Showing papers by "Susan M. Domchek published in 2014"

Breast-Cancer Risk in Families with Mutations in PALB2

Abstract: 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. (Funded by the European Research Council and others.) abstr act

Modifiers of Cancer Risk in BRCA1 and BRCA2 Mutation Carriers: Systematic Review and Meta-Analysis

Abstract: Inherited mutations in BRCA1and BRCA2 (BRCA1/2) are associated with an increased risk of developing breast and ovarian cancer (1,2). However, there is substantial interindividual variability in both the age at diagnosis and site of cancer occurrence in BRCA1/2 mutation carriers. A number of lines of evidence suggest that additional modifying factors influence cancer penetrance among BRCA1/2 mutation carriers. Cancer occurrences vary even among members of the same family who carry the same BRCA1/2 mutation (3). Begg et al. (4) reported that biases may exist in penetrance estimates (eg, lifetime cancer risk) if relevant covariables are ignored in estimating penetrance and concluded that modifiers are likely to exist that affect BRCA1/2-associated cancer penetrance. These observations suggest that modifiers of cancer risk may exist that could improve risk assessment in this high-risk population. Specific factors have been reported to be associated with modified cancer risk. Genetic variation at other loci affects breast or ovarian cancer penetrance in women who carry an inherited BRCA1/2 mutation (5–15). Studies of many of these factors have been undertaken using large samples and validated using state-of-the-art genome-wide association approaches. These loci are very likely to be valid modifiers of cancer risk in BRCA1/2 mutation carriers. A variety of exposures and lifestyle factors have been proposed to modify breast and ovarian cancer risk in BRCA1/2 mutation carriers (16). These modifiers of cancer risk include reproductive history and exposures such as smoking, alcohol consumption, or exogenous hormones. However, many of the studies published to date involve small sample sizes, “convenience” samples of BRCA1/2 mutation carriers, retrospective evaluation of risk factors, and other study design limitations. Many of these reports have not been validated using epidemiologically appropriate independent study samples. Thus, it remains unclear which (if any) of the putative modifiers of risk may truly influence a woman’s breast or ovarian cancer risk if she has inherited a BRCA1/2 mutation. Given the importance of accurate risk assessment information in this high-risk population, it is critical to understand the role that risk modifiers may contribute to the risk assessment process. Therefore, we undertook a systematic review of the literature regarding cancer risk modifiers in BRCA1/2 mutation carriers and have performed a meta-analysis of relevant data. Our results should inform the use of risk modifiers in cancer risk counseling, as well as highlight areas of research that are needed to resolve questions about modifiers that have been inadequately studied to date.

DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers

Abstract: Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7 × 10(-3)) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8 × 10(-3)). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.

Refined histopathological predictors of BRCA1 and BRCA2 mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

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.

Use of risk-reducing surgeries in a prospective cohort of 1,499 BRCA1 and BRCA2 mutation carriers.

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.

Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

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.

Impact of shortages of injectable oncology drugs on patient care.

Abstract: Purpose Results of a survey regarding shortages of injectable oncology drugs in U.S. hospitals and health systems are presented. Methods An online survey was sent to all members of the American Society of Health-System Pharmacists self-identified as directors of pharmacy. Survey participants provided information on the extent to which their facilities were affected by oncology drug shortages, strategies for responding to shortages, and the effects of shortages on costs, patient safety, and outcomes. Results Ninety-eight percent of the 358 survey respondents reported at least one drug shortage during the previous 12 months, with 70% reporting instances of an inadequate supply to treat patients and 63% reporting that their facility had completely run out of at least one injectable oncology drug. Sixty-two percent of respondents reported using alternative drug regimens due to shortages; 46% reported drug dosage changes, 43% reported treatment delays, and 21% reported patient referrals to or from other facilities as a result of shortages. Survey respondents indicated the use of various strategies to manage oncology drug shortages (e.g., increasing inventories of certain drugs, identifying alternatives and substitution protocols, altered purchasing practices), all of which have led to cost increases. Twenty-five percent of respondents reported safety events resulting from oncology drug shortages. Only 40% of respondents agreed that currently available information is useful in mitigating the effects of shortages. Conclusion Shortages of injectable oncology drugs appear to be widespread and to be having a significant impact on patient care. Currently available information about shortages does not meet administrative or clinical needs.

Original research article Contraceptive use and the role of contraceptive counseling in reproductive-aged women with cancer ☆,☆☆

Abstract: Objective: Few dataoncontraceptivechoices inwomen withcancer exist.Contraceptionischallenging for women withcancer, particularlythose with breast cancer, who are limited to nonhormonal methods. This study characterized contraceptive use during cancer treatment in a group of reproductive-aged women with a recent cancer diagnosis and assessed the impact of contraceptive counseling on the methods they selected. Study Design: Cross-sectional, survey study of reproductive-aged women at a large tertiary care health system with a recent cancer diagnosis. Results: A total of 107 women completed the survey. Eighty-two women reported 101 contraceptive choices. Twenty-seven percent (27/101) of all methods selected were Tier I/II, and 35% (35/101) were Tier III/IV. Only 4 used an intrauterine device (IUD). Among women reporting sexual activity after diagnosis, 19 (27%) of 71 reported using Tier I/II methods, 21 (30%) of 71 reported using Tier III/IV methods, 16 (23%) of 71 reported abstinence and 10 (14%) of 71 reported using no method. Factors significantly associated with Tier I/II use in the multivariable model included not having a college degree [odds ratio (OR) 0.21, 95% confidence interval (CI) 0.05–0.92, p=.038], intercourse during treatment (OR 5.92, 95% CI 1.48–23.66, p=.012) and non-breast cancer (OR 3.60, 95% CI 1.03–12.64, p=.046). Report of contraceptive counseling was positively associated with Tier I/II contraceptive use during cancer treatment (OR 6.92, 95% CI 1.14–42.11, p=.036). Conclusion: Reproductive-aged women diagnosed with cancer underutilized Tier I/II contraceptive agents, especially IUDs. Contraceptive counseling by physicians increases contraceptive use, particularly methods most effective at preventing pregnancy. Implications: The study uniquely described the contraceptive practices of over 100 women with cancer. The study sample commonly reported abstinence and use of contraceptive methods with high failure rates. Our data suggest that contraceptive counseling from a health care provider may increase use of more effective methods among women with cancer.

Long-term risk of medical conditions associated with breast cancer treatment

Abstract: Early and late effects of cancer treatment are of increasing concern with growing survivor populations, but relevant data are sparse. We sought to determine the prevalence and hazard ratio of such effects in breast cancer cases. Women with invasive breast cancer and women with no cancer history recruited for a cancer research cohort completed a mailed questionnaire at a median of 10 years post-diagnosis or matched reference year (for the women without cancer). Reported medical conditions including lymphedema, osteopenia, osteoporosis, and heart disease (congestive heart failure, myocardial infarction, coronary heart disease) were assessed in relation to breast cancer therapy and time since diagnosis using Cox regression. The proportion of women currently receiving treatment for these conditions was calculated. Study participants included 2,535 women with breast cancer and 2,428 women without cancer (response rates 66.0 % and 50.4 %, respectively) Women with breast cancer had an increased risk of lymphedema (Hazard ratio (HR) 8.6; 95 % confidence interval (CI) 6.3–11.6), osteopenia (HR 2.1; 95 % CI 1.8–2.4), and osteoporosis (HR 1.5; 95 % CI 1.2–1.9) but not heart disease, compared to women without cancer Hazard ratios varied by treatment and time since diagnosis. Overall, 49.3 % of breast cancer cases reported at least one medical condition, and at 10 or more years post-diagnosis, 37.7 % were currently receiving condition-related treatment. Responses from survivors a decade following cancer diagnosis demonstrate substantial treatment-related morbidity, and emphasize the need for continued medical surveillance and follow-up care into the second decade post-diagnosis.

A phase I trial of palbociclib and paclitaxel in metastatic breast cancer.

Abstract: 527 Background: Palbociclib (Palb) is an oral CDK 4/6 inhibitor that is under development in breast cancer as a single agent and in combination with endocrine therapy. Preclinical studies suggest t...

Prevalence of mutations in a panel of breast cancer susceptibility genes in patients with early onset breast cancer.

Abstract: 1510 Background: Approximately 5-10% of breast cancers are attributable to inherited single gene mutations. Clinical testing for germline variation in multiple cancer susceptibility genes is availa...

Breast-cancer risk in families with mutations in PALB2

Abstract: Germline mutations in the BRCA1 and BRCA2 genes confer a marked increase in risk of breast cancer. Loss-of-function mutations have been identified in the PALB2 gene that also increase the risk of breast cancer. PALB2 interacts with BRCA1 and BRCA2 genes. In previous studies, the risk of brea

Quality of life in BRCA1 and BRCA2 mutation carriers (B1/2) following risk-reducing salpingo-oophorectomy (RRSO).

Abstract: 1508 Background: RRSO is associated with a decreased risk of breast cancer, ovarian cancer and improved survival in B1/2. Timing of RRSO must balance the known benefits against the impact of early ...

A phase 2, open-label study of rucaparib in patients with pancreatic cancer and a known deleterious BRCA mutation.

Abstract: TPS4161 Background: Approximately 5% of unselected pancreatic cancer (PC) patients (pts), 10% of PC pts of Ashkenazi Jewish descent, and up to 19% of familial PC families, harbor a germline BRCA mu...

Abstract 1291: High and moderate penetrance germline mutations in a number of genes are responsible for a small proportion of familial breast cancer risk in BRCAx families

Abstract: BRCA1 and BRCA2 (BRCA) testing is uninformative in approximately 80% of families with clinical features of inherited susceptibility to breast cancer. Early identification of the individuals at risk in BRCAx families may lead to enhanced screening and prevention strategies, and potentially improved overall survival as has been seen for carriers of BRCA1/2 mutations. A proportion of these families are likely explained by mutations in other high penetrance and moderate penetrance breast cancer susceptibility genes. Although multi-gene panels are now commercially available for clinical testing, only limited information is available on the spectrum of mutations in breast cancer susceptibility genes in specific subgroups of high-risk breast cancer patients. We performed whole exome sequencing in 278 BRCA1/2 negative individuals with high-risk familial breast cancer, defined as a proband and at least two first or second degree relatives with breast cancer. Samples included 232 individuals from 97 families and 49 unrelated individuals, for a total of 146 independent cases. Data were analyzed for identification of all variants in 18 known high and moderate penetrance breast cancer susceptibility genes, in addition to BRCA1 and BRCA2. Two of the 97 families and one of the 49 singletons (2% of independent cases) were found to have deleterious mutations in high penetrance genes, namely TP53 (2) and CDH1 (1). In addition, nine of 146 independent cases (6%) were found to have deleterious mutations in the other predisposition genes. Mutations in ATM and CHEK2 accounted for seven of the ten moderate penetrance mutations identified; additionally one family had a mutation in BLM, one in MRE11A, and one in PALB2. Furthermore, 15 of 146 independent cases (10%) were found to have variants of unknown significance (VUS) in one of eight genes. There were no deleterious mutations or VUS in eight of the 18 genes. Our data show that significant genetic heterogeneity exists in BRCAx families. Large-scale collaborative efforts will be required to attain sufficient power to understand how to appropriately apply these results clinically in cancer risk evaluation. Citation Format: Kara N. Maxwell, Lucia Guidugli, Kasmintan Schrader, Steven Hart, Vijai Joseph, Tinu Thomas, Xianshu Wang, Bradley Wubbenhorst, Robert Klein, Susan M. Domchek, Csilla Szabo, Susan Neuhausen, Jeffrey Weitzel, Katherine L. Nathanson, Kenneth Offit, Fergus Couch. High and moderate penetrance germline mutations in a number of genes are responsible for a small proportion of familial breast cancer risk in BRCAx families. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1291. doi:10.1158/1538-7445.AM2014-1291

Abstract B11: Replication of previously identified breast cancer susceptibility loci in a breast cancer case-control study on women of African ancestry

Abstract: To date, more than 100 single nucleotide polymorphisms (SNPs) have been found to be associated with breast cancer susceptibility in large genome-wide association studies (GWAS) conducted predominantly in women of European and Asian ancestries. To identify breast cancer susceptibility alleles in populations of African ancestry, we performed a GWAS in 3,686 subjects from Nigeria, Barbados and the United States (Baltimore, Chicago, Detroit, Philadelphia and the Southern Community Cohort Study), using the Illumina HumanOmni2.5 array. Using stringent quality control criteria, a total of 1,657 cases (777 with known estrogen receptor [ER] status) and 2,029 controls were successfully genotyped for 2,116,365 SNPs. Subsequently, imputation was conducted using reference panels from The 1000 Genomes Project and logistic regression models controlling age and global ancestry were applied to examine the association of 78 known breast cancer GWAS index SNPs and 44 iCOGS (Illumina iSelect genotyping array for Collaborative Oncological Gene-Environment Study) SNPs with breast cancer risk in our study population. Only 4 SNPs were statistically significant (unadjusted P Citation Format: Yonglan Zheng, Dezheng Huo, Temidayo O. Ogundiran, Adeyinka G. Falusi, Oladosu Ojengbede, Clement Adebamowo, William J. Blot, Wei Zheng, Qiuyin Cai, Lisa B. Signorello, Katherine L. Nathanson, Susan M. Domchek, Timothy R. Rebbeck, Michael S. Simon, Anselm J.M. Hennis, Barbara Nemesure, Suh-Yuh Wu, Maria Cristina Leske, Stefan Ambs, Abayomi Odetunde, Imaria Anetor, Stella Akinleye, Qun Niu, Jing Zhang, Anna Pluzhnikov, Anuar Konkashbaev, Lin Chen, Eric R. Gamazon, Younghee Lee, Nancy J. Cox, Olufunmilayo O. Olopade. Replication of previously identified breast cancer susceptibility loci in a breast cancer case-control study on women of African ancestry. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr B11. doi:10.1158/1538-7755.DISP13-B11