Mark E. Robson

Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial

BACKGROUND Olaparib, a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor, induced synthetic lethality in BRCA-deficient cells. A maximum tolerated dose and initial signal of efficacy in BRCA-deficient ovarian cancers have been reported. We therefore assessed the efficacy, safety, and tolerability of olaparib alone in women with BRCA1 or BRCA2 mutations and advanced breast cancer. METHODS Women (aged >or=18 years) with confirmed BRCA1 or BRCA2 mutations and recurrent, advanced breast cancer were assigned to two sequential cohorts in a phase 2 study undertaken in 16 centres in Australia, Germany, Spain, Sweden, the UK, and the USA. The first cohort (n=27) was given continuous oral olaparib at the maximum tolerated dose (400 mg twice daily), and the second (n=27) was given a lower dose (100 mg twice daily). The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov, number NCT00494234. FINDINGS Patients had been given a median of three previous chemotherapy regimens (range 1-5 in cohort 1, and 2-4 in cohort 2). ORR was 11 (41%) of 27 patients (95% CI 25-59) in the cohort assigned to 400 mg twice daily, and six (22%) of 27 (11-41) in the cohort assigned to 100 mg twice daily. Toxicities were mainly at low grades. The most frequent causally related adverse events in the cohort given 400 mg twice daily were fatigue (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), nausea (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), vomiting (grade 1 or 2, three [11%]; grade 3 or 4, three [11%]), and anaemia (grade 1 or 2, one [4%]; grade 3 or 4, three [11%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, 11 [41%]; none grade 3 or 4) and fatigue (grade 1 or 2, seven [26%]; grade 3 or 4, one [4%]). INTERPRETATION The results of this study provide positive proof of concept for PARP inhibition in BRCA-deficient breast cancers and shows a favourable therapeutic index for a novel targeted treatment strategy in patients with tumours that have genetic loss of function of BRCA1-associated or BRCA2-associated DNA repair. Toxicity in women with BRCA1 and BRCA2 mutations was similar to that reported previously in those without such mutations. FUNDING AstraZeneca.

Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a case-control study

BACKGROUND Women with a mutation in BRCA1 or BRCA2 have a high risk of developing breast cancer and of contralateral cancer after the initial diagnosis of breast cancer. Tamoxifen protects against contralateral breast cancer in the general population, but whether it protects against contralateral breast cancer in BRCA1 or BRCA2 mutation carriers is not known. METHODS We compared 209 women with bilateral breast cancer and BRCA1 or BRCA2 mutation (bilateral-disease cases), with 384 women with unilateral disease and BRCA1 or BRCA2 mutation (controls) in a matched case-control study. Age and age at diagnosis of breast cancer (range 24-74 years) were much the same in bilateral-disease cases and controls, and both groups had been followed up for the same time for a second primary breast cancer. History of tamoxifen use for first breast cancer was obtained by interview, or by self-administered questionnaire. FINDINGS The multivariate odds ratio for contralateral breast cancer associated with tamoxifen use was 0.50 (95% CI 0.28-0.89). Tamoxifen protected against contralateral breast cancer for carriers of BRCA1 mutations (odds ratio 0.38, 95% CI 0.19-0.74) and for those with BRCA2 mutations (0.63, 0.20-1.50). In women who used tamoxifen for 2-4 years, the risk of contralateral breast cancer was reduced by 75%. A reduction in risk of contralateral cancer was also seen with oophorectomy (0.42, 0.22-0.83) and with chemotherapy (0-40, 0.26-0.60). INTERPRETATION Tamoxifen use reduces the risk of contralateral breast cancer in women with pathogenic mutations in the BRCA1 or BRCA2 gene. The protective effect of tamoxifen seems independent of that of oophorectomy.

Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk.

PURPOSE Previous studies of mutations in BRCA1 or BRCA2 have used detection methods that may underestimate the actual frequency of mutations and have analyzed women using heterogeneous criteria for risk of hereditary cancer. PATIENTS AND METHODS A total of 238 women with breast cancer before age 50 or ovarian cancer at any age and at least one first- or second-degree relative with either diagnosis underwent sequence analysis of BRCA1 followed by analysis of BRCA2 (except for 27 women who declined analysis of BRCA2 after a deleterious mutation was discovered in BRCA1). Results were correlated with personal and family history of malignancy. RESULTS Deleterious mutations were identified in 94 (39%) women, including 59 of 117 (50%) from families with ovarian cancer and 35 of 121 (29%) from families without ovarian cancer. Mutations were identified in 14 of 70 (20%) women with just one other relative who developed breast cancer before age 50. In women with breast cancer, mutations in BRCA1 and BRCA2 were associated with a 10-fold increased risk of subsequent ovarian carcinoma (P = .005). CONCLUSION Because mutations in BRCA1 and BRCA2 in women with breast cancer are associated with an increased risk of ovarian cancer, analysis of these genes should be considered for women diagnosed with breast cancer who have a high probability of carrying a mutation according to the statistical model developed with these data.

Outcome of Preventive Surgery and Screening for Breast and Ovarian Cancer in BRCA Mutation Carriers

PURPOSE To prospectively determine the impact of genetic counseling and testing on risk-reduction strategies and cancer incidence in a cohort of individuals at hereditary risk for breast and ovarian cancer. PATIENTS AND METHODS Two hundred fifty-one individuals with BRCA mutations were identified at a single comprehensive cancer center from May 1, 1995, through October 31, 2000. Uniform recommendations regarding screening and preventive surgery were provided in the context of genetic counseling. Patients were followed for a mean of 24.8 months (range, 1.6 to 66.0 months) using standardized questionnaires, chart reviews, and contact with primary physicians. RESULTS Frequency of cancer surveillance by physical examinations and imaging studies increased after genetic counseling and testing. Twenty-one breast, ovarian, primary peritoneal, or fallopian tube cancers were detected after receipt of genetic test results. Among 29 individuals choosing risk-reducing mastectomy after testing, two were found to have occult intraductal breast cancers. Among 90 individuals who underwent risk-reducing salpingo-oophorectomy, one early-stage ovarian neoplasm and one early-stage fallopian tube neoplasm were found. Radiographic or tumor marker-based screening detected six breast cancers, five of which were stage 0/I, one early-stage primary peritoneal cancer, and three stage I or II ovarian cancers. Six additional breast cancers were detected by physical examination between radiographic screening intervals; four of these six tumors were stage I. No stage III or stage IV malignancies were detected after genetic testing. CONCLUSION This study provides prospective evidence that genetic counseling and testing increased surveillance and led to risk-reducing operations, which resulted in diagnosis of early-stage tumors in patients with BRCA1 and BRCA2 mutations.

Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study.

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

Gene-Panel Sequencing and the Prediction of Breast-Cancer Risk

An international group of cancer geneticists review the level of evidence for the association of gene variants with the risk of breast cancer. It is difficult to draw firm conclusions from the data because of ascertainment bias and the lack of data from large populations.

BRCA-associated breast cancer in young women.

PURPOSE To delineate the clinical characteristics and outcomes of breast cancer that arises in the setting of a germline BRCA mutation and to compare BRCA-associated breast cancers (BABC) with those that arise in women without mutations. PATIENTS AND METHODS We reviewed the clinical records of 91 Ashkenazi Jewish women ascertained during studies of the genetics of early-onset breast cancer. All women underwent testing for the BRCA1 mutations 185delAG and 5382insC. After the discovery of BRCA2, 79 women were also tested for the BRCA2 mutation 6174delT. RESULTS Mutations were identified in 30 women (33%). BABC were less likely to present with stage I disease than cases in women without mutations (27% v 46%), more likely to have axillary nodal involvement (54% v46%), and more likely to have extensive axillary involvement (25% v 17%). These differences were not statistically significant. BABC were significantly more likely to be histologic grade III (100% v 59%, P=.04) and to be estrogen receptor-negative (70% v 34%, P=.04). In the entire cohort, there were no significant differences between BABC and non-BRCA-associated cancers in 5-year relapse-free survival (65% v 69%, P=not significant [NS]), 5-year event-free survival (57% v 68%, P=NS), or 5-year overall survival. However, among cases diagnosed within 2 years of study entry, there was a trend toward shorter event-free survival in BRCA heterozygotes, but not relapse-free survival. Women with germline BRCA mutations were significantly more likely to develop contralateral breast cancer at 5 years (31% v 4%, P=.0007). CONCLUSION BABC present with adverse clinical and histopathologic features when compared with cases not associated with BRCA mutations. However, the prognosis of BABC appears to be similar to that of nonassociated cancer. Further studies of incident cases are necessary to define the independent prognostic significance of germline BRCA mutations.

A combined analysis of outcome following breast cancer: differences in survival based on BRCA1/BRCA2 mutation status and administration of adjuvant treatment.

BackgroundThe prognostic significance of germline mutations in BRCA1 and BRCA2 in women with breast cancer remains unclear. A combined analysis was performed to address this uncertainty.MethodsTwo retrospective cohorts of Ashkenazi Jewish women undergoing breast-conserving treatment for invasive cancer between 1980 and 1995 (n = 584) were established. Archived tissue blocks were used as the source of DNA for Ashkenazi Jewish BRCA1/BRCA2 founder mutation analysis. Paraffin-embedded tissue and follow-up information was available for 505 women.ResultsGenotyping was successful in 496 women, of whom 56 (11.3%) were found to carry a BRCA1/BRCA2 founder mutation. After a median follow-up period of 116 months, breast cancer specific survival was worse in women with BRCA1 mutations than in those without (62% at 10 years versus 86%; P < 0.0001), but not in women with the BRCA2 mutation (84% versus 86% at 10 years; P = 0.76). Germline BRCA1 mutations were an independent predictor of breast cancer mortality in multivariate analysis (hazard ratio 2.4, 95% confidence interval 1.2–4.8; P = 0.01). BRCA1 status predicted breast cancer mortality only among women who did not receive chemotherapy (hazard ratio 4.8, 95% confidence interval 2.0–11.7; P = 0.001). The risk for metachronous ipsilateral cancer was not greater in women with germline BRCA1/BRCA2 founder mutations than in those without mutations (P = 0.68).ConclusionBRCA1 mutations, but not BRCA2 mutations, are associated with reduced survival in Ashkenazi women undergoing breast-conserving treatment for invasive breast cancer, but the poor prognosis associated with germline BRCA1 mutations is mitigated by adjuvant chemotherapy. The risk for metachronous ipsilateral disease does not appear to be increased for either BRCA1 or BRCA2 mutation carriers, at least up to 10 years of follow up.

Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer

BACKGROUND Inherited mutations in DNA-repair genes such as BRCA2 are associated with increased risks of lethal prostate cancer. Although the prevalence of germline mutations in DNA-repair genes among men with localized prostate cancer who are unselected for family predisposition is insufficient to warrant routine testing, the frequency of such mutations in patients with metastatic prostate cancer has not been established. METHODS We recruited 692 men with documented metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis. We isolated germline DNA and used multiplex sequencing assays to assess mutations in 20 DNA-repair genes associated with autosomal dominant cancer-predisposition syndromes. RESULTS A total of 84 germline DNA-repair gene mutations that were presumed to be deleterious were identified in 82 men (11.8%); mutations were found in 16 genes, including BRCA2 (37 men [5.3%]), ATM (11 [1.6%]), CHEK2 (10 [1.9% of 534 men with data]), BRCA1 (6 [0.9%]), RAD51D (3 [0.4%]), and PALB2 (3 [0.4%]). Mutation frequencies did not differ according to whether a family history of prostate cancer was present or according to age at diagnosis. Overall, the frequency of germline mutations in DNA-repair genes among men with metastatic prostate cancer significantly exceeded the prevalence of 4.6% among 499 men with localized prostate cancer (P<0.001), including men with high-risk disease, and the prevalence of 2.7% in the Exome Aggregation Consortium, which includes 53,105 persons without a known cancer diagnosis (P<0.001). CONCLUSIONS In our multicenter study, the incidence of germline mutations in genes mediating DNA-repair processes among men with metastatic prostate cancer was 11.8%, which was significantly higher than the incidence among men with localized prostate cancer. The frequencies of germline mutations in DNA-repair genes among men with metastatic disease did not differ significantly according to age at diagnosis or family history of prostate cancer. (Funded by Stand Up To Cancer and others.).

Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients

Tumor molecular profiling is a fundamental component of precision oncology, enabling the identification of genomic alterations in genes and pathways that can be targeted therapeutically. The existence of recurrent targetable alterations across distinct histologically defined tumor types, coupled with an expanding portfolio of molecularly targeted therapies, demands flexible and comprehensive approaches to profile clinically relevant genes across the full spectrum of cancers. We established a large-scale, prospective clinical sequencing initiative using a comprehensive assay, MSK-IMPACT, through which we have compiled tumor and matched normal sequence data from a unique cohort of more than 10,000 patients with advanced cancer and available pathological and clinical annotations. Using these data, we identified clinically relevant somatic mutations, novel noncoding alterations, and mutational signatures that were shared by common and rare tumor types. Patients were enrolled on genomically matched clinical trials at a rate of 11%. To enable discovery of novel biomarkers and deeper investigation into rare alterations and tumor types, all results are publicly accessible.