Showing papers by "Susan M. Domchek published in 2012"
University of Cambridge1, University of Toronto2, University of Pennsylvania3, University of Southampton4, University of Helsinki5, University of Southern California6, QIMR Berghofer Medical Research Institute7, Columbia University8, National Institutes of Health9, Mayo Clinic10, Leipzig University11, Claude Bernard University Lyon 112, University of Melbourne13, University of Utah14, Cancer Prevention Institute of California15, Vilnius University16, University of Latvia17, University of Copenhagen18, Complutense University of Madrid19, University of Turin20, University of Florence21, Sapienza University of Rome22, German Cancer Research Center23, Memorial Hospital of South Bend24, Erasmus University Rotterdam25, Utrecht University26, Royal Devon and Exeter Hospital27, Churchill Hospital28, University Hospital of Wales29, University College London30, Fox Chase Cancer Center31, University of Kansas32, University of Cologne33, Technische Universität München34, Dresden University of Technology35, University of Kiel36, University of Düsseldorf37, Heidelberg University38, University of Ulm39, Hannover Medical School40, University of Münster41, Charité42, University of Würzburg43, University of Paris44, Georgetown University45, Laval University46, University of Padua47, Peter MacCallum Cancer Centre48, University of Chicago49, Harvard University50, University of Delaware51, American Cancer Society52, Medical University of Vienna53, Ohio State University54, University of Southern Denmark55, University of Pisa56, Karolinska Institutet57, Lund University58, City of Hope National Medical Center59, University of California, San Francisco60, Roswell Park Cancer Institute61, Cedars-Sinai Medical Center62
TL;DR: Pathologic characteristics of BRCA1 and BRCa2 tumors may be useful for improving risk-prediction algorithms and informing clinical strategies for screening and prophylaxis.
Abstract: BACKGROUND: Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization.METHODS: We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian, and contralateral breast cancers.RESULTS: There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (P-trend = 1.2 × 10(-5)), but increased with age at diagnosis among BRCA2, carriers (P-trend = 6.8 × 10(-6)). The proportion of triple-negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histologic grade than ER-positive tumors (grade 3 vs. grade 1; P = 1.2 × 10(-13) for BRCA1 and P = 0.001 for BRCA2). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status [ER-positive odds ratio (OR) for BRCA2 = 9.4, 95% CI: 7.0-12.6 and PR-positive OR = 1.7, 95% CI: 1.3-2.3, under joint analysis]. Lobular tumors were more likely to be BRCA2-related (OR for BRCA2 = 3.3, 95% CI: 2.4-4.4; P = 4.4 × 10(-14)), and medullary tumors BRCA1-related (OR for BRCA2 = 0.25, 95% CI: 0.18-0.35; P = 2.3 × 10(-15)). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (P = 0.0004 for BRCA1; P = 0.002 for BRCA2). There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous: 67%; mucinous: 1%; endometrioid: 12%; clear-cell: 2%).Conclusions/Impact: Pathologic characteristics of BRCA1 and BRCA2 tumors may be useful for improving risk-prediction algorithms and informing clinical strategies for screening and prophylaxis. Cancer Epidemiol Biomarkers Prev; 1-14. ©2011 AACR.
514 citations
TL;DR: It is concluded that CD25 blockade depletes and selectively reprograms Tregs in concert with active immune therapy in cancer patients, suggesting a mechanism to target cancer-associated T Regs while avoiding autoimmunity.
Abstract: Regulatory T cells (Tregs) are key mediators of immune tolerance and feature prominently in cancer. Depletion of CD25+ FoxP3+ Tregs in vivo may promote T cell cancer immunosurveillance, but no strategy to do so in humans while preserving immunity and preventing autoimmunity has been validated. We evaluated the Food and Drug Administration–approved CD25-blocking monoclonal antibody daclizumab with regard to human Treg survival and function. In vitro, daclizumab did not mediate antibody-dependent or complement-mediated cytotoxicity but rather resulted in the down-regulation of FoxP3 selectively among CD25high CD45RAneg Tregs. Moreover, daclizumab-treated CD45RAneg Tregs lost suppressive function and regained the ability to produce interferon-γ, consistent with reprogramming. To understand the impact of daclizumab on Tregs in vivo, we performed a clinical trial of daclizumab in combination with an experimental cancer vaccine in patients with metastatic breast cancer. Daclizumab administration led to a marked and prolonged decrease in Tregs in patients. Robust CD8 and CD4 T cell priming and boosting to all vaccine antigens were observed in the absence of autoimmunity. We conclude that CD25 blockade depletes and selectively reprograms Tregs in concert with active immune therapy in cancer patients. These results suggest a mechanism to target cancer-associated Tregs while avoiding autoimmunity.
278 citations
QIMR Berghofer Medical Research Institute1, University of Queensland2, University of Utah3, Leiden University4, Utrecht University5, Erasmus University Rotterdam6, Karolinska Institutet7, Uppsala University8, Leipzig University9, Technische Universität München10, French Institute of Health and Medical Research11, Mayo Clinic12, University of Copenhagen13, Odense University14, University of Southampton15, Children's Medical Research Institute16, University of Pennsylvania17, Ohio State University18, University of Pretoria19, University of Cologne20
TL;DR: The results provide substantial evidence that the BRCA1 c.5096G>A p.Arg1699Gln (R1699Q) variant, demonstrating ambiguous functional deficiency across multiple assays, is associated with intermediate risk of breast and ovarian cancer, highlighting challenges for risk modelling and clinical management of patients of this and other potential moderate-risk variants.
Abstract: Background Clinical classification of rare sequence changes identified in the breast cancer susceptibility genes BRCA1 and BRCA2 is essential for appropriate genetic counselling of individuals carr ...
95 citations
Antonis C. Antoniou1, Karoline Kuchenbaecker1, Penny Soucy, Jonathan Beesley2 +177 more•Institutions (85)
TL;DR: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCa1 and BRCA2 mutation carriers.
Abstract: Introduction: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). Methods: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. Results: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 x 10(-4)). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 x 10(-5), P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df P = 0.007; rs1292011 2df P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 x 10(-5)) and there was marginal evidence of association with ER- negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049). Conclusions: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.
92 citations
TL;DR: Diagnostic testing has a central role in targeted cancer therapeutics for both somatic and germline mutations and the development of PARP inhibitors has not been as rapid as anticipated and has been more challenging than expected.
Abstract: Identification of germline mutations associated with significant cancer susceptibility has the potential to change all aspects of an individual's care, from screening to cancer treatment. For example, women with germline mutations in BRCA1 and BRCA2 have markedly elevated risks of breast and ovarian cancer and the identification of these germline mutations has led to specific screening and prevention strategies. More recently, advances in the understanding of the biological function of BRCA1 and BRCA2 have led to clinical trials testing targeted therapies in this population, particularly poly(ADP-ribose) polymerase (PARP) inhibitors. Unfortunately, the development of PARP inhibitors has not been as rapid as anticipated and has been more challenging than expected. Somatic mutations identified in many cancer types have allowed the development of therapeutics that target these mutated genes, and many of these agents obtained rapid regulatory approval and are currently in widespread clinical practice. Diagnostic testing has a central role in targeted cancer therapeutics for both somatic and germline mutations. Although the era of molecular medicine and targeted therapies has led to significant changes in the practice of oncology, new challenges continue to arise.
73 citations
TL;DR: This study highlights the complexity of applying current GWAS findings across racial/ethnic groups, as none of GWAS-identified index SNPs could be replicated in women of African ancestry.
Abstract: Multiple breast cancer susceptibility loci have been identified in genome-wide association studies (GWAS) in populations of European and Asian ancestry using array chips optimized for populations of European ancestry. It is important to examine whether these loci are associated with breast cancer risk in women of African ancestry. We evaluated 25 single nucleotide polymorphisms (SNPs) at 19 loci in a pooled case–control study of breast cancer, which included 1509 cases and 1383 controls. Cases and controls were enrolled in Nigeria, Barbados and the USA; all women were of African ancestry. We found significant associations for three SNPs, which were in the same direction and of similar magnitude as those reported in previous fine-mapping studies in women of African ancestry. The allelic odds ratios were 1.24 [95% confidence interval (CI): 1.04–1.47; P = 0.018] for the rs2981578-G allele (10q26/FGFR2), 1.34 (95% CI: 1.10–1.63; P = 0.0035) for the rs9397435-G allele (6q25) and 1.12 (95% CI: 1.00–1.25; P = 0.04) for the rs3104793-C allele (16q12). Although a significant association was observed for an additional index SNP (rs3817198), it was in the opposite direction to prior GWAS studies. In conclusion, this study highlights the complexity of applying current GWAS findings across racial/ethnic groups, as none of GWAS-identified index SNPs could be replicated in women of African ancestry. Further fine-mapping studies in women of African ancestry will be needed to reveal additional and causal variants for breast cancer.
66 citations
TL;DR: The prevalence of non-cancer endpoints in a cohort of B1/2 mutation carriers is reported and a particularly high rate of osteopenia and osteoporosis is noted in B 1/2 with breast cancer undergoing RRSO prior to 50.
Abstract: Risk-reducing salpingo-oophorectomy (RRSO) significantly reduces the risk of ovarian cancer and breast cancer in pre-menopausal women with BRCA1 and BRCA2 (B1/2) mutations. Despite its clear benefits, little is known about non-cancer endpoints in this population. Medical records were examined in 226 B1/2 mutation carriers, who had previously undergone RRSO with a focus on bone health as well as the frequency of hypertension, hyperlipidemia, coronary artery disease (CAD), myocardial infarction (MI), diabetes, hypothyroidism and depression. From the medical records, DEXA scans, medications and medical conditions were recorded. Of the 226 patient records examined, 16% (36/226) had hypertension, 17% (39/226) hyperlipidemia, 2% (5/226) CAD or MI, 2% (4/226) diabetes, 13% (29/226) hypothyroidism and 14% (31/226) depression. DEXA results were available in 152 women. Of those DEXA scans, 71% (108/152) were abnormal (57% osteopenia and 14% osteoporosis). Among women who underwent RRSO prior to age 50, 71% (62/88) had osteopenia/osteoporosis. Although there was no difference in osteopenia/osteoporosis in women with RRSO prior to age 50 compared to those RRSO > 50, the age at follow up in these two groups differs greatly (mean age 44.7 vs. 60.6), suggesting that both current age and age at RRSO contribute to bone health assessment. In summary, here, we report the prevalence of non-cancer endpoints in a cohort of B1/2 mutation carriers and note a particularly high rate of osteopenia and osteoporosis in B1/2 with breast cancer undergoing RRSO prior to 50. Despite the risk reduction RRSO offers, attention should be paid to non-cancer endpoints, particularly bone health, in this population.
55 citations
TL;DR: Findings from genome-wide association studies can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and B RCA2 mutation carriers.
Abstract: Background: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Methods: Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined. Results: We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07-1.27; P = 7.42 x 10(-4)] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73-0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94-1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05-1.29; P = 3.8 x 10(-4)) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10-1.52; P = 1.8 x 10(-3)). Conclusions: 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers. Impact: These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 21(4); 645-57. (C) 2012 AACR.
53 citations
Susan J. Ramus1, Antonis C. Antoniou2, Karoline Kuchenbaecker2, Penny Soucy3 +189 more•Institutions (84)
TL;DR: The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCa2 mutations regarding their risk of ovarian cancer.
Abstract: Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 × 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 × 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 × 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer.
40 citations
TL;DR: African Americans may consider a number of ethical, legal, and social issues when making a decision to participate in cancer genetics research, and these issues should be addressed as part of recruitment efforts.
Abstract: Purpose Understanding genetic factors that contribute to racial differences in cancer outcomes may reduce racial disparities in cancer morbidity and mortality. Achieving this goal will be limited by low rates of African American participation in cancer genetics research. Method We conducted a qualitative study with African American adults (n = 91) to understand attitudes about participating in cancer genetics research and to identify factors that are considered when making a decision about participating in this type of research. Results Participants would consider the potential benefits to themselves, family members, and their community when making a decision to participate in cancer genetics research. However, concerns about exploitation, distrust of researchers, and investigators' motives were also important to participation decisions. Individuals would also consider who has access to their personal information and what would happen to these data. Side effects, logistical issues, and the potential to gain knowledge about health issues were also described as important factors in decision making. Conclusion African Americans may consider a number of ethical, legal, and social issues when making a decision to participate in cancer genetics research. These issues should be addressed as part of recruitment efforts.
37 citations
TL;DR: The findings highlight the importance ensuring that racial differences that are due to preferences and values are not misclassified as disparities in order to identify and address the root causes of disparate treatment.
Abstract: Low rates of genetic counseling among African American women have generated concerns about disparities; however, to the extent that women's decisions to accept or decline counseling are consistent with their values, then lower participation may reflect preferences and not disparities. We evaluated the extent to which women were satisfied with their decision about participating in genetic counseling for BRCA1/2 mutations and identified variables that were associated significantly with satisfaction. Prospective study of decision satisfaction with 135 African American women who had a minimum 5% prior probability of having a BRCA1/2 mutation. Decision satisfaction was evaluated one month after women were offered participation in genetic counseling using a structured questionnaire. Women were satisfied with their participation decision; more than 80% reported that their decision was consistent with their family values. However, women who declined pre-test counseling had significantly lower satisfaction scores. Our findings highlight the importance ensuring that racial differences that are due to preferences and values are not misclassified as disparities in order to identify and address the root causes of disparate treatment.
University of Pennsylvania1, University of Chicago2, Medical University of Vienna3, Baylor University Medical Center4, Harvard University5, City of Hope National Medical Center6, Creighton University7, Duke University8, Fox Chase Cancer Center9, Georgetown University10, Guy's Hospital11, Mayo Clinic12, Netherlands Cancer Institute13, The Royal Marsden NHS Foundation Trust14, St Mary's Hospital15, University of California, Los Angeles16, University of Texas Southwestern Medical Center17, University of Texas Health Science Center at San Antonio18, University of Toronto19, Yale Cancer Center20
TL;DR: Risks for breast and ovarian cancer varied by CJM in BRCA1/2 carriers, in particular, 6174delT carriers had a lower risk of breast cancer.
Abstract: Purpose Mutations in BRCA1/2 dramatically increase the risk of both breast and ovarian cancers. Three mutations in these genes (185delAG, 5382insC, and 6174delT) occur at high frequency in Ashkenazi Jews. We evaluated how these common Jewish mutations (CJMs) affect cancer risks and risk reduction. Methods Our cohort comprised 4,649 women with disease-associated BRCA1/2 mutations from 22 centers in the Prevention and Observation of Surgical End Points Consortium. Of these women, 969 were self-identified Jewish women. Cox proportional hazards models were used to estimate breast and ovarian cancer risks, as well as risk reduction from risk-reducing salpingo-oophorectomy (RRSO), by CJM and self-identified Jewish status. Results Ninety-one percent of Jewish BRCA1/2-positive women carried a CJM. Jewish women were significantly more likely to undergo RRSO than non-Jewish women (54% v 41%, respectively; odds ratio, 1.87; 95% CI, 1.44 to 2.42). Relative risks of cancer varied by CJM, with the relative risk of breast cancer being significantly lower in 6174delT mutation carriers than in non-CJM BRCA2 carriers (hazard ratio, 0.35; 95% CI, 0.18 to 0.69). No significant difference was seen in cancer risk reduction after RRSO among subgroups. Conclusion Consistent with previous results, risks for breast and ovarian cancer varied by CJM in BRCA1/2 carriers. In particular, 6174delT carriers had a lower risk of breast cancer. This finding requires additional confirmation in larger prospective and population-based cohort studies before being integrated into clinical care.
TL;DR: Although overall quality of life is good in this population of women living long term with metastatic breast cancer, there is a subset of women who are dealing with significant anxiety and depression, and a larger group who are experiencing burdensome sadness, hopelessness, and apprehension about their disease.
Pomeranian Medical University1, University of Szczecin2, University of Cambridge3, University of Newcastle4, QIMR Berghofer Medical Research Institute5, University of Lyon6, Rappaport Faculty of Medicine7, University of Toronto8, Mount Sinai Hospital, Toronto9, Odense University Hospital10, University of Pisa11, Karolinska Institutet12, Lund University13, Uppsala University14, University of Gothenburg15, Linköping University16, Umeå University17, University of Pennsylvania18, Carlos III Health Institute19, Netherlands Cancer Institute20, University of Amsterdam21, University of Groningen22, Leiden University23, Maastricht University24, Radboud University Nijmegen25, Erasmus University Rotterdam26, Utrecht University27, Central Manchester University Hospitals NHS Foundation Trust28, The Royal Marsden NHS Foundation Trust29, Guy's and St Thomas' NHS Foundation Trust30, University of Southampton31, Boston Children's Hospital32, University of Kansas33, Fox Chase Cancer Center34, Curie Institute35, Paris Descartes University36, Claude Bernard University Lyon 137, French Institute of Health and Medical Research38, University of Iceland39, Georgetown University40, University of Cologne41, Ludwig Maximilian University of Munich42, University of Kiel43, Charité44, University of Düsseldorf45, University Hospital Heidelberg46, University of Ulm47, University of Münster48, Laval University49, Mayo Clinic50, National Institutes of Health51
TL;DR: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers, and this association need to be evaluated in larger series of BRCC mutation carriers.
Abstract: BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively. RESULTS: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95% CI 1.10-2.04 and HR 2.16, 95% CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers. British Journal of Cancer (2012) 106, 2016-2024. doi:10.1038/bjc.2012.160 www.bjcancer.com Published online 15 May 2012 (C) 2012 Cancer Research UK
TL;DR: Multiple factors influence decision making in BPM and reconstruction, with the ultimate choice in reconstruction involving tissue availability, appearance of implant reconstructions, total amount of surgery required, and extent of visible scars.
Abstract: Summary Background Utilization of bilateral prophylactic mastectomy (BPM) and reconstruction has increased secondary to numerous medical advances. The purpose of this study was to examine decision making in women electing this therapy to further understand what influences and drives this decision. Methods The authors conducted a survey study, enrolling patients who elected BPM and reconstruction. Participants were mailed structured questionnaires utilizing validated and study specific tools addressing: demographics, treatment decisions, autonomy, decision making and information seeking preferences, and breast cancer treatment knowledge. Analysis was performed overall and by reconstruction. Results 40 patients responded (20 autologous, 19 implant and 1 combination, 66% response rate). The cohort was well educated and wealthy. Reconstructive options played a large role in the consideration of BPM. Patients were influenced by their physicians and less so by non-traditional means (media, internet, etc). Autologous reconstructions had a stronger desire to utilize their own tissue ( p p = 0.01). Implant reconstructions more often stated that they did not have enough tissue for autologous reconstruction ( p p = 0.03). Additionally, they were more influenced by non-traditional means ( p p = 0.02). Conclusions Multiple factors influence decision making in BPM and reconstruction, with the ultimate choice in reconstruction involving tissue availability, appearance of implant reconstructions, total amount of surgery required, and extent of visible scars. Patients were strongly influenced by their physicians, and less so by non-traditional means.
TL;DR: This work identified small-effect genetic variants associated with allelic expression differences in BRCA2 which could possibly affect the risk in mutation carriers through altering expression levels of the wild-type allele.
Abstract: Introduction: Cis-acting regulatory single nucleotide polymorphisms (SNPs) at specific loci may modulate penetrance of germline mutations at the same loci by introducing different levels of expression of the wild-type allele. We have previously reported that BRCA2 shows differential allelic expression and we hypothesize that the known variable penetrance of BRCA2 mutations might be associated with this mechanism. Methods: We combined haplotype analysis and differential allelic expression of BRCA2 in breast tissue to identify expression haplotypes and candidate cis-regulatory variants. These candidate variants underwent selection based on in silico predictions for regulatory potential and disruption of transcription factor binding, and were functionally analyzed in vitro and in vivo in normal and breast cancer cell lines. SNPs tagging the expression haplotypes were correlated with the total expression of several genes in breast tissue measured by Taqman and microarray technologies. The effect of the expression haplotypes on breast cancer risk in BRCA2 mutation carriers was investigated in 2,754 carriers. Results: We identified common haplotypes associated with differences in the levels of BRCA2 expression in human breast cells. We characterized three cis-regulatory SNPs located at the promoter and two intronic regulatory elements which affect the binding of the transcription factors C/EBPa, HMGA1, D-binding protein (DBP) and ZF5. We showed that the expression haplotypes also correlated with changes in the expression of other genes in normal breast. Furthermore, there was suggestive evidence that the minor allele of SNP rs4942440, which is associated with higher BRCA2 expression, is also associated with a reduced risk of breast cancer (per-allele hazard ratio (HR) = 0.85, 95% confidence interval (CI) = 0.72 to 1.00, P-trend = 0.048). Conclusions: Our work provides further insights into the role of cis-regulatory variation in the penetrance of disease-causing mutations. We identified small-effect genetic variants associated with allelic expression differences in BRCA2 which could possibly affect the risk in mutation carriers through altering expression levels of the wildtype allele.
TL;DR: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCa2 mutation carriers and breast cancer riskIn carriers with class II mutations than class I mutations, these findings may prove useful for risk prediction for breast and ovarian cancers.
Abstract: Background: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers. Methods: IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers. Results: Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P-difference, 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03). Conclusion: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers. Impact: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 21(8); 1362-70. (C)2012 AACR.
TL;DR: Adherence to BI-RADS category 3 follow-up recommendation is often low and women with a history of breast cancer or who were BRCA carriers were significantly more likely to adhere to follow- up recommendation.
TL;DR: Genotyping eleven SNPs in 2,892 women of African descent was unable to detect any significant association between TERT-CLPTM1L SNPs and their predispositions for breast cancer risk, and these findings suggest that larger independent studies from diverse populations are expected to evaluate the importance of the TERT.
Abstract: As one of the most common cancers worldwide, breast cancer places an extraordinary burden on the populations of African ancestry. Common SNPs in the TERT-CLPTM1L locus have been reported to be associated with several types of cancer, including breast cancer. We sought to investigate whether the previously reported common single nucleotide polymorphisms (SNPs) in the TERT-CLPTM1L locus could also contribute to the breast cancer risk in women of African ancestry. We genotyped eleven SNPs in 2,892 women of African descent but were unable to detect any significant association between TERT-CLPTM1L SNPs and their predispositions for breast cancer risk. Given the differences in linkage disequilibrium patterns across populations, our findings suggest that larger independent studies from diverse populations are expected to evaluate the importance of the TERT-CLPTM1L locus in breast cancer.
TL;DR: The association between established T2D genetic susceptibility variants and breast cancer risk in women of African or European ancestry is likely weak, if it does exist.
Abstract: Background: Epidemiologic studies have reported a positive association between type 2 diabetes
(T2D) and breast cancer risk, independent of body weight.
Methods: We investigated 40 genetic variants known to be associated with T2D in relation to
breast cancer risk among 2651 breast cancer cases and 2520 controls of African or European
ancestry that were pooled from seven studies.
Results: We found that two T2D risk alleles in Caucasian women (rs5945326-G, rs12518099-C)
and one in women of African ancestry (rs7578597-T) were positively associated with breast
cancer risk at a nominal significance level of 0.05, whereas two T2D risk alleles were inversely
associated with breast cancer risk in Caucasian women (rs1111875-C, rs10923931-T). The
composite T2D susceptibility score (the number of risk allele) was not significantly associated
with breast cancer risk.
Conclusion: The association between established T2D genetic susceptibility variants and breast
cancer risk in women of African or European ancestry is likely weak, if it does exist.
Impact: The pleiotropic effects of known T2D risk alleles cannot explain the association between
T2D and breast cancer risk.
TL;DR: Veliparib and C/P were evaluated in a CTEP Phase 1 study as discussed by the authors, where the primary objective was progression-free survival (PFS) using RECIST 1.
Abstract: Background: Veliparib is a potent, oral PARP inhibitor that inhibits DNA repair, primarily through single strand break repair. BRCA1/2 mutated tumors are defective in homologous recombination, leading to more error prone mechanisms of DNA repair and increased sensitivity to PARP inhibition. Veliparib and TMZ recently demonstrated promising activity in BRCA1/2 mutation carriers, and veliparib and C/P is being evaluated in a CTEP Phase 1 study. This Phase 2 multinational study will evaluate veliparib in combination with TMZ and in combination with C/P compared to an active, placebo-controlled arm of C/P in subjects with BRCA1 or BRCA2 mutation and metastatic breast cancer. Methods: Approximately 240 subjects will be randomized in a 1:1:1 ratio to: 1) Veliparib 40 mg BID D1-7 + TMZ (150–200 mg/m 2 QD D1-5) of every 28 day cycle; or 2) Veliparib 120 mg BID D1-7 + C (AUC 6, D3) and P (175 mg/m 2 , D3) of every 21 day cycle or 3) placebo BID D1-7 + C/P. Key eligibility includes known deleterious BRCA1/2 mutation, ≤1 prior chemotherapy for metastatic disease, and no prior platinum agent. Randomization will be stratified by hormone receptor positive versus negative, prior vs. no prior cytotoxic therapy, and ECOG 0–1 vs 2. The primary objective is progression-free survival (PFS) using RECIST 1.1. Secondary objectives include overall survival, objective response rate, duration of response and safety/tolerability. Optional paired tissue biopsies will be obtained at baseline and at progression to evaluate markers of response and resistance. Additional correlatives for response include assessment of peripheral blood, CTCs, and archived tissue for markers of disease status, gene methylation and mutational status, and tumor-specific alteration of cellular proteins/peptides and/or nucleic acids. Using the log-rank test for PFS, with 150 PFS events the study will have ≥ 80% power at 2-sided α level of 0.05 to detect a statistically significant treatment effect assuming a true hazard ratio of 0.58 favoring the 2 treatment groups containing veliparib. As of June 11, 2012, 5 subjects have been enrolled. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-3-07.
TL;DR: Test results with VUS increase, rather than decrease, uncertainty for the patient in a situation with particularly high stakes and present a challenge to the clinician in devising appropriate responses.
Abstract: Genetic testing for inherited cancer susceptibility is an increasingly valuable tool in medical oncology. The identification of mutations in the BRCA1 and BRCA2 genes, for example, leads to specific clinical recommendations for screening or surgery that can improve survival.1 However, genetic testing can also identify variants of uncertain significance (VUS), changes in the genetic code that have an unknown effect on disease risk. Roughly 7% of women tested for BRCA1 and BRCA2 have one of these variants.2 Test results with VUS increase, rather than decrease, uncertainty for the patient in a situation with particularly high stakes and present a challenge to the clinician in devising appropriate responses.
TL;DR: This review summarizes data from both retrospective and prospective studies examining the impact of bilateral prophylactic mastectomy and risk-reducing salpingo-oophorectomy on reducing the risk of developing breast and, for the latter, ovarian cancer.
Abstract: Women with either BRCA1 or BRCA2 germline mutations have a significantly elevated risk of breast and ovarian cancer. Approximately 60 %–70 % of BRCA1 carriers and 45 %–60 % of BRCA2 carriers will develop a breast cancer by age 70, and there is a lower but very significant risk of developing ovarian cancer in both BRCA1 and BRCA2 carriers. This review summarizes data from both retrospective and prospective studies examining the impact of bilateral prophylactic mastectomy and risk-reducing salpingo-oophorectomy on reducing the risk of developing breast and, for the latter, ovarian cancer. In addition, we review data on the mortality benefit from risk-reducing salpino-oophorectomy.
TL;DR: The BRCA1 mutation detection rate with current comprehensive clinical testing using linkage analysis as the comparator is assessed using BRCAPRO, BOADICEA, and other risk estimation models as a comparator.
Abstract: 1506 Background: Specific clinical interventions in BRCA mutation carriers reduces the risk of breast and ovarian cancers and may improve survival; thus,identification of mutation carriers is important. The sensitivity of current BRCA mutation testing is unclear as a “gold standard” test is lacking. We assessed the BRCA1 mutation detection rate with current comprehensive clinical testing using linkage analysis as the comparator. Methods: 26 families with linkage analyses results available were included in this analysis. BRCAPRO, BOADICEA, and other risk estimation models were applied. Maximum-likelihood linkage analyses were performed to compute two-point and multipoint LOD scores using previously described BRCA1 –linked genetic markers; scores were classified as linked, not linked, or suggestive. At least one individual from each family underwent comprehensive testing. Results: Of 26 families analyzed, 9 demonstrated linkage and 4 demonstrated suggestive linkage to BRCA1. Of these 13 families, 12 were fo...
TL;DR: In this paper, the authors developed a study to determine molecular signatures of BRCA1 and BRCa2-mutated breast cancers and identified specific genomic rearrangements in these breast cancers, which could be used to find new markers for such breast cancers.
Abstract: Background: Germline mutation screening of BRCA1 and BRCA2 genes is performed in suspected familial breast cancer cases, but a causative mutation is found in only 30% of patients. The development of additional methods to identify good candidates for BRCA1 and BRCA2 analysis would therefore increase the efficacy of diagnostic mutation screening. With this in mind, we developed a study to determine molecular signatures of BRCA1—or BRCA2—mutated breast cancers. Materials and Methods: Array-cgh (comparative genomic hybridization) and transcriptomic analysis were performed on a series of 103 familial breast cancers. The series included 7 breast cancers with a BRCA1 mutation and 5 breast cancers with a BRCA2 mutation. The remaining 91 cases were obtained from 73 families selected on the basis of at least 3 affected first-degree relatives or at least 2 affected first-degree relatives with breast cancer at an average age of 45 years. Array-cgh analyses were performed on a 4407 BAC-array (CIT-V8) manufactured by IntegraGen. Transcriptomic analyses were performed using an Affymetrix Human Genome U133 Plus 2.0 chip. Results: Using supervised clustering analyses we identified two transcriptomic signatures: one for BRCA1-mutated breast cancers consisting of 600 probe sets and another for BRCA2-mutated breast cancers also consisting of 600 probes sets. We also defined cgh-array signatures, based on the presence of specific genomic rearrangements, one for BRCA1-mutated breast cancers and one for BRCA2-mutated breast cancers. Conclusions: This study identified molecular signatures of breast cancers with BRCA1 or BRCA2 germline mutations. Genes present in these signatures could be exploited to find new markers for such breast cancers. We also identified specific genomic rearrangements in these breast cancers, which could be screened for in a diagnostic setting using fluorescence in situ hybridization, thus improving patient selection for BRCA1 and BRCA2 molecular genetic analysis.