidt, Daniel F. , Sharma, Priyanka , Shu, Xiao‐Ou , Singer, Christian F. , Southey, Melissa C. , Spurdle, Amanda B. , Swerdlow, Anthony J. , Tischkowitz, Marc D. , Toland, Amanda Ewart , Truong, Thérèse , Tung, Nadine , Vachon, Celine M. , Asperen, Christi J. van , Rensburg, Elizabeth J. van , Yannoukakos, Drakoulis , Ziogas, Argyrios , Milne, Roger L. , Zheng, Wei , Kraft, Peter , Jiang, Xia
Genetic Epidemiology | March 2, 2020 | Volume: 44 | Issue: 5 | Pages: 442-468
AbstractPrevious transcriptome‐wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome‐wide association studies (GWAS), but analyses of breast cancer subtype‐specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta‐analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER−). We further compared associations with ER+ and ER− subtypes, using a case‐only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER– breast cancer. We further identified 30 TWAS‐significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast‐cancer gene in three of six regions harboring multiple TWAS‐significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER− breast cancer.
BRCA1andBRCA2pathogenic sequence variants in women of African origin or ancestry
Friebel, Tara M. , Andrulis, Irene L. , Balmañà, Judith , Blanco, Amie , Daly, Mary B., Domchek, Susan M. , Easton, Douglas F. , Foulkes, William D. , Ganz, Patricia A. , Glendon, Gord , Greene, Mark H. , Hulick, Peter J. , Jankowitz, Rachel C. , Kirk, Judy, Kwong, Ava , Lee, Annette, Lesueur, Fabienne , Lu, Karen H. , Nathanson, Katherine L. , Offit, Kenneth , Palmero, Edenir Inêz , Rensburg, Elizabeth J. van , Vega, Ana , Weitzel, Jeffrey N. , Collaborators, GEMO Study, Hoskins, Kent , Maga, Tara, McGuffog, Lesley , Antoniou, Antonis C. , Chenevix‐Trench, Georgia , Huo, Dezheng , Olopade, Olufunmilayo I. , Caputo, Sandrine M. , Domchek, Susan M , Foulkes, William D , Toland, Amanda Ewart , Vega, Ana , Parsons, Michael T , Rebbeck, Timothy R , Hulick, Peter J , Lesueur, Fabienne , van Rensburg, Elizabeth J , Weitzel, Jeffrey N , Olopade, Olufunmilayo I , Palmero, Edenir I , Nathanson, Katherine L , Chenevix-Trench, Georgia , Couch, Fergus J. , Garber, Judy E. , Isaacs, Claudine , Karlan, Beth Y. , Neuhausen, Susan L. , Sharma, Priyanka , Tischkowitz, Marc D. , Tung, Nadine , Parsons, Michael T. , Rebbeck, Timothy R. , Balmaña, Judith , Kwong, Ava
Human Mutation | May 21, 2019 | Volume: 40 | Issue: 10 | Pages: 1781-1796
TBCRC 022: A Phase II Trial of Neratinib and Capecitabine for Patients With Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer and Brain Metastases
Gelman, Rebecca , Anders, Carey K. , Melisko, Michelle , Parsons, Heather A. , Cropp, Anne B., Silvestri, Kelly M., Cotter, Christine M., Componeschi, Kathryn P., Marte, Juan M., Connolly, Roisín M. , Poznak, Catherine Van , Blackwell, Kimberly , Puhalla, Shannon L. , Jankowitz, Rachel C. , Ibrahim, Nuhad K. , Moynihan, Timothy J. , O’Sullivan, Ciara C. , Nangia, Julie R. , Pohlmann, Paula R. , Burns, Robyn, Rimawi, Mothaffar F. , Krop, Ian E. , O'Sullivan, Ciara C, Rimawi, Mothaffar , Freedman, Rachel A. , Moy, Beverly , Smith, Karen L. , Niravath, Polly Ann , Tung, Nadine , Wolff, Antonio C. , Winer, Eric P. , Lin, Nancy U. , Pohlmann, Paula
Journal of Clinical Oncology | March 12, 2019 | Volume: 37 | Issue: 13 | Pages: 1081-1089
PURPOSE Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)–positive breast cancer to the CNS are limited. We previously reported modest activity of neratinib monotherapy for HER2-positive breast cancer brain metastases. Here we report the results from additional study cohorts. PATIENTS AND METHODS Patients with measurable, progressive, HER2-positive brain metastases (92% after receiving CNS surgery and/or radiotherapy) received neratinib 240 mg orally once per day plus capecitabine 750 mg/m 2 twice per day for 14 days, then 7 days off. Lapatinib-naïve (cohort 3A) and lapatinib-treated (cohort 3B) patients were enrolled. If nine or more of 35 (cohort 3A) or three or more of 25 (cohort 3B) had CNS objective response rates (ORR), the drug combination would be deemed promising. The primary end point was composite CNS ORR in each cohort separately, requiring a reduction of 50% or more in the sum of target CNS lesion volumes without progression of nontarget lesions, new lesions, escalating steroids, progressive neurologic signs or symptoms, or non-CNS progression. RESULTS Forty-nine patients enrolled in cohorts 3A (n = 37) and 3B (n = 12; cohort closed for slow accrual). In cohort 3A, the composite CNS ORR = 49% (95% CI, 32% to 66%), and the CNS ORR in cohort 3B = 33% (95% CI, 10% to 65%). Median progression-free survival was 5.5 and 3.1 months in cohorts 3A and 3B, respectively; median survival was 13.3 and 15.1 months. Diarrhea was the most common grade 3 toxicity (29% in cohorts 3A and 3B). Neratinib plus capecitabine is active against refractory, HER2-positive breast cancer brain metastases, adding additional evidence that the efficacy of HER2-directed therapy in the brain is enhanced by chemotherapy. For optimal tolerance, efforts to minimize diarrhea are warranted.