PARP inhibitors – a new direction in the treatment of breast and ovarian cancer

Eligibility Criteria and Genetic Testing Results from a High-Risk Cohort for Hereditary Breast and Ovarian Cancer Syndrome in Southeastern Ontario

The role of testing for BRCA1 and BRCA2 mutations in cancer prevention.

PARP inhibitor and chemotherapy combination trials for the treatment of advanced malignancies: does a development pathway forward exist?

Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. To identify mutation-specific cancer risks for carriers of BRCA1/2. 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. Mutations of BRCA1 or BRCA2. Breast and ovarian cancer risks. 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. 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.

Introduction: BRCA1/2 mutation carriers are at increased risk of developing breast cancer (BC) and ovarian cancer (OC). However, for BRCA1/2 mutation carriers previously affected with OC, primary BC (PBC) and contralateral BC (CBC) risks might be lowered due to OC treatment, but data hereon are limited. Accurate BC risk estimates are essential for counseling and optimal decision making on BC surveillance and risk-reducing mastectomy (RRM) after diagnosis of BRCA1/2-associated OC. Methods: From the national HEBON cohort study, we selected female BRCA1/2 mutation carriers born from 1940 and at risk of PBC (n=2019; 1194 BRCA1, 825 BRCA2) or at risk of CBC (n=1276; 839 BRCA1, 437 BRCA2). Eligibility criteria for the PBC risk analyses included no history of PBC and both breasts in situ at DNA testing. For the CBC risk analyses, CBC before DNA testing was not allowed and the contralateral breast had to be unaffected at DNA testing. To estimate the association between OC and BC risk, we used the Fine and Gray regression model, with OC as a time-dependent variable and death as competing risk event. The observation started at the age of DNA testing, age 35, or – for the CBC risk analyses – age at PBC diagnosis, whichever came last. Censoring events were RRM, study closing date (i.e. 2014-12-31), and – for the CBC risk analyses – ipsilateral BC recurrence. All analyses were performed separately for BRCA1 and BRCA2 mutation carriers. Results: For the PBC analyses, we selected 236 BRCA1/2 mutation carriers with OC and 1783 BRCA1/2 mutation carriers without OC (median age at start study 53 and 41 years, respectively). During a mean follow-up (FU) of 5.2 years, 15 (6%) OC patients developed PBC after OC, while PBC was diagnosed in 262 (15%) women without OC. OC diagnosis was associated with a lower PBC risk in BRCA1 mutation carriers (HR, 0.27; 95% CI, 0.14–0.53) but not in BRCA2 mutation carriers (HR, 0.88; 95% CI, 0.34–2.27). The cumulative PBC incidence at age 70 in BRCA1 mutation carriers was 25% for OC patients and 66% for women without OC, and in BRCA2 mutation carriers 49% for OC patients and 53% for women without OC. For the CBC analyses, we selected 99 BRCA1/2 mutation carriers affected with PBC and OC, and 1177 BRCA1/2-associated PBC patients without OC (median age at start study 54 and 46 years, respectively). During a mean FU of 3.5 years, 8 (8%) PBC/OC patients developed CBC after OC, while CBC was diagnosed in 131 (11%) PBC patients without OC. In BRCA1 mutation carriers, OC diagnosis was non-significantly associated with a lower CBC risk (HR, 0.44; 95% CI, 0.19–1.03). For BRCA2 mutation carriers the HR was 1.65 (95% CI, 0.34–8.04). The cumulative CBC incidence at age 70 in BRCA1 mutation carriers was 40% for OC patients and 68% for patients without OC; for BRCA2 mutation carriers the number of CBCs was too small to obtain meaningful estimates. Conclusion:­ For BRCA1 mutation carriers affected with OC the risk of developing subsequent BC is lower than for BRCA1 mutation carriers without OC. Our data suggest that the current BC prevention strategies should be reconsidered for OC patients carrying a BRCA1 mutation, possibly including less intensive BC surveillance, and RRM being indicated only for a subgroup of OC patients. Citation Format: Heemskerk-Gerritsen BAM, Hooning MJ, van Doorn HC, Collée MJ, Koppert LB, Jager A, van den Ouweland AMW, Netherlands H, Seynaeve C, Kriege M. Risk of primary and contralateral breast cancer in BRCA1/2 mutation carriers previously affected with ovarian cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-07-04.

Introduction to epidemiology of breast and ovarian cancers

Breast cancer, menopause, and long-term survivorship: critical issues for the 21st century

Familial breast cancer was first recognized in the Roman medical literature of 100 AD [1]. The first documentation of familial clustering of breast cancer in modern times was published by Broca, who reported 10 cases of breast cancer in 4 generations of his wife's family [2]. In the middle of the nineteen nineties it was proven at the molecular level that a substantial number of breast and ovarian cancers has hereditary monogenic aetiology [3,4]. Evaluation of frequency of pedigree-clinical signs characteristic for strong aggregations of breast/ovarian cancers among consecutive cases of cancers of these organs as well as analyses of cancer incidence in monozygotic twins indicate that about 30% of breast and ovarian cancers develop because of a strong genetic predisposition [5]. In other breast/ovarian cancers the significance of genetic factors was underestimated. However, recently it has been possible to show the characteristic constitutional background influencing development of cancer also in patients sporadic neoplasms. Therefore now scientists think that in almost all patients cancer a certain genetic background should be detectable, although influencing cancer risk to a various degree. Genetic abnormalities strongly related to cancer are called high risk changes (genes) and abnormalities influencing cancer development to a lower degree are called moderate risk changes (genes). Most frequently strong genetic predisposition to breast/ovarian cancers are related to mutations in the BRCA1 and BRCA2 genes and most often it appears as syndromes of hereditary breast cancer -site-specific (HBC-ss), hereditary breast-ovarian cancer (HBOC) and hereditary ovarian cancer (HOC). In family members of families HBC-ss syndrome only breast cancers but not ovarian cancers are observed. In HBOC syndrome families both breast and ovarian cancers are diagnosed, and in HOC syndrome only ovarian but not breast cancers are detected. Operational clinical-pedigree criteria which we use in order to diagnose definitively or with high probability the discussed syndromes are summarized in Table ​Table1.1. In the vast majority of cancer cases related to moderate risk genes family history is negative. HBC-ss, HBOC and HOC syndromes are clinically and molecularly heterogeneous. Mutations in the BRCA1 and BRCA2 genes are the most frequent cause of these syndromes. Table 1 Pedigree-clinical diagnostic criteria of HBC-ss, HBOC and HOC syndromes [6] BRCA1 syndrome In this syndrome women carry a germline mutation in the BRCA1 gene. Carriers of a BRCA1 mutation have approximately 50-80% lifetime risk of breast cancer and 40% risk of ovarian cancer [7]. We estimate that these risks are 66% for breast cancer and 44% for ovarian cancer in the Polish population (Table ​(Table2).2). Both risks appear to be dependent on the type and localization of the mutation [8-10]. Our findings suggest that the risk of breast cancer in women 5382insC is two times higher than in women 4153delA. Table 2 Risk of breast and ovarian cancer in BRCA1 mutation carriers in Poland [8] Incomplete penetrance of BRCA1 suggests that other factors, genetic and non-genetic modifiers, are important in carcinogenesis in the mutation carriers. The risk of ovarian cancer is modified by VNTR locus for HRAS 1 and is increased 2-fold in BRCA1 carriers harbouring one or two rare alleles of HRAS 1 [11]. We reported that the 135G>C variant in the RAD51 gene is strongly protective (OR = 0.5) against both ovarian and breast cancer [12,13]. Carriers of a BRCA1 mutation are also at about 10% lifetime risk of fallopian tube and peritoneal cancers [14]. These data about the frequency of ovarian cancer in BRCA1 carriers appear to reflect the combined frequency of ovarian, fallopian tube and peritoneal cancers, because these tumours were diagnosed as ovarian cancers in the past, and because they share similar morphology and cause elevated levels of the marker CA 125. The risk of cancer at other sites may be increased in carriers of a BRCA1 mutation as well, but the evidence is controversial and needs further studies. Breast and ovarian cancer in BRCA1 carriers have particular clinical characteristics. The mean age at onset of breast cancer is about 42-45 years [15,16] and of ovarian cancer is about 54 years [17,18]. 18-32% of breast cancers are bilateral [19,20]. These are rapidly growing tumours: >90% of cases have G3 grade at the time of diagnosis and almost all ovarian cancers in women a BRCA1 mutation are diagnosed in FIGO stage III°/IV°. Medullary, atypical medullary, ducal and oestrogen receptor negative (ER) breast tumours are common in BRCA1 carriers. BRCA1 mutation-positive tumours constitute about 10-15% of all ER-breast cancers [21-23]. Most carriers of a BRCA1 mutation report a positive family history of breast or ovarian cancer (Figure ​(Figure1).1). However, 45% of BRCA1 carriers report a negative family history, mainly because of paternal inheritance and incomplete penetrance (Figure ​(Figure3)3) [20]. Figure 1 Family HOC syndrome and diagnosed constitutional 4153delA BRCA1 gene mutation. Figure 3 Patient ovarian cancer and detected 5382insC BRCA1 mutation from family negative family history.

Inhibited, trapped or adducted: the optimal selective synthetic lethal mix for BRCAness

Research Highlights

Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2. We genotyped rs3814113 in 10,029 BRCA1 mutation carriers and 5837 BRCA2 mutation carriers. Associations with ovarian and breast cancer were assessed with a retrospective likelihood approach. All statistical tests were two-sided. The minor allele of rs3814113 was associated with a reduced risk of ovarian cancer among BRCA1 mutation carriers (per-allele hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.72 to 0.85; P = 4.8 × 10(-9)) and BRCA2 mutation carriers (hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.67 to 0.90; P = 5.5 × 10(-4)). This SNP was not associated with breast cancer risk among either BRCA1 or BRCA2 mutation carriers. BRCA1 mutation carriers with the TT genotype at SNP rs3814113 were predicted to have an ovarian cancer risk to age 80 years of 48%, and those with the CC genotype were predicted to have a risk of 33%. Common genetic variation at the 9p22.2 locus was associated with decreased risk of ovarian cancer for carriers of a BRCA1 or BRCA2 mutation.

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

BRCA in breast cancer: ESMO Clinical Recommendations

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates.Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]–positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS.Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2×10−53). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2×10−20). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS.Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.

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. 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. 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). 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. These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.