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Grant Details

Grant Number: 5R01CA083855-11 Interpret this number
Primary Investigator: Rebbeck, Timothy
Organization: University Of Pennsylvania
Project Title: Prophytactic Surgery in Carriers of Brca 1/2 Mutations
Fiscal Year: 2010
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Abstract

DESCRIPTION (provided by applicant): The availability of genetic testing for inherited mutations in BRCA1 and BRCA2 (BRCA1/2) provides potentially valuable information to women at high risk of breast or ovarian cancer. Unfortunately, carriers of inherited mutations in BRCA1/2 have relatively few clinical management options available to reduce their cancer risk. These options include the use of bilateral prophylactic oophorectomy (BPO) to reduce both breast and ovarian cancer risk. However, decisions about the type and timing of this surgery, as well as the use of post-BPO hormone replacement therapy (HRT) are not supported by existing data. Furthermore, BRCA1/2-associated breast tumors appear to have a unique phenotype that may be influenced by exposures such as BPO or HRT use. Thus, while the use of BPO reduces subsequent breast cancer risk in BRCA1/2 mutation carriers, the biological underpinnings of this risk reduction are not clear. In order to address the clinical and biological correlates of breast cancer risk and prevention in BRCA1/2 mutation carriers, we propose the continuation of a cohort study using a sample of BRCA1/2 mutation carriers to evaluate the role of BPO and other hormonal exposures in reducing breast cancer risk. Building on the cohort of nearly 2000 women that comprise the ongoing PROSE ("Prevention and Observation of Surgical Endpoints") multicenter consortium, we propose a continuation of this research to address the following three specific aims: 1) Evaluate the effect of post-BPO HRT on breast cancer risk reduction; 2) Evaluate whether the timing of BPO with respect to age and reproductive events affects the magnitude of cancer risk reduction; and 3) Evaluate the effect of HRT and BPO on histopathological and biomarker-based characteristics in breast tumor, considering tumors arising from BRCA1 and BRCA2 mutations separately. To achieve these aims, we will study surgical subjects who have undergone BPO, and compare the rate of breast cancer in these women with controls who have no history of BPO. Analyses will be taken to assess the effect of clinically relevant hormonal exposures including BPO, HRT, and reproductive history on breast cancer risk. Furthermore, we will evaluate the biological basis for breast cancer risk and risk reduction associated with these hormonal exposures by characterizing the phenotype of BRCA1/2-associated breast tumors using array-based comparative genome hybridization (aCGH). In completing these aims, we will better understand the role of clinically relevant hormone exposures (i.e., BPO, HRT, reproductive history) on cancer risk, and understand the phenotype of breast tumors in women with these exposures. These studies will motivate future studies of BRCA1/2-associated breast tumor biology, prevention, and treatment.

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Publications

Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality.
Authors: Domchek SM, Friebel TM, Singer CF, Evans DG, Lynch HT, Isaacs C, Garber JE, Neuhausen SL, Matloff E, Eeles R, Pichert G, Van t'veer L, Tung N, Weitzel JN, Couch FJ, Rubinstein WS, Ganz PA, Daly MB, Olopade OI, Tomlinson G, Schildkraut J, Blum JL, Rebbeck TR
Source: JAMA, 2010 Sep 1;304(9), p. 967-75.
PMID: 20810374
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Occult ovarian cancers identified at risk-reducing salpingo-oophorectomy in a prospective cohort of BRCA1/2 mutation carriers.
Authors: Domchek SM, Friebel TM, Garber JE, Isaacs C, Matloff E, Eeles R, Evans DG, Rubinstein W, Singer CF, Rubin S, Lynch HT, Daly MB, Weitzel J, Ganz PA, Pichert G, Olopade OI, Tomlinson G, Tung N, Blum JL, Couch F, Rebbeck TR
Source: Breast Cancer Res Treat, 2010 Nov;124(1), p. 195-203.
EPub date: 2010 Feb 24.
PMID: 20180014
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Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study.
Authors: Kauff ND, Domchek SM, Friebel TM, Robson ME, Lee J, Garber JE, Isaacs C, Evans DG, Lynch H, Eeles RA, Neuhausen SL, Daly MB, Matloff E, Blum JL, Sabbatini P, Barakat RR, Hudis C, Norton L, Offit K, Rebbeck TR
Source: J Clin Oncol, 2008 Mar 10;26(8), p. 1331-7.
EPub date: 2008 Feb 11.
PMID: 18268356
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Mortality after bilateral salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers: a prospective cohort study.
Authors: Domchek SM, Friebel TM, Neuhausen SL, Wagner T, Evans G, Isaacs C, Garber JE, Daly MB, Eeles R, Matloff E, Tomlinson GE, Van't Veer L, Lynch HT, Olopade OI, Weber BL, Rebbeck TR
Source: Lancet Oncol, 2006 Mar;7(3), p. 223-9.
PMID: 16510331
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The joint effect of smoking and AIB1 on breast cancer risk in BRCA1 mutation carriers.
Authors: Colilla S, Kantoff PW, Neuhausen SL, Godwin AK, Daly MB, Narod SA, Garber JE, Lynch HT, Brown M, Weber BL, Rebbeck TR
Source: Carcinogenesis, 2006 Mar;27(3), p. 599-605.
EPub date: 2005 Oct 22.
PMID: 16244359
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Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group.
Authors: Rebbeck TR, Friebel T, Wagner T, Lynch HT, Garber JE, Daly MB, Isaacs C, Olopade OI, Neuhausen SL, van 't Veer L, Eeles R, Evans DG, Tomlinson G, Matloff E, Narod SA, Eisen A, Domchek S, Armstrong K, Weber BL, PROSE Study Group
Source: J Clin Oncol, 2005 Nov 1;23(31), p. 7804-10.
EPub date: 2005 Oct 11.
PMID: 16219936
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Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group.
Authors: Rebbeck TR, Friebel T, Lynch HT, Neuhausen SL, van 't Veer L, Garber JE, Evans GR, Narod SA, Isaacs C, Matloff E, Daly MB, Olopade OI, Weber BL
Source: J Clin Oncol, 2004 Mar 15;22(6), p. 1055-62.
EPub date: 2004 Feb 23.
PMID: 14981104
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Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations.
Authors: Rebbeck TR, Lynch HT, Neuhausen SL, Narod SA, Van't Veer L, Garber JE, Evans G, Isaacs C, Daly MB, Matloff E, Olopade OI, Weber BL, Prevention and Observation of Surgical End Points Study Group
Source: N Engl J Med, 2002 May 23;346(21), p. 1616-22.
EPub date: 2002 May 20.
PMID: 12023993
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