Breast Neoplasms: Rebbeck TR

Rebbeck TR, Domchek SM. · Center for Clinical Epidemiology and Biostatistics and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. · Breast Cancer Res. · Pubmed #18710587 links to  free full text

Abstract: Genetic testing for BRCA1 and BRCA2 (BRCA1/2) mutations can provide important information for women who are concerned about their breast and ovarian cancer risks and need to make relevant prevention and medical management decisions. However, lifetime risks of breast cancer in individual BRCA1/2 mutation carriers have been confusing to apply in clinical decision-making. Published risk estimates vary significantly and are very dependent on the characteristics of the population under study. Recently, Begg and colleagues estimated cancer risks in a population-based study of BRCA1/2 mutation carriers. Here, we discuss the clinical decision-making implications of this research in the context of risk factors that may influence risk estimates in BRCA1/2 mutation carriers.

Rebbeck TR. · Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, and Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6021, USA. · Breast Cancer Res. · Pubmed #12052249 links to  free full text

Abstract: The etiology of breast cancer is complex, and is likely to involve the actions of genes at multiple levels along the multistage carcinogenesis process. These inherited genotypes include those that affect the propensity to be exposed to breast carcinogens, and those associated with breast tumorigenesis directly. In addition, inherited genotypes may influence response to breast cancer chemoprevention and treatment. Studies relating inherited genotypes with breast cancer incidence and mortality should consider a broader spectrum of genes and their potential roles in multistage carcinogenesis than have been typically evaluated to date. Understanding the role of inherited genotype at different stages of carcinogenesis could improve our understanding of cancer biology, may identify specific exposures or events that correlate with carcinogenesis, or target relevant biochemical pathways for the development of preventive or therapeutic interventions.

Domchek SM, Rebbeck TR. · Abramson Cancer Center, Philadelphia, Pennsylvania, USA. · Curr Opin Obstet Gynecol. · Pubmed #17218848 No free full text.

Abstract: PURPOSE OF REVIEW: Bilateral prophylactic salpingo-oophorectomy is widely used for cancer risk reduction in women with BRCA1/2 mutations. Bilateral prophylactic salpingo-oophorectomy significantly reduces breast cancer risk by approximately 50% and ovarian cancer risk by 80-95% but may be accompanied by menopausal symptoms, impaired quality of life and accelerated bone loss. Therefore, decisions regarding the timing of bilateral prophylactic salpingo-oophorectomy and the use of post-bilateral prophylactic salpingo-oophorectomy hormone replacement therapy must be carefully considered. RECENT FINDINGS: Over the last year, studies have further examined issues related to quality of life associated with bilateral prophylactic salpingo-oophorectomy and have demonstrated that hormone replacement therapy following bilateral prophylactic salpingo-oophorectomy in unaffected women does not negate the breast cancer risk reduction that bilateral prophylactic salpingo-oophorectomy provides. Studies have provided additional information on the residual risk of cancer following bilateral prophylactic salpingo-oophorectomy, have demonstrated its benefit in Lynch syndrome and have suggested a short-term mortality benefit following bilateral prophylactic salpingo-oophorectomy in BRCA1/2 mutation carriers. SUMMARY: We review the recent studies regarding bilateral prophylactic salpingo-oophorectomy and their implications for the clinical management of women who are at increased cancer risk.

Domchek SM, Stopfer JE, Rebbeck TR. · Abramson Cancer Center, University of Pennsylvania, 14 Penn Tower, Philadelphia, PA 19104, USA. · J Natl Compr Canc Netw. · Pubmed #16451773 No free full text.

Abstract: Bilateral risk-reducing oophorectomy (BRRO) is widely used for cancer risk reduction in women with BRCA1 and BRCA2 (BRCA1/2) mutations. BRRO significantly reduces breast cancer risk by approximately 50% and ovarian cancer risk by 85% to 95%, but it may be accompanied by menopausal symptoms, impaired quality of life, and accelerated bone loss. Therefore, decisions regarding the timing of BRRO, the risks and benefits of a simultaneous hysterectomy, and the use of hormone replacement therapy (HRT) must be made in concert with the patient and individualized to their circumstances. However, recent data demonstrate that HRT after BRRO in unaffected premenopausal women does not negate the breast cancer risk reduction that BRRO provides. This article reviews the studies regarding BRRO in BRCA1/2 mutation carriers, with particular focus on the use of HRT.

Rebbeck TR. · Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine and Cancer Center, Philadelphia, Pennsylvania 19104-6021, USA. · Environ Mol Mutagen. · Pubmed #11921193 No free full text.

Abstract: Germline mutations in the BRCA1 and BRCA2 (BRCA1/2) genes explain a substantial proportion of hereditary breast and ovarian cancer. Women who have inherited a mutation in one of these genes are at increased risk to develop breast and/or ovarian cancer, although there is variability in the manifestation of tumors by age and site. This variability may be explained, in part, by the BRCA1/2 mutation type or location. However, it is also possible that risk-modifying factors exist that explain interindividual variability in cancer risk. These factors include genes at other loci and endogenous or exogenous exposures. A more complete understanding of factors that modify cancer risk in BRCA1 and BRCA2 mutation carriers may help to refine estimates of cancer risk. A number of exposures, including reproductive history and exogenous hormone use, have been implicated as BRCA1/2-associated cancer risk modifiers. Similarly, genes involved in hormone metabolism, including the AIB1 and AR genes, have been linked with altered breast cancer risk. Therefore, although germline BRCA1/2 mutations raise a woman's breast and ovarian cancer risk, other factors may interact with BRCA1/2 mutations to modulate this risk.

Rebbeck TR. · Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. · J Clin Oncol. · Pubmed #11060335 No free full text.

Abstract: The availability of genetic testing for inherited mutations in the BRCA1 and BRCA2 genes provides potentially valuable information to women at elevated risk of breast or ovarian cancer. Unfortunately, women who have inherited a mutation in BRCA1 or BRCA2 have relatively few clinical management options available to reduce their risk of developing breast or ovarian cancer. Because most options for ovarian cancer prevention are not highly efficacious, many high-risk women consider the option of bilateral prophylactic oophorectomy (BPO), in the hope that removal of healthy ovarian tissue will reduce their risk of developing invasive malignancy. It is clear that BPO cannot completely prevent the subsequent development of ovarian cancers because reports have been made of patients who have developed cancers of epithelial ovarian origin subsequent to surgery. However, a number of studies have suggested that BPO may reduce the risk of subsequent breast or ovarian cancers in women. In general, these studies have been conducted in women who represent a heterogeneous group with respect to breast/ovarian cancer risk. Only one study of BPO has been undertaken in women whose elevated cancer risk has been based on knowledge of inherited mutations. This study indicated that a 50% to 70% breast cancer risk reduction could be achieved in women with BRCA1 mutations who underwent BPO. However, substantial additional information is required to provide clinically useful information about cancer prevention to women who carry mutations in BRCA1 or BRCA2.

Eisen A, Rebbeck TR, Wood WC, Weber BL. · Department of Medicine, Biostatistics and Epidemiology, and Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. · J Clin Oncol. · Pubmed #10784640 No free full text.

Abstract: PURPOSE: To review the published literature on the efficacy and adverse effects of prophylactic mastectomy (PM) and prophylactic oophorectomy (PO) in women with a hereditary predisposition to breast and ovarian cancer and to provide management recommendations for these women. METHODS: Using the terms "prophylactic," "preventive," "bilateral," "mastectomy," "oophorectomy," and "ovariectomy," a MEDLINE search of the English-language literature for articles related to PM and PO was performed. The bibliographies of these articles were reviewed to identify additional relevant references. RESULTS: There have been no prospective trials of PM or PO for the reduction of breast cancer or ovarian cancer incidence or mortality. Most of the available retrospective studies are composed of women who had surgery for a variety of indications and in whom genetic risk was not well characterized. However, some reports in women at increased risk of breast or ovarian cancer have shown that PM and PO can reduce cancer incidence. CONCLUSION: Interest in and use of PM and PO are high among physicians and high-risk women. PM and PO seem to be associated with considerable reduction in the risk of breast and ovarian cancer, albeit incomplete. The surgical morbidity of PM and PO is low, but the complications of premature menopause may be significant, and few studies address quality-of-life issues in women who have opted for PM and PO. Management recommendations for high-risk individuals are presented on the basis of the available evidence.

Rebbeck TR. · Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia 19104-6021, USA. · Cancer. · Pubmed #10630175 links to  free full text

Abstract: Two classes of inherited susceptibility genes may be considered in the etiology of breast and other common cancers. First, genes have been identified that confer a high degree of breast cancer (BC) risk, usually associated with hereditary syndromes, but disease-associated germline variants in these genes are relatively rare in the general population. These include BRCA1, BRCA2, and TP53. The proportion of BC in the general population that can be explained by these genes is relatively small. Second, variant genotypes at other loci may confer a relatively smaller degree of cancer risk, but they are carried by a larger proportion of the general population. As a result, the proportion of BC that could be explained by these genes may be relatively large. To understand the genetic basis for BCs in the general population, both of these classes of genes may need to be considered. This paper presents an overview of genes thought to be involved in BC susceptibility. Genes that confer a high degree of risk are more likely to result in hereditary patterns of cancer that are amenable to identification by genetic epidemiologic methods using pedigree data. More common (e.g., nonhereditary) forms of BC may be optimally analyzed by molecular epidemiologic studies using case-case, case-control, or cohort designs. The use of an appropriate study design is crucial to the identification of genes with relatively small effects on BC risk. To understand the inherited factors that explain BC in the general population, consideration should be given to genes with different allele frequencies and magnitudes of effect, using appropriate analytical approaches. By understanding the complex interactions of these genes with one another and with exposures, improved risk assessment and potential for targeted cancer prevention strategies may be possible.

Mushlin RA, Gallagher S, Kershenbaum A, Rebbeck TR. · PsychoGenics Inc, Tarrytown, NY, USA. · PLoS One. · Pubmed #19287484 links to  free full text

Abstract: BACKGROUND: Commonly-occurring disease etiology may involve complex combinations of genes and exposures resulting in etiologic heterogeneity. We present a computational algorithm that employs clique-finding for heterogeneity and multidimensionality in biomedical and epidemiological research (the "CHAMBER" algorithm). METHODOLOGY/PRINCIPAL FINDINGS: This algorithm uses graph-building to (1) identify genetic variants that influence disease risk and (2) predict individuals at risk for disease based on inherited genotype. We use a set-covering algorithm to identify optimal cliques and a Boolean function that identifies etiologically heterogeneous groups of individuals. We evaluated this approach using simulated case-control genotype-disease associations involving two- and four-gene patterns. The CHAMBER algorithm correctly identified these simulated etiologies. We also used two population-based case-control studies of breast and endometrial cancer in African American and Caucasian women considering data on genotypes involved in steroid hormone metabolism. We identified novel patterns in both cancer sites that involved genes that sulfate or glucuronidate estrogens or catecholestrogens. These associations were consistent with the hypothesized biological functions of these genes. We also identified cliques representing the joint effect of multiple candidate genes in all groups, suggesting the existence of biologically plausible combinations of hormone metabolism genes in both breast and endometrial cancer in both races. CONCLUSIONS: The CHAMBER algorithm may have utility in exploring the multifactorial etiology and etiologic heterogeneity in complex disease.

Rebbeck TR, Kauff ND, Domchek SM. · Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6021, USA. · J Natl Cancer Inst. · Pubmed #19141781 links to  free full text

Abstract: BACKGROUND: Risk-reducing salpingo-oophorectomy (RRSO) is widely used by carriers of BRCA1 or BRCA2 (BRCA1/2) mutations to reduce their risks of breast and ovarian cancer. To guide women and their clinicians in optimizing cancer prevention strategies, we summarized the magnitude of the risk reductions in women with BRCA1/2 mutations who have undergone RRSO compared with those who have not. METHODS: All reports of RRSO and breast and/or ovarian or fallopian tube cancer in BRCA1/2 mutation carriers published between 1999 and 2007 were obtained from a PubMed search. Hazard ratio (HR) estimates were identified directly from the original articles. Pooled results were computed from nonoverlapping studies by fixed-effects meta-analysis. RESULTS: Ten studies investigated breast or gynecologic cancer outcomes in BRCA1/2 mutation carriers who had undergone RRSO. Breast cancer outcomes were investigated in three nonoverlapping studies of BRCA1/2 mutation carriers, four of BRCA1 mutation carriers, and three of BRCA2 mutation carriers. Gynecologic cancer outcomes were investigated in three nonoverlapping studies of BRCA1/2 mutation carriers and one of BRCA1 mutation carriers. RRSO was associated with a statistically significant reduction in risk of breast cancer in BRCA1/2 mutation carriers (HR = 0.49; 95% confidence interval [CI] = 0.37 to 0.65). Similar risk reductions were observed in BRCA1 mutation carriers (HR = 0.47; 95% CI = 0.35 to 0.64) and in BRCA2 mutation carriers (HR = 0.47; 95% CI = 0.26 to 0.84). RRSO was also associated with a statistically significant reduction in the risk of BRCA1/2-associated ovarian or fallopian tube cancer (HR = 0.21; 95% CI = 0.12 to 0.39). Data were insufficient to obtain separate estimates for ovarian or fallopian tube cancer risk reduction with RRSO in BRCA1 or BRCA2 mutation carriers. CONCLUSION: The summary estimates presented here indicate that RRSO is strongly associated with reductions in the risk of breast, ovarian, and fallopian tube cancers and should provide guidance to women in planning cancer risk reduction strategies.

Rebbeck TR, DeMichele A, Tran TV, Panossian S, Bunin GR, Troxel AB, Strom BL. · Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · Carcinogenesis. · Pubmed #19028704 No free full text.

Abstract: FGFR2 and MAP3K1 are members of the RAS/RAF/MEK/ERK-signaling pathway and have been identified from genome-wide association studies to be breast cancer susceptibility genes. Potential interactions of these genes and their role with respect to tumor markers, hormonal factors and race on breast cancer risk have not been explored. We examined FGFR2 and MAP3K1 variants, breast tumor characteristics and hormone exposures in a population-based case-control sample of 1225 European-American (EA) and 584 African-American (AA) women. FGFR2 rs1219648 and rs2981582 genotypes were significantly associated with breast cancer in EA only in estrogen receptor-positive (ER+), progesterone receptor-positive (PR+) and HER2/Neu-negative (HER2-) tumors. MAP3K1 was not associated with breast cancer in EA women, but it was associated with breast cancer in AA women, again limited to ER+, PR+ and HER2- tumors. An interaction was observed between combined hormone replacement therapy use and FGFR2 rs1219648 genotypes on breast cancer risk in EA women (P = 0.010). Finally, we observed a significant interaction between MAP3K1 rs889312 and FGFR2 rs2981582 (P = 0.022) in AA but not EA women. These results confirm that FGFR2 and MAP3K1 are involved in breast cancer susceptibility and confer their effects primarily in ER+ and PR+ tumors. We further report that these genes confer their effects in HER2- tumors, interact with one another to confer breast cancer susceptibility in AA women and interact with hormone exposures in AA and EA women.

DeMichele A, Troxel AB, Berlin JA, Weber AL, Bunin GR, Turzo E, Schinnar R, Burgh D, Berlin M, Rubin SC, Rebbeck TR, Strom BL. · Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA. · J Clin Oncol. · Pubmed #18757329 No free full text.

Abstract: PURPOSE: Raloxifene reduces breast cancer risk in women with osteoporosis, and both tamoxifen and raloxifene prevent breast cancer in high-risk women. However, in vitro, raloxifene does not share the pro-estrogenic effects of tamoxifen on the endometrium. Randomized trials of these agents have provided limited information about endometrial cancer risk in the general population. We sought to compare endometrial cancer risks associated with raloxifene, tamoxifen, and nonusers of a selective estrogen receptor modulator (SERM) in the general population and characterize the endometrial tumors occurring in these groups. METHODS: We performed a case-control study of white and African American women age 50 to 79 years in the Philadelphia area. Patients were diagnosed with endometrial cancer between July 1999 and June 2002. Controls were identified through random-digit dialing. RESULTS: We analyzed 547 cases and 1,410 controls. Among cases, 3.3% had taken raloxifene; 6.2% had taken tamoxifen. Among controls, 6.6% had taken raloxifene; 2.4% had taken tamoxifen. After adjustment for other risk factors, the odds of endometrial cancer among raloxifene users was 50% that of nonusers (odds ratio [OR] = 0.50; 95% CI, 0.29 to 0.85), whereas tamoxifen users had three times the odds of developing endometrial cancer compared with raloxifene users (OR = 3.0; 95% CI, 1.3 to 6.9). Endometrial tumors in raloxifene users had a more favorable histologic profile and were predominantly International Federation of Gynecology and Obstetrics stage I and low grade. CONCLUSION: Raloxifene users had significantly lower odds of endometrial cancer compared with both tamoxifen users and SERM nonusers, suggesting a role for raloxifene in endometrial cancer prevention and individualization of SERM therapy.

Palma MD, Domchek SM, Stopfer J, Erlichman J, Siegfried JD, Tigges-Cardwell J, Mason BA, Rebbeck TR, Nathanson KL. · Division of Medical Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. · Cancer Res. · Pubmed #18703817 No free full text.

Abstract: The demand for BRCA1 and BRCA2 mutation screening is increasing as their identification will affect medical management. However, both the contribution of different mutation types in BRCA1 and BRCA2 and whom should be offered testing for large genomic rearrangements have not been well established in the U.S. high-risk population. We define the prevalence and spectrum of point mutations and genomic rearrangements in BRCA genes in a large U.S. high-risk clinic population of both non-Ashkenazi and Ashkenazi Jewish descent, using a sample set representative of the U.S. genetic testing population. Two hundred fifty-one probands ascertained through the University of Pennsylvania high-risk clinic, all with commercial testing for BRCA1 and BRCA2, with an estimated prevalence of BRCA mutation >or=10% using the Myriad II model and a DNA sample available, were studied. Individuals without deleterious point mutations were screened for genomic rearrangements in BRCA1 and BRCA2. In the 136 non-Ashkenazi Jewish probands, 36 (26%) BRCA point mutations and 8 (6%) genomic rearrangements (7 in BRCA1 and 1 in BRCA2) were identified. Forty-seven of the 115 (40%) Ashkenazi Jewish probands had point mutations; no genomic rearrangements were identified in the group without mutations. In the non-Ashkenazi Jewish probands, genomic rearrangements constituted 18% of all identified BRCA mutations; estimated mutation prevalence (Myriad II model) was not predictive of their presence. Whereas these findings should be confirmed in larger sample sets, our data suggest that genomic rearrangement testing be considered in all non-Ashkenazi Jewish women with an estimated mutation prevalence >or=10%.

Finlay E, Stopfer JE, Burlingame E, Evans KG, Nathanson KL, Weber BL, Armstrong K, Rebbeck TR, Domchek SM. · Division of Hematology/Oncology, Department of Internal Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-4283, USA. · Genet Test. · Pubmed #18373407 No free full text.

Abstract: BACKGROUND: Uptake of genetic testing remains low, even in families with known BRCA1 and BRCA2 (BRCA1/2) mutations, despite effective interventions to reduce risk. We report disclosure and uptake patterns by BRCA1/2-positive individuals to at-risk relatives, in the setting of no-cost genetic counseling and testing. METHODS: Relatives of BRCA1/2-positive individuals were offered cost-free and confidential genetic counseling and testing. If positive for a BRCA1/2 mutation, participants were eligible to complete a survey about their disclosure of mutation status and the subsequent uptake of genetic testing by at-risk family members. RESULTS: One hundred and fifteen of 142 eligible individuals responded to the survey (81%). Eighty-eight (77%) of those surveyed disclosed results to all at-risk relatives. Disclosure to first-degree relatives (FDRs) was higher than to second-degree relatives (SDRs) and third-degree relatives (TDR) (95% vs. 78%; p < 0.01). Disclosure rates to male versus female relatives were similar, but reported completion of genetic testing was higher among female versus male FDRs (73% vs. 49%; p < 0.01) and SDRs (68% vs. 43%; p < 0.01), and among members of maternal versus paternal lineages (63% vs. 0%; p < 0.01). Men were more likely than women to express general difficulty discussing positive BCRA1/2 results with at-risk family members (90% vs. 70%; p = 0.03), while women reported more emotional distress associated with disclosure than men (48% vs. 13%; p < 0.01). DISCUSSION: We report a very high rate of disclosure of genetic testing information to at-risk relatives. However, uptake of genetic testing among at-risk individuals was low despite cost-free testing services, particularly in men, SDRs, and members of paternal lineages. The complete lack of testing among paternally related at-risk individuals and the lower testing uptake among men signify a significant barrier to testing and a challenge for genetic counselors and physicians working with high-risk groups. Further research is necessary to ensure that family members understand their risk and the potential benefits of genetic counseling.

Antoniou AC, Spurdle AB, Sinilnikova OM, Healey S, Pooley KA, Schmutzler RK, Versmold B, Engel C, Meindl A, Arnold N, Hofmann W, Sutter C, Niederacher D, Deissler H, Caldes T, Kämpjärvi K, Nevanlinna H, Simard J, Beesley J, Chen X, Anonymous00035, Neuhausen SL, Rebbeck TR, Wagner T, Lynch HT, Isaacs C, Weitzel J, Ganz PA, Daly MB, Tomlinson G, Olopade OI, Blum JL, Couch FJ, Peterlongo P, Manoukian S, Barile M, Radice P, Szabo CI, Pereira LH, Greene MH, Rennert G, Lejbkowicz F, Barnett-Griness O, Andrulis IL, Ozcelik H, Anonymous00036, Gerdes AM, Caligo MA, Laitman Y, Kaufman B, Milgrom R, Friedman E, Anonymous00037, Domchek SM, Nathanson KL, Osorio A, Llort G, Milne RL, Benítez J, Hamann U, Hogervorst FB, Manders P, Ligtenberg MJ, van den Ouweland AM, Anonymous00038, Peock S, Cook M, Platte R, Evans DG, Eeles R, Pichert G, Chu C, Eccles D, Davidson R, Douglas F, Anonymous00039, Godwin AK, Barjhoux L, Mazoyer S, Sobol H, Bourdon V, Eisinger F, Chompret A, Capoulade C, Bressac-de Paillerets B, Lenoir GM, Gauthier-Villars M, Houdayer C, Stoppa-Lyonnet D, Anonymous00040, Chenevix-Trench G, Easton DF, Anonymous00041. · Cancer Research UK, Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK. · Am J Hum Genet. · Pubmed #18355772 links to  free full text

Abstract: Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A recent genome-wide association study has shown that common alleles at single nucleotide polymorphisms (SNPs) in FGFR2 (rs2981582), TNRC9 (rs3803662), and MAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers, we genotyped these SNPs in a sample of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk in BRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95% CI: 1.20-1.45, p(trend) = 1.7 x 10(-8) and HR = 1.12, 95% CI: 1.02-1.24, p(trend) = 0.02) but not in BRCA1 carriers. rs3803662 was associated with increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers (per-allele HR = 1.13, 95% CI: 1.06-1.20, p(trend) = 5 x 10(-5) in BRCA1 and BRCA2 combined). These loci appear to interact multiplicatively on breast cancer risk in BRCA2 mutation carriers. The differences in the effects of the FGFR2 and MAP3K1 SNPs between BRCA1 and BRCA2 carriers point to differences in the biology of BRCA1 and BRCA2 breast cancer tumors and confirm the distinct nature of breast cancer in BRCA1 mutation carriers.

Friebel TM, Domchek SM, Neuhausen SL, Wagner T, Evans DG, Isaacs C, Garber JE, Daly MB, Eeles R, Matloff E, Tomlinson G, Lynch HT, Tung N, Blum JL, Weitzel J, Rubinstein WS, Ganz PA, Couch F, Rebbeck TR. · Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6021, USA. · Clin Breast Cancer. · Pubmed #18269778 No free full text.

Abstract: BACKGROUND: Women with BRCA1 or BRCA2 (BRCA1/2) mutations can reduce cancer incidence and mortality by using bilateral prophylactic oophorectomy (BPO) or bilateral prophylactic mastectomy (BPM). The availability of these risk-reduction strategies is an important consideration in the decision to undergo genetic testing. PATIENTS AND METHODS: We evaluated the use of BPO and BPM in a prospective sample of 537 female BRCA1/2 mutation carriers from 17 centers in North America and Europe. These women were aged > 30 years, had no BPM, BPO, breast cancer, or ovarian cancer before the disclosure of their genetic test results and were followed for > or = 6 months. RESULTS: Bilateral prophylactic oophorectomy is used significantly more frequently than BPM (55% vs. 21%; P < .001). Bilateral prophylactic oophorectomy was more common among women age > or = 40 years compared with women aged < 40 years (68% vs. 43%; P < .001) and among parous women compared with nulliparous women (60% vs. 39%; P < .001). There was no difference in BPM (P = .83) or BPO (P = .09) in BRCA1 versus BRCA2 carriers. Multivariate models identified age and parity as a predictor of BPO in BRCA1 carriers; age and ovarian cancer family history in BRCA2 carriers; parity and ovarian cancer family history as a predictor of BPM in BRCA1 carriers; and smoking and ovarian cancer family history in BRCA2 carriers. CONCLUSION: Bilateral prophylactic oophorectomy is more commonly used than BPM in unaffected BRCA1/2 mutation carriers. Parity, age, and family history can also influence BPO and BPM uptake. Consistent with current recommendations, BPO is used by the majority of parous women aged > 40 years.

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. · Clinical Genetics and Gynecology Services, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 192, New York, NY 10021, USA. · J Clin Oncol. · Pubmed #18268356 No free full text.

Abstract: PURPOSE: Risk-reducing salpingo-oophorectomy (RRSO) has been widely adopted as a key component of breast and gynecologic cancer risk-reduction for women with BRCA1 and BRCA2 mutations. Despite 17% to 39% of all BRCA mutation carriers having a mutation in BRCA2, no prospective study to date has evaluated the efficacy of RRSO for the prevention of breast and BRCA-associated gynecologic (ovarian, fallopian tube or primary peritoneal) cancer when BRCA2 mutation carriers are analyzed separately from BRCA1 mutation carriers. PATIENTS AND METHODS: A total of 1,079 women 30 years of age and older with ovaries in situ and a deleterious BRCA1 or BRCA2 mutation were enrolled onto prospective follow-up studies at one of 11 centers from November 1, 1994 to December 1, 2004. Women self-selected RRSO or observation. Follow-up information through November 30, 2005, was collected by questionnaire and medical record review. The effect of RRSO on time to diagnosis of breast or BRCA-associated gynecologic cancer was analyzed using a Cox proportional-hazards model. RESULTS: During 3-year follow-up, RRSO was associated with an 85% reduction in BRCA1-associated gynecologic cancer risk (hazard ratio [HR] = 0.15; 95% CI, 0.04 to 0.56) and a 72% reduction in BRCA2-associated breast cancer risk (HR = 0.28; 95% CI, 0.08 to 0.92). While protection against BRCA1-associated breast cancer (HR = 0.61; 95% CI, 0.30 to 1.22) and BRCA2-associated gynecologic cancer (HR = 0.00; 95% CI, not estimable) was suggested, neither effect reached statistical significance. CONCLUSION: The protection conferred by RRSO against breast and gynecologic cancers may differ between carriers of BRCA1 and BRCA2 mutations. Further studies evaluating the efficacy of risk-reduction strategies in BRCA mutation carriers should stratify by the specific gene mutated.

Antoniou AC, Sinilnikova OM, Simard J, Léoné M, Dumont M, Neuhausen SL, Struewing JP, Stoppa-Lyonnet D, Barjhoux L, Hughes DJ, Coupier I, Belotti M, Lasset C, Bonadona V, Bignon YJ, Anonymous00135, Rebbeck TR, Wagner T, Lynch HT, Domchek SM, Nathanson KL, Garber JE, Weitzel J, Narod SA, Tomlinson G, Olopade OI, Godwin A, Isaacs C, Jakubowska A, Lubinski J, Gronwald J, Górski B, Byrski T, Huzarski T, Peock S, Cook M, Baynes C, Murray A, Rogers M, Daly PA, Dorkins H, Anonymous00136, Schmutzler RK, Versmold B, Engel C, Meindl A, Arnold N, Niederacher D, Deissler H, Anonymous00137, Spurdle AB, Chen X, Waddell N, Cloonan N, Anonymous00138, Kirchhoff T, Offit K, Friedman E, Kaufmann B, Laitman Y, Galore G, Rennert G, Lejbkowicz F, Raskin L, Andrulis IL, Ilyushik E, Ozcelik H, Devilee P, Vreeswijk MP, Greene MH, Prindiville SA, Osorio A, Benitez J, Zikan M, Szabo CI, Kilpivaara O, Nevanlinna H, Hamann U, Durocher F, Arason A, Couch FJ, Easton DF, Chenevix-Trench G, Anonymous00139. · Cancer Research UK, Genetic Epidemiology Unit, Strangeways Research Laboratory, Cambridge, CB1 8RN, UK. · Am J Hum Genet. · Pubmed #17999359 links to  free full text

Abstract: RAD51 is an important component of double-stranded DNA-repair mechanisms that interacts with both BRCA1 and BRCA2. A single-nucleotide polymorphism (SNP) in the 5' untranslated region (UTR) of RAD51, 135G-->C, has been suggested as a possible modifier of breast cancer risk in BRCA1 and BRCA2 mutation carriers. We pooled genotype data for 8,512 female mutation carriers from 19 studies for the RAD51 135G-->C SNP. We found evidence of an increased breast cancer risk in CC homozygotes (hazard ratio [HR] 1.92 [95% confidence interval {CI} 1.25-2.94) but not in heterozygotes (HR 0.95 [95% CI 0.83-1.07]; P=.002, by heterogeneity test with 2 degrees of freedom [df]). When BRCA1 and BRCA2 mutation carriers were analyzed separately, the increased risk was statistically significant only among BRCA2 mutation carriers, in whom we observed HRs of 1.17 (95% CI 0.91-1.51) among heterozygotes and 3.18 (95% CI 1.39-7.27) among rare homozygotes (P=.0007, by heterogeneity test with 2 df). In addition, we determined that the 135G-->C variant affects RAD51 splicing within the 5' UTR. Thus, 135G-->C may modify the risk of breast cancer in BRCA2 mutation carriers by altering the expression of RAD51. RAD51 is the first gene to be reliably identified as a modifier of risk among BRCA1/2 mutation carriers.

Rebbeck TR, Troxel AB, Norman S, Bunin G, DeMichele A, Schinnar R, Berlin JA, Strom BL. · Center for Clinical Epidemiology and Biostatistics and Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA. · Am J Epidemiol. · Pubmed #17827444 links to  free full text

Abstract: Combined hormone replacement therapy (CHRT) containing estrogens and progestins is associated with breast cancer risk. The authors evaluated interactions between CHRT use and progestin metabolism genotypes at CYP3A4 and the progesterone receptor (PGR) and their effects on breast cancer risk using the population-based Women's Insights and Shared Experiences (WISE) Study (1999-2002) of postmenopausal Caucasian women (522 breast cancer cases, 708 controls). The authors observed an elevated risk of ductal tumors in women with 3 or more years of CHRT use and PGR 331A alleles compared with those who had neither factor (odds ratio = 3.35, 95% confidence interval (CI): 1.13, 9.99; two-sided p(interaction) = 0.035). They also observed an elevated risk of progesterone receptor-positive tumors in women who had had 3 or more years of CHRT use and PGR 331A alleles compared with those who had neither factor (odds ratio = 3.82, 95% CI: 1.26, 11.55; p = 0.028). Finally, they observed an increased risk of estrogen receptor-negative tumors in women without CHRT exposure and CYP3A4*1B alleles compared with those who had neither factor (odds ratio = 6.46, 95% CI: 2.02, 20.66; p = 0.024), although the biologic interpretation of this result requires further study. When stratified by recency of use, PGR effects were observed only in current CHRT users, while CYP3A4 effects were observed only in former CHRT users. Breast cancer risk in women who have used CHRT may be influenced by genetic factors involved in progestin metabolism.

Couch FJ, Sinilnikova O, Vierkant RA, Pankratz VS, Fredericksen ZS, Stoppa-Lyonnet D, Coupier I, Hughes D, Hardouin A, Berthet P, Peock S, Cook M, Baynes C, Hodgson S, Morrison PJ, Porteous ME, Jakubowska A, Lubinski J, Gronwald J, Spurdle AB, Anonymous00430, Schmutzler R, Versmold B, Engel C, Meindl A, Sutter C, Horst J, Schaefer D, Offit K, Kirchhoff T, Andrulis IL, Ilyushik E, Glendon G, Devilee P, Vreeswijk MP, Vasen HF, Borg A, Backenhorn K, Struewing JP, Greene MH, Neuhausen SL, Rebbeck TR, Nathanson K, Domchek S, Wagner T, Garber JE, Szabo C, Zikan M, Foretova L, Olson JE, Sellers TA, Lindor N, Nevanlinna H, Tommiska J, Aittomaki K, Hamann U, Rashid MU, Torres D, Simard J, Durocher F, Guenard F, Lynch HT, Isaacs C, Weitzel J, Olopade OI, Narod S, Daly MB, Godwin AK, Tomlinson G, Easton DF, Chenevix-Trench G, Antoniou AC, Anonymous00431. · Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, MN 55905, USA. · Cancer Epidemiol Biomarkers Prev. · Pubmed #17627006 links to  free full text

Abstract: The AURKA oncogene is associated with abnormal chromosome segregation and aneuploidy and predisposition to cancer. Amplification of AURKA has been detected at higher frequency in tumors from BRCA1 and BRCA2 mutation carriers than in sporadic breast tumors, suggesting that overexpression of AURKA and inactivation of BRCA1 and BRCA2 cooperate during tumor development and progression. The F31I polymorphism in AURKA has been associated with breast cancer risk in the homozygous state in prior studies. We evaluated whether the AURKA F31I polymorphism modifies breast cancer risk in BRCA1 and BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2. Consortium of Investigators of Modifiers of BRCA1/2 was established to provide sufficient statistical power through increased numbers of mutation carriers to identify polymorphisms that act as modifiers of cancer risk and can refine breast cancer risk estimates in BRCA1 and BRCA2 mutation carriers. A total of 4,935 BRCA1 and 2,241 BRCA2 mutation carriers and 11 individuals carrying both BRCA1 and BRCA2 mutations was genotyped for F31I. Overall, homozygosity for the 31I allele was not significantly associated with breast cancer risk in BRCA1 and BRCA2 carriers combined [hazard ratio (HR), 0.91; 95% confidence interval (95% CI), 0.77-1.06]. Similarly, no significant association was seen in BRCA1 (HR, 0.90; 95% CI, 0.75-1.08) or BRCA2 carriers (HR, 0.93; 95% CI, 0.67-1.29) or when assessing the modifying effects of either bilateral prophylactic oophorectomy or menopausal status of BRCA1 and BRCA2 carriers. In summary, the F31I polymorphism in AURKA is not associated with a modified risk of breast cancer in BRCA1 and BRCA2 carriers.

Rebbeck TR, Troxel AB, Shatalova EG, Blanchard R, Norman S, Bunin G, Demichele A, Schinnar R, Berlin JA, Strom BL. · Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6021, USA. · Cancer Epidemiol Biomarkers Prev. · Pubmed #17548708 links to  free full text

This publication has no abstract.

Rebbeck TR, Troxel AB, Walker AH, Panossian S, Gallagher S, Shatalova EG, Blanchard R, Norman S, Bunin G, DeMichele A, Berlin M, Schinnar R, Berlin JA, Strom BL. · Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, 904 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104-6021, USA. · Cancer Epidemiol Biomarkers Prev. · Pubmed #17372239 links to  free full text

Abstract: Estrogen exposures have been associated with breast cancer risk, and genes involved in estrogen metabolism have been reported to mediate that risk. Our goal was to better understand whether combinations of candidate estrogen metabolism genotypes are associated with breast cancer etiology. A population-based case-control study in three counties of the Philadelphia Metropolitan area was undertaken. We evaluated seven main effects and 21 first-order interactions in African Americans and European Americans for genotypes at COMT, CYP1A1, CYP1A2, CYP1B1, CYP3A4, SULT1A1, and SULT1E1 in 878 breast cancer cases and 1,409 matched random digit-dialed controls. In European Americans, we observed main effect associations of genotypes containing any CYP1A1*2C (odds ratio, 1.71; 95% confidence interval, 1.09-2.67) and breast cancer. No significant main effects were observed in African Americans. Three significant first-order interactions were observed. In European Americans, interactions between SULT1A1*2 and CYP1A1*2C genotypes (P(interaction) < 0.001) and between SULT1E1 and CYP1A2*1F genotypes were observed (P(interaction) = 0.006). In African Americans, an interaction between SULT1A1*2 and CYP1B1*4 was observed (P(interaction) = 0.041). We applied the false-positive report probability approach, which suggested that these associations were noteworthy; however, we cannot rule out the possibility that chance led to these associations. Pending future confirmation of these results, our data suggest that breast cancer etiology in both European American and African American postmenopausal women may involve the interaction of a gene responsible for the generation of catecholestrogens with a gene involved in estrogen and catecholestrogen sulfation.

Rebbeck TR, Troxel AB, Norman S, Bunin GR, DeMichele A, Baumgarten M, Berlin M, Schinnar R, Strom BL. · Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6021, USA. · Int J Cancer. · Pubmed #17205521 No free full text.

Abstract: Hormone-related supplements (HRS), many of which contain phytoestrogens, are widely used to manage menopausal symptoms, yet their relationship with breast cancer risk has generally not been evaluated. We evaluated whether use of HRS was associated with breast cancer risk, using a population-based case-control study in 3 counties of the Philadelphia metropolitan area consisting of 949 breast cancer cases and 1,524 controls. Use of HRS varied significantly by race, with African American women being more likely than European American women to use any herbal preparation (19.2% vs. 14.7%, p=0.003) as well as specific preparations including black cohosh (5.4% vs. 2.0%, p=0.003), ginseng (12.5% vs. 7.9%, p<0.001) and red clover (4.7% vs. 0.6%, p<0.001). Use of black cohosh had a significant breast cancer protective effect (adjusted odds ratio 0.39, 95% CI: 0.22-0.70). This association was similar among women who reported use of either black cohosh or Remifemin (an herbal preparation derived from black cohosh; adjusted odds ratio 0.47, 95% CI: 0.27-0.82). The literature reports that black cohosh may be effective in treating menopausal symptoms, and has antiestrogenic, antiproliferative and antioxidant properties. Additional confirmatory studies are required to determine whether black cohosh could be used to prevent breast cancer.

Pierce LJ, Levin AM, Rebbeck TR, Ben-David MA, Friedman E, Solin LJ, Harris EE, Gaffney DK, Haffty BG, Dawson LA, Narod SA, Olivotto IA, Eisen A, Whelan TJ, Olopade OI, Isaacs C, Merajver SD, Wong JS, Garber JE, Weber BL. · Department of Radiation Oncology, University of Michigan School of Medicine, Ann Arbor, MI 48109-0010, USA. · J Clin Oncol. · Pubmed #16636335 No free full text.

Abstract: PURPOSE: We compared the outcome of breast-conserving surgery and radiotherapy in BRCA1/2 mutation carriers with breast cancer versus that of matched sporadic controls. METHODS: A total of 160 BRCA1/2 mutation carriers with breast cancer were matched with 445 controls with sporadic breast cancer. Primary end points were rates of in-breast tumor recurrence (IBTR) and contralateral breast cancers (CBCs). Median follow-up was 7.9 years for mutation carriers and 6.7 years for controls. RESULTS: There was no significant difference in IBTR overall between carriers and controls; 10- and 15-year estimates were 12% and 24% for carriers and 9% and 17% for controls, respectively (hazard ratio [HR], 1.37; P = .19). Multivariate analyses for IBTR found BRCA1/2 mutation status to be an independent predictor of IBTR when carriers who had undergone oophorectomy were removed from analysis (HR, 1.99; P = .04); the incidence of IBTR in carriers who had undergone oophorectomy was not significantly different from that in sporadic controls (P = .37). CBCs were significantly greater in carriers versus controls, with 10- and 15-year estimates of 26% and 39% for carriers and 3% and 7% for controls, respectively (HR, 10.43; P < .0001). Tamoxifen use significantly reduced risk of CBCs in mutation carriers (HR, 0.31; P = .05). CONCLUSION: IBTR risk at 10 years is similar in BRCA1/2 carriers treated with breast conservation surgery who undergo oophorectomy versus sporadic controls. As expected, CBCs are significantly increased in carriers. Although the incidence of CBCs was significantly reduced in mutation carriers who received tamoxifen, this rate remained significantly greater than in controls. Additional strategies are needed to reduce contralateral cancers in these high-risk women.

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. · Abramson Cancer Centre, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6021, USA. · Lancet Oncol. · Pubmed #16510331 No free full text.

Abstract: BACKGROUND: Bilateral prophylactic salpingo-oophorectomy (BPSO) is used widely used to reduce the risk of breast and ovarian cancer in women with BRCA1 and BRCA2 mutations. However, the reduction in mortality after this surgery is unclear. We aimed to assess whether BPSO improves overall mortality or cancer-specific mortality in BRCA1 and BRCA2 mutation carriers. METHODS: We identified a prospective cohort of 666 women with disease-associated germline mutations in BRCA1 or BRCA2 and no previous cancer diagnosis. In our primary analysis, we compared 155 women who had had BPSO and 271 women matched for age at BPSO who had not had BPSO. In our secondary analysis, we compared 188 women who had had BPSO with 478 women who had not. In both analyses, we compared overall mortality and cancer-specific mortality. All analyses were adjusted for centre, mutation (BRCA1 vs BRCA2), and birth year. FINDINGS: In the primary analysis, mean follow-up from BPSO to censoring was 3.1 years [SD 2.4] in the BPSO group and 2.1 years [2.0] in the non-BPSO group. The hazard ratio (HR) for overall mortality was 0.24 (95% CI 0.08-0.71), for breast-cancer-specific mortality was 0.10 (0.02-0.71), and for ovarian-cancer-specific mortality was 0.05 (0.01-0.46) for women who had BPSO compared with those who had not. In secondary analysis, BPSO was associated with reduced overall mortality (HR 0.28 [95% CI 0.10-0.74]), but not with breast-cancer-specific mortality (0.15 [0.02-1.18] or ovarian-cancer-specific mortality (0.23 [0.02-1.87]. When regarded as a time-dependent covariate, BPSO was not associated significantly with mortality. INTERPRETATION: If confirmed, the finding that BPSO improves overall survival and cancer-specific survival in women with BRCA mutations will complement our existing knowledge of cancer-risk reduction associated with BPSO. Together, these data could give information to women who are considering genetic testing.