Susan M Domchek

University of Pennsylvania, Filadelfia, Pennsylvania, United States

Are you Susan M Domchek?

Claim your profile

Publications (213)1593.84 Total impact

  • Source
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: IMPORTANCE: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE:To identify mutation-specific cancer risks for carriers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS:Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. EXPOSURES:Mutations of BRCA1 or BRCA2. MAIN OUTCOMES AND MEASURES: Breast and ovarian cancer risks. RESULTS:Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. CONCLUSIONS AND RELEVANCE: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.
    JAMA The Journal of the American Medical Association 04/2015; 313(13):1347-61. DOI:10.1001/jama.2014.5985 · 30.39 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The risks, benefits, and utilities of multiplex panels for breast cancer susceptibility are unknown, and new counseling and informed consent models are needed. We sought to obtain patient feedback and early outcome data with a novel tiered-binned model for multiplex testing. BRCA1/2-negative and untested patients completed pre- and posttest counseling and surveys evaluating testing experiences and cognitive and affective responses to multiplex testing. Of 73 patients, 49 (67%) completed pretest counseling. BRCA1/2-negative patients were more likely to proceed with multiplex testing (86%) than those untested for BRCA1/2 (43%; P < 0.01). Many patients declining testing reported concern for uncertainty and distress. Most patients would not change anything about their pre- (76%) or posttest (89%) counseling sessions. Thirty-three patients (72%) were classified as making an informed choice, including 81% of those who proceeded with multiplex testing. Knowledge increased significantly. Anxiety, depression, uncertainty, and cancer worry did not significantly increase with multiplex testing. Some patients, particularly those without prior BRCA1/2 testing, decline multiplex testing. Most patients who proceeded with testing did not experience negative psychological responses, but larger studies are needed. The tiered-binned approach is an innovative genetic counseling and informed consent model for further study in the era of multiplex testing.Genet Med advance online publication 02 April 2015Genetics in Medicine (2015); doi:10.1038/gim.2015.19.
    Genetics in medicine: official journal of the American College of Medical Genetics 04/2015; DOI:10.1038/gim.2015.19 · 6.44 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04 - 1.15, p = 1.9 x 10-4 (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03 - 1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers. PMID: 25830658 [PubMed - in process]
    PLoS ONE 04/2015; 10(4). · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: OBJECTIVE. The purpose of this article is to assess the difference in fibroglandular volume and background parenchymal enhancement in BRCA1 and BRCA2 mutation carriers on contrast-enhanced breast MRI (CE-MRI) performed before and immediately after risk-reducing salpingo-oophorectomy (RRSO). MATERIALS AND METHODS. We retrospectively compared fibroglandular volume and background parenchymal enhancement in 55 female BRCA1 and BRCA2 mutation carriers before and after RRSO using standard BI-RADS categories and a paired Wilcoxon and Mann-Whitney U test. A two-sample Wilcoxon test was performed to compare fibroglandular volume and background parenchymal enhancement in women with and without subsequent breast cancer diagnosis on follow-up. RESULTS. The median time to post-RRSO CE-MRI was 8 months (range, 1-40 months). There was no difference in fibroglandular volume before and after RRSO (p = 0.65). The mean background parenchymal enhancement was 2.5 (range, 1-4) before and 1.5 (range, 1-4) after RRSO (overall range, -2.5 to 1.5; p = 0.0001). Breast cancer was detected in nine women at a median time of 4.8 years (range, 1.8-13.3 years) after RRSO. For women who received a diagnosis of breast cancer after RRSO compared with those who did not, mean background parenchymal enhancement before RRSO was 3 (range, 2-4) versus 2.5 (range, 1-4; p = 0.001), and mean background parenchymal enhancement after RRSO was 2.5 (range, 1.5-4) versus 1.5 (range 2-4; p = 0.0018). There was no difference in fibroglandular volume before and after RRSO. CONCLUSION. In BRCA1 and BRCA2 mutation carriers, we observed a significant reduction in background parenchymal enhancement on the first CE-MRI after RRSO and no significant change in fibroglandular volume. Higher background parenchymal enhancement before and after RRSO was observed in women who subsequently received a diagnosis of breast cancer. This suggests that background parenchymal enhancement, rather than fibro-glandular volume, may be a more sensitive imaging biomarker of breast cancer risk.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: IntroductionMammography screening results in a significant number of false-positives. The use of pre-test breast cancer risk factors to guide follow-up of abnormal mammograms could improve the positive predictive value of screening. We evaluated the use of the Gail model, body mass index (BMI), and genetic markers to predict cancer diagnosis among women with abnormal mammograms. We also examined the extent to which pre-test risk factors could reclassify women without cancer below the biopsy threshold.Methods We recruited a prospective cohort of women referred to biopsy with abnormal (BI-RADS 4) mammograms. Breast cancer risk factors were assessed prior to biopsy. A validated panel of 12 single nucleotide polymorphisms (SNPs) associated with breast cancer were measured. Logistic regression was used to assess the association of Gail risk factors, BMI and SNPs with cancer diagnosis (invasive or DCIS). Model discrimination was assessed using area under the receiver operating curve and calibration was assessed using the Hosmer-Lemeshow goodness of fit test. Finally, the distribution of predicted probabilities of cancer diagnosis were compared for women with and without breast cancer.ResultsIn the multivariate model, age (OR¿=¿1.05, 95% CI 1.03 to 1.08 P <0.001), SNP panel relative risk (OR¿=¿2.30, 95% CI 1.06 to 4.99, P¿=¿0.035), and BMI (¿30 kg/m2 versus <25 kg/m2, OR¿=¿2.20, 95% CI 1.05 to 4.58, P¿=¿0.036) were significantly associated with breast cancer diagnosis. Older women were more likely to be diagnosed with breast cancer. The SNP Panel RR remained strongly associated with breast cancer diagnosis after multivariable adjustment. Higher BMI was also strongly associated with increased odds of breast cancer diagnosis. Obese women (OR¿=¿2.20, 95% CI 1.05 to 4.58, P¿=¿0.036) had more than twice the odds of cancer diagnosis compared to women with BMI <25 kg/m2. The SNP Panel appeared to have predictive ability among both white and black women.Conclusions Breast cancer risk factors, including BMI and genetic markers are predictive of cancer diagnosis among women with BI-RADS 4 mammograms. Using pre-test risk factors to guide follow-up of abnormal mammograms could reduce the burden of false-positive mammograms.
    Breast cancer research: BCR 01/2015; 17(1):1. DOI:10.1186/s13058-014-0509-4 · 5.88 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Women at elevated risk for breast cancer are motivated to reduce their risk. Current approaches rely primarily on hormonal intervention. A preventive exercise intervention might address the same hormonal issues, yet have fewer serious side effects and less negative impact on quality of life as compared to prophylactic mastectomy. WISER Sister was a randomized controlled trial which examined effects of two doses of exercise training on endogenous sex hormone exposure, hormonally active breast tissue, and other breast cancer risk factors.
    Contemporary Clinical Trials 01/2015; 41. DOI:10.1016/j.cct.2014.12.016 · 1.99 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Breast density and single-nucleotide polymorphisms (SNPs) have both been associated with breast cancer risk. To determine the extent to which these two breast cancer risk factors are associated, we investigate the association between a panel of validated SNPs related to breast cancer and quantitative measures of mammographic density in a cohort of Caucasian and African-American women. In this IRB-approved, HIPAA-compliant study, we analyzed a screening population of 639 women (250 African American and 389 Caucasian) who were tested with a validated panel assay of 12 SNPs previously associated to breast cancer risk. Each woman underwent digital mammography as part of routine screening and all were interpreted as negative. Both absolute and percent estimates of area and volumetric density were quantified on a per-woman basis using validated software. Associations between the number of risk alleles in each SNP and the density measures were assessed through a race-stratified linear regression analysis, adjusted for age, BMI, and Gail lifetime risk. The majority of SNPs were not found to be associated with any measure of breast density. SNP rs3817198 (in LSP1) was significantly associated with both absolute area (p = 0.004) and volumetric (p = 0.019) breast density in Caucasian women. In African-American women, SNPs rs3803662 (in TNRC9/TOX3) and rs4973768 (in NEK10) were significantly associated with absolute (p = 0.042) and percent (p = 0.028) volume density respectively. The majority of SNPs investigated in our study were not found to be significantly associated with breast density, even when accounting for age, BMI, and Gail risk, suggesting that these two different risk factors contain potentially independent information regarding a woman's risk to develop breast cancer. Additionally, the few statistically significant associations between breast density and SNPs were different for Caucasian versus African American women. Larger prospective studies are warranted to validate our findings and determine potential implications for breast cancer risk assessment.
    BMC Cancer 01/2015; 15(1):1159. DOI:10.1186/s12885-015-1159-3 · 3.32 Impact Factor
  • Karoline B Kuchenbaecker, Susan L Neuhausen, Mark Robson, Daniel Barrowdale, Lesley McGuffog, Anna Marie Mulligan, Irene L Andrulis, Amanda B Spurdle, Marjanka K Schmidt, Rita K Schmutzler, [......], Niklas Loman, Ake Borg, Hans Ehrencrona, Olufunmilayo I Olopade, Jacques Simard, Douglas F Easton, Georgia Chenevix-Trench, Kenneth Offit, Fergus J Couch, Antonis C Antoniou
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. Methods We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. Results The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10−6 in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement. Conclusions Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction. Electronic supplementary material The online version of this article (doi:10.1186/s13058-014-0492-9) contains supplementary material, which is available to authorized users.
    Breast Cancer Research 12/2014; 16(6). DOI:10.1186/s13058-014-0492-9 · 5.33 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach. ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)). These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.
    Breast cancer research: BCR 12/2014; 16(6):3419. DOI:10.1186/s13058-014-0474-y · 5.88 Impact Factor
  • Susan M Domchek
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose:Clinical testing for germ-line variation in multiple cancer susceptibility genes is available using massively parallel sequencing. Limited information is available for pretest genetic counseling regarding the spectrum of mutations and variants of uncertain significance in defined patient populations.Methods:We performed massively parallel sequencing using targeted capture of 22 cancer susceptibility genes in 278 BRCA1/2-negative patients with early-onset breast cancer (diagnosed at younger than 40 years of age).Results:Thirty-one patients (11%) were found to have at least one deleterious or likely deleterious variant. Seven patients (2.5% overall) were found to have deleterious or likely deleterious variants in genes for which clinical guidelines exist for management, namely TP53 (4), CDKN2A (1), MSH2 (1), and MUTYH (double heterozygote). Twenty-four patients (8.6%) had deleterious or likely deleterious variants in a cancer susceptibility gene for which clinical guidelines are lacking, such as CHEK2 and ATM. Fifty-four patients (19%) had at least one variant of uncertain significance, and six patients were heterozygous for a variant in MUTYH.Conclusion:These data demonstrate that massively parallel sequencing identifies reportable variants in known cancer susceptibility genes in more than 30% of patients with early-onset breast cancer. However, only few patients (2.5%) have definitively actionable mutations given current clinical management guidelines.Genet Med advance online publication 11 December 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.176.
    Genetics in medicine: official journal of the American College of Medical Genetics 12/2014; DOI:10.1038/gim.2014.176 · 6.44 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: The G1/S checkpoint of the cell cycle is frequently dysregulated in breast cancer (BC). Palbociclib (PD0332991) is an oral inhibitor of CDK4/6. Based upon preclinical/phase I activity, we performed a phase II, single-arm trial of palbociclib in advanced BC. Experimental Design: Eligible patients had histologically confirmed, metastatic BC positive for retinoblastoma (Rb) protein and measureable disease. Palbociclib was given at 125 mg orally on days 1-21 of a 28-day cycle. Primary objectives were tumor response and tolerability. Secondary objectives included progression-free survival (PFS) and assessment of Rb expression/localization, KI-67, p16 loss and CCND1 amplification. Results: 37 patients were enrolled; 84% hormone-receptor (HR)+/Her2-, 5% HR+/Her2+ and 11% HR-/Her2-, with a median of 2 prior cytotoxic regimens. Two patients had partial response (PR) and 5 had stable disease > 6 months for a clinical benefit rate (CBR=PR+6moSD) of 19% overall, 21% in HR+ and 29% in HR+/Her2- who had progressed through > 2 prior lines of hormonal therapy. Median PFS overall was 3.7 months (95% CI 1.9-5.1), but significantly longer for those with HR+ vs. HR- disease (p=0.03) and those who had previously progressed through endocrine therapy for advanced disease (p=0.02). Grade 3/4 toxicities included neutropenia (51%), anemia (5%), and thrombocytopenia (22%). 24% had treatment interruption and 51% had dose reduction, all for cytopenias. No biomarker identified a sensitive tumor population. Conclusion: Single-agent palbociclib is well tolerated and active in patients with endocrine-resistant, hormone-receptor positive, Rb -positive breast cancer. Cytopenias were uncomplicated and easily managed with dose-reduction. Copyright © 2014, American Association for Cancer Research.
    Clinical Cancer Research 12/2014; DOI:10.1158/1078-0432.CCR-14-2258 · 8.19 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Olaparib is an oral poly (ADP-ribose) polymerase inhibitor with activity in germline BRCA1 and BRCA2 (BRCA1/2) -associated breast and ovarian cancers. We evaluated the efficacy and safety of olaparib in a spectrum of BRCA1/2-associated cancers.
    Journal of Clinical Oncology 11/2014; 33(3). DOI:10.1200/JCO.2014.56.2728 · 17.88 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and non-genetic modifying factors. In this study we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n=3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed p-values of association ranged between 0.005-1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.
    Cancer Epidemiology Biomarkers & Prevention 10/2014; 24:308-16. DOI:10.1158/1055-9965.EPI-14-0532 · 4.32 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Inherited mutations in BRCA1 or BRCA2 (BRCA1/2) confer very high risk of breast and ovarian cancers. Genetic testing and counseling can reduce risk and death from these cancers if appropriate preventive strategies are applied, including risk-reducing salpingo-oophorectomy (RRSO) or risk-reducing mastectomy (RRM). However, some women who might benefit from these interventions do not take full advantage of them. We evaluated RRSO and RRM use in a prospective cohort of 1,499 women with inherited BRCA1/2 mutations from 20 centers who enrolled in the study without prior cancer or RRSO or RRM and were followed forward for the occurrence of these events. We estimated the age-specific usage of RRSO/RRM in this cohort using Kaplan-Meier analyses. Use of RRSO was 45 % for BRCA1 and 34 % for BRCA2 by age 40, and 86 % for BRCA1 and 71 % for BRCA2 by age 50. RRM usage was estimated to be 46 % by age 70 in both BRCA1 and BRCA2 carriers. BRCA1 mutation carriers underwent RRSO more frequently than BRCA2 mutation carriers overall, but the uptake of RRSO in BRCA2 was similar after mutation testing and in women born since 1960. RRM uptake was similar for both BRCA1 and BRCA2. Childbearing influenced the use of RRSO and RRM in both BRCA1 and BRCA2. Uptake of RRSO is high, but some women are still diagnosed with ovarian cancer before undergoing RRSO. This suggests that research is needed to understand the optimal timing of RRSO to maximize risk reduction and limit potential adverse consequences of RRSO.
    Breast Cancer Research and Treatment 10/2014; 148(2). DOI:10.1007/s10549-014-3134-0 · 4.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose:Multiplex genetic testing, including both moderate- and high-penetrance genes for cancer susceptibility, is associated with greater uncertainty than traditional testing, presenting challenges to informed consent and genetic counseling. We sought to develop a new model for informed consent and genetic counseling for four ongoing studies. Methods:Drawing from professional guidelines, literature, conceptual frameworks, and clinical experience, a multidisciplinary group developed a tiered-binned genetic counseling approach proposed to facilitate informed consent and improve outcomes of cancer susceptibility multiplex testing.Results:In this model, tier 1 "indispensable" information is presented to all patients. More specific tier 2 information is provided to support variable informational needs among diverse patient populations. Clinically relevant information is "binned" into groups to minimize information overload, support informed decision making, and facilitate adaptive responses to testing. Seven essential elements of informed consent are provided to address the unique limitations, risks, and uncertainties of multiplex testing.Conclusion:A tiered-binned model for informed consent and genetic counseling has the potential to address the challenges of multiplex testing for cancer susceptibility and to support informed decision making and adaptive responses to testing. Future prospective studies including patient-reported outcomes are needed to inform how to best incorporate multiplex testing for cancer susceptibility into clinical practice.Genet Med advance online publication 09 October 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.134.
    Genetics in medicine: official journal of the American College of Medical Genetics 10/2014; DOI:10.1038/gim.2014.134 · 6.44 Impact Factor
  • Fertility and Sterility 09/2014; 102(3):e105. DOI:10.1016/j.fertnstert.2014.07.361 · 4.30 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND Germline loss-of-function mutations in PALB2 are known to confer a predisposition to breast cancer. However, the lifetime risk of breast cancer that is conferred by such mutations remains unknown. METHODS We analyzed the risk of breast cancer among 362 members of 154 families who had deleterious truncating, splice, or deletion mutations in PALB2. The age-specific breast-cancer risk for mutation carriers was estimated with the use of a modified segregation-analysis approach that allowed for the effects of PALB2 genotype and residual familial aggregation. RESULTS The risk of breast cancer for female PALB2 mutation carriers, as compared with the general population, was eight to nine times as high among those younger than 40 years of age, six to eight times as high among those 40 to 60 years of age, and five times as high among those older than 60 years of age. The estimated cumulative risk of breast cancer among female mutation carriers was 14% (95% confidence interval [CI], 9 to 20) by 50 years of age and 35% (95% CI, 26 to 46) by 70 years of age. Breast-cancer risk was also significantly influenced by birth cohort (P < 0.001) and by other familial factors (P = 0.04). The absolute breast-cancer risk for PALB2 female mutation carriers by 70 years of age ranged from 33% (95% CI, 25 to 44) for those with no family history of breast cancer to 58% (95% CI, 50 to 66) for those with two or more first-degree relatives with breast cancer at 50 years of age. CONCLUSIONS Loss-of-function mutations in PALB2 are an important cause of hereditary breast cancer, with respect both to the frequency of cancer-predisposing mutations and to the risk associated with them. Our data suggest the breast-cancer risk for PALB2 mutation carriers may overlap with that for BRCA2 mutation carriers.
    New England Journal of Medicine 08/2014; 371(6):497-506. DOI:10.1056/NEJMoa1400382 · 54.42 Impact Factor

Publication Stats

6k Citations
1,593.84 Total Impact Points


  • 2002–2015
    • University of Pennsylvania
      • • Department of Medicine
      • • "Abramson" Cancer Center
      • • Division of Hematology/Oncology
      • • Department of Biology
      Filadelfia, Pennsylvania, United States
    • Dana-Farber Cancer Institute
      • Department of Medical Oncology
      Boston, Massachusetts, United States
  • 2007–2014
    • William Penn University
      Filadelfia, Pennsylvania, United States
    • University of Toronto
      • Department of Nutritional Sciences
      Toronto, Ontario, Canada
    • The Philadelphia Center
      Philadelphia, Pennsylvania, United States
  • 2012
    • Treatment Research Institute, Philadelphia PA
      Philadelphia, Pennsylvania, United States
  • 2010–2012
    • Queensland Institute of Medical Research
      Brisbane, Queensland, Australia
  • 2009–2012
    • Memorial Sloan-Kettering Cancer Center
      New York City, New York, United States
  • 2007–2012
    • Mayo Clinic - Rochester
      • • Department of Health Science Research
      • • Department of Laboratory Medicine & Pathology
      Рочестер, Minnesota, United States
  • 2011
    • University College London
      Londinium, England, United Kingdom
    • Hospital of the University of Pennsylvania
      Philadelphia, Pennsylvania, United States
  • 2007–2010
    • University of Cambridge
      • Department of Public Health and Primary Care
      Cambridge, ENG, United Kingdom
  • 2005–2008
    • Creighton University
      Omaha, Nebraska, United States
    • Harvard University
      • Department of Society, Human Development, and Health
      Cambridge, Massachusetts, United States
  • 2000
    • Massachusetts General Hospital
      Boston, Massachusetts, United States