BRCA Mutation Status Research Articles

Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer

BackgroundOlaparib has shown significant clinical benefit as maintenance therapy in women with newly diagnosed advanced ovarian cancer with a BRCA mutation. The effect of combining maintenance olaparib and bevacizumab in patients regardless of BRCA mutation status is unknown.MethodsWe conducted a randomized, double-blind, international phase 3 trial. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were having a response after first-line platinum–taxane chemotherapy plus bevacizumab. Patients were eligible regardless of surgical outcome or BRCA mutation status. Patients were randomly assigned in a 2:1 ratio to receive olaparib tablets (300 mg twice daily) or placebo for up to 24 months; all the patients received bevacizumab at a dose of 15 mg per kilogram of body weight every 3 weeks for up to 15 months in total. The primary end point was the time from randomization until investigator-assessed disease progression or death.ResultsOf the 806 patients who underwent randomization, 537 were assigned to receive olaparib and 269 to receive placebo. After a median follow-up of 22.9 months, the median progression-free survival was 22.1 months with olaparib plus bevacizumab and 16.6 months with placebo plus bevacizumab (hazard ratio for disease progression or death, 0.59; 95% confidence interval [CI], 0.49 to 0.72; P<0.001). The hazard ratio (olaparib group vs. placebo group) for disease progression or death was 0.33 (95% CI, 0.25 to 0.45) in patients with tumors positive for homologous-recombination deficiency (HRD), including tumors that had BRCA mutations (median progression-free survival, 37.2 vs. 17.7 months), and 0.43 (95% CI, 0.28 to 0.66) in patients with HRD-positive tumors that did not have BRCA mutations (median progression-free survival, 28.1 vs. 16.6 months). Adverse events were consistent with the established safety profiles of olaparib and bevacizumab.ConclusionsIn patients with advanced ovarian cancer receiving first-line standard therapy including bevacizumab, the addition of maintenance olaparib provided a significant progression-free survival benefit, which was substantial in patients with HRD-positive tumors, including those without a BRCA mutation. (Funded by ARCAGY Research and others; PAOLA-1 ClinicalTrials.gov number, NCT02477644.)

Next-Generation Sequencing Identifies BRCA1 and/or BRCA2 Mutations in Women at High Hereditary Risk for Breast Cancer with Shorter Telomere Length.

Telomeres, and telomere length in particular, have broad significance for genome biology and thus are prime research targets for complex diseases such as cancers. In this context, BRCA1 and BRCA2 gene mutations have been implicated in relationship to telomere length, and breast cancer susceptibility. Yet, the linkages among human genetic variation and telomere length in persons with high hereditary cancer risk are inadequately mapped. We report here original findings in 113 unrelated women at high hereditary risk for breast cancer, who were characterized for the BRCA1 and BRCA2 mutations using next-generation sequencing. Thirty-one BRCA2 and 21 BRCA1 mutations were identified in 47 subjects (41.6%). The women with a mutation in BRCA1 and/or BRCA2 genes had, on average, 12% shorter telomere compared to women with no BRCA1 or BRCA2 mutation (p = 0.0139). Moreover, the association between telomere length and BRCA mutation status held up upon stratified analysis in those with or without a breast cancer diagnosis. We also indentified two rare mutations, c.536_537insT and c.10078A>G, and a novel mutation c.8680C>G in BRCA2 that was studied further by homology modeling of the DNA binding tower domain of BRCA2 and the structure of the protein. These data collectively lend evidence to the idea that BRCA1 and BRCA2 mutations play a role in telomere length in women at high hereditary risk for breast cancer. Further clinical and diagnostics discovery research on BRCA1 and BRCA2 variation, telomere length, and breast cancer mechanistic linkages are called for in larger study samples.

Expression of the Immune Checkpoints LAG-3 and PD-L1 in High-grade Serous Ovarian Carcinoma: Relationship to Tumor-associated Lymphocytes and Germline BRCA Status.

Ovarian high-grade serous carcinomas (HGSC) have shown lackluster responses to immunotherapies targeting the PD-1/PD-L1 axis, perhaps due to the coexistence of other mechanisms of immune evasion in this tumor type. Lymphocyte activation gene-3 (LAG-3) is another inhibitory immune checkpoint often expressed on tumor-associated lymphocytes which is targeted by drugs currently in clinical trials. Forty-eight HGSC with known germline BRCA mutation status were immunohistochemically stained for LAG-3, CD8, and FOXP3. Positive tumor-associated lymphocytes were enumerated and averaged over 10 high-power fields (HPF). PD-L1 immunostaining was also preformed and expression was evaluated on tumor cells and using the combined positive score (CPS). The average number of LAG-3-positve tumor-associated lymphocytes was 6/HPF (range: 0-25.6). Cytotoxic (CD8) T cells averaged 30/HPF (range: 0-168.9), and regulatory (FOXP3) cells averaged 6.6/HPF (range: 0-76.3). Tumoral PD-L1 expression of ≥1% was observed in 27% (13/48) of cases, with only 8% (4/48) showing >5% staining; 81% (39/48) cases had a CPS ≥1. LAG-3-positive lymphocytes and PD-L1 expression were positively correlated, even after controlling for the overall level of CD8 and FOX3P lymphocyte infiltration. Germline BRCA status was not significantly associated with LAG-3, CD8, FOXP3, or PD-L1 expression. These findings indicate that immunotherapies targeting LAG-3 may benefit some ovarian HGSC patients, particularly when used in conjunction with anti-PD-1/PD-L1 approaches. The typically limited expression of LAG-3 and PD-L1 suggests that immunotherapeutic response may be muted in most HGSC even with a combination approach.

The Interaction of PI3K Inhibition with Homologous Recombination Repair in Triple Negative Breast Cancer Cells.

Aberrant activation of the phosphatidylinositol 3'-kinase (PI3K)-Akt signaling pathway is observed in many types of human cancer including triple negative breast cancer (TNBC). Additionally, dysregulation in the homologous recombination (HR)-dependent DNA-repair is associated with TNBC phenotype due to BRCA1/2 mutations or HR deficiency. Therefore, the hypothesis of this study was to evaluate the association of PI3K inhibition with HR pathway in TNBC in terms of BRCA1 mutation status. To examine the potential therapeutic effect of LY294002, an inhibitor of PI3K, on TNBC cell lines with known BRCA1 status, WST-1, annexin V, cell cycle analysis and AO/EB staining were performed. Additionally, RT-PCR and immunofluorescence analysis was used to explore the interaction between the inhibition of PI3K and HR functionality. The findings showed that LY294002 could significantly inhibited the proliferation of TNBC cells. Furthermore, the suppression of PI3K resulted in HR impairment by BRCA1 and RAD51 downregulation and apoptotic cell death by the induction of DNA damage and BAX overexpression. Therefore, LY294002 was more effective in BRCA1-deficient TNBC cells. Consequently, targeted therapies based on the interaction of PI3K inhibition with BRCA1 mutations or HR deficiency in TNBC may be a promising strategy for the treatment of patients with TNBC.

Treatment of recurrent epithelial ovarian cancer.

The majority of patients with advanced ovarian cancer progress after first-line therapy and require further treatment. Tumor biology, prior chemotherapy, responses to previous therapy, performance status, and toxicity are the characteristics that influence treatment choice. These criteria have been linked to the time between relapse and last platinum therapy: the platinum-free interval. Today, patients are classified as either those who are eligible for a new platinum-based therapy or those for whom platinum is not an option. A nonplatinum regimen should be administered to patients who are not candidates for platinum re-treatment. This group includes patients with early relapse after, or progression during, previous platinum-based chemotherapy and patients with platinum intolerability. A single agent such as weekly paclitaxel, pegylated liposomal doxorubicin (PLD), gemcitabine, or topotecan represents the standard. For patients not treated with bevacizumab in the first line, this drug should be added to chemotherapy. For patients for whom platinum rechallenge is an option (because they are potentially platinum-responsive), different strategies are available with the incorporation of biological drugs targeting angiogenesis or the mechanisms of DNA repair. A BRCA mutation status predicts a better response to platinum and poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition. PARP inhibitors and antiangiogenic drugs have proven efficacy as maintenance therapy after chemotherapy and concurrently with chemotherapy, respectively. These agents have changed current practice, although few biomarkers are available to guide decisions. Patients potentially responsive to platinum who cannot receive the drug again can be treated with a combination of trabectedin and PLD, the most active nonplatinum therapy in this setting.

Incidence of germline BRCA1/2 mutations in women with tubo-ovarian high-grade serous carcinomas with and without serous tubal intra-epithelial carcinomas

ObjectiveTo compare the germline BRCA1 and BRCA2 mutation (gBRCA) status in women with high-grade serous tubo-ovarian and primary peritoneal carcinoma with and without serous tubal intra-epithelial carcinomas (serous tubal intra-epithelial...

Breast cancer surveillance for BRCA1/2 mutation carriers – is “early detection” early enough?

BackgroundAnnual MRI screening is associated with a significant reduction in advanced-stage breast cancer diagnosis in BRCA1/2 mutation carriers. The impact that early detection has on subsequent oncological treatment is less frequently reported. In this study we compared disease stage and therapeutic approaches in BRCA1/2 mutation carriers who developed breast cancer while adhering to the recommended surveillance scheme (“known carriers”), with women who became aware of their BRCA mutation status after breast cancer diagnosis (“latent carriers"). MethodsData on tumor characteristics, disease stage, and therapeutic decisions were collected on BRCA1/2 mutation carriers treated for breast cancer at the Chaim Sheba Medical Center. ResultsData were available for 298 BRCA1/2 carriers. Median follow-up was 77.4 months (range, 3.5–520). Age at diagnosis was not statistically different between known carriers (n = 96; median age at diagnosis 44.7 years) and latent carriers (n = 202; 43.7 years); p = 0.8284. Of known carriers, 19.8% were diagnosed with carcinoma in situ vs. 5% of latent carriers (p = 0.0012). Stage T1N0 disease was diagnosed in 54/96 (56.3%) of known carriers vs. 59/202 (29.2%) of latent carriers (p < 0.00001). Neoadjuvant or adjuvant chemotherapy was administered to 46/96 (47.9%) of known carriers compared with 162/202 (80.2%) of latent carriers (p < 0.00001). ConclusionsWhile early stage breast cancer was diagnosed frequently among known BRCA1/2 carriers under tight surveillance, almost half of these women were treated with chemotherapy. Healthy BRCA1/2 mutation carriers should be informed about these rates while discussing risk-reducing surgical options.

PARP1 Inhibition Radiosensitizes Models of Inflammatory Breast Cancer to Ionizing Radiation.

Sustained locoregional control of disease is a significant issue in patients with inflammatory breast cancer (IBC), with local control rates of 80% or less at 5 years. Given the unsatisfactory outcomes for these patients, there is a clear need for intensification of local therapy, including radiation. Inhibition of the DNA repair protein PARP1 has had little efficacy as a single agent in breast cancer outside of studies restricted to patients with BRCA mutations; however, PARP1 inhibition (PARPi) may lead to the radiosensitization of aggressive tumor types. Thus, this study investigates inhibition of PARP1 as a novel and promising radiosensitization strategy in IBC. In multiple existing IBC models (SUM-149, SUM-190, MDA-IBC-3), PARPi (AZD2281-olaparib and ABT-888-veliparib) had limited single-agent efficacy (IC50 > 10 μmol/L) in proliferation assays. Despite limited single-agent efficacy, submicromolar concentrations of AZD2281 in combination with RT led to significant radiosensitization (rER 1.12-1.76). This effect was partially dependent on BRCA1 mutational status. Radiosensitization was due, at least in part, to delayed resolution of double strand DNA breaks as measured by multiple assays. Using a SUM-190 xenograft model in vivo, the combination of PARPi and RT significantly delays tumor doubling and tripling times compared with PARPi or RT alone with limited toxicity. This study demonstrates that PARPi improves the effectiveness of radiotherapy in IBC models and provides the preclinical rationale for the opening phase II randomized trial of RT ± PARPi in women with IBC (SWOG 1706, NCT03598257).

Antitumor activity of the poly(ADP-ribose) polymerase inhibitor rucaparib as monotherapy in patients with platinum-sensitive, relapsed, BRCA-mutated, high-grade ovarian cancer, and an update on safety

ObjectiveTo report results from an integrated efficacy and safety analysis supporting the European Commission's approval of the poly(ADP-ribose) polymerase inhibitor rucaparib as monotherapy treatment for relapsed, platinum-sensitive, BRCA-mutated ovarian cancer.MethodsEfficacy...

1014P - Response to chemotherapy in ovarian cancer (OC) patients with or without prior breast cancer (BC), stratified by BRCA mutation (BRCAm) status

BackgroundWomen with OC due to an underlying BRCAm have enhanced responses to platinum and often improved progression free survival. BRCAm carriers also have an increased risk of BC, which often predates OC and may impact later treatment response. MethodsWomen with OC treated at The Royal Marsden Hospital between 01/06/13 and 31/5/17 with known BRCAm status were identified from the electronic patient record. The primary endpoint was progression free survival (PFS) after first line treatment for OC, stratified for BRCAm and BC status. Secondary endpoints were time to second subsequent treatment (TSST) and type of BRCA mutation (BRCA1 vs BRCA2). Results575 patients were identified, 502 high grade (HG), 73 low grade (LG) OC. Histology was HG serous (77%), endometroid (10%), clear cell (5%), LG serous (4%), other (4%). 158 (27%) had a BRCAm, 92 (58%) BRCA1 and 66 (42%) BRCA2. Mean age of OC diagnosis was 59 (19-98) yrs. Prior BC was noted in 79 patients – 51 BRCAm, 28WT; 21 patients had >1 BC (14 BRCA, 7WT). Mean age of first BC diagnosis was 50 yrs (30-75). Median PFS (mths) was 19.6 (BC, WT) vs 23.6 (no BC, WT) vs 25.4 (BC, BRCAm) vs 27.1 (no BC, BRCAm), p=0.08. TSST(mths) was significantly different at 23.1 (BC, WT) vs 30 (no BC, WT) vs 34 (BC, BRCAm) vs 42.6 (no BC, BRCAm), p=0.02. There was no significant difference in PFS between those who did/did not receive chemotherapy for prior breast cancer; nor between those with a BRCA1 vs BRCA2 mutation. ConclusionsWithin the limits of a retrospective audit, there was no significant difference in PFS for women with OC irrespective of prior BC diagnosis or BRCAm status, but there was a significant difference in TSST. A similar trend was seen in both groups, with poorest PFS/TSST in those with prior BC/BRCA WT; and best PFS/TSST in those with no prior BC/BRCAm. Prior BC diagnosis may be another factor in response to OC chemotherapy. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

1029P - Response to pegylated liposomal doxorubicin (PLD) and weekly paclitaxel (wpac) in platinum resistant (PR) ovarian cancer (OC) by BRCA mutation status

BackgroundWomen with OC due to an underlying BRCA mutation (BRCAm) are known to have enhanced responses to platinum and PLD, but their relative response rates to wpac are unclear. Both PLD and wpac are commonly used in women with PROC. Our aim was to assess the response rates to both agents, stratified by BRCAm staus. MethodsWomen with PR OC treated at The Royal Marsden Hospital between 2007 and 2017 with known BRCAm status were identified from the electronic patient record. Included patients underwent a minimum of 3 cycles and radiological restaging for inclusion. The primary endpoint was radiological response (RR) by BRCA status - BRCAm or BRCA wildtype (WT). Secondary endpoints were clinical benefit rate (CBR), CA-125 response, and line of treatment as a predictor of response. Results231pt were identified, 38 BRCAm, 193WT; median age 58 yrs (36-88) BRCAm, 62 yrs (44-85) WT. Histology was 90% HGS, 4% endometroid, 3% clear cell, 1% mucinous, 2% other. Overall 102 (44%) were treated with PLD; 129 (56%) received wpac with RR 14% PLD and 38% wpac; CBR of 49% PLD and 83% wpac (p=0.01). When stratified by BRCAm, RR to PLD was 28% (BRCAm) vs 13% (WT; p=0.01); and wpac 37% (BRCAm) vs 38% (WT, ns). CBR was 64% (BRCAm) vs 48% (WT) with PLD (p=0.02) and 81% vs 83% with wpac (WT, ns). GCIG CA-125 responses were present in 110/231 (48%) – 24 PLD and 86 wpac, for CA-125 RR of 24% and 66% respectively (p<0.001). Choice of first line treatment was PLD (49%) and wpac (51%); use in 2nd line was 44% and 56% respectively. Line of treatment was not an independent predictor of RR. ConclusionsWithin the limits of a retrospective audit, BRCAm carriers had significantly higher RR to PLD than WT patients; with equivalent responses to wpac. Wpac may be a preferred choice over PLD in BRCA WT patients with PROC. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

The BRCA2 mutation status shapes the immune phenotype of prostate cancer

Defects in DNA damage repair caused by mutations in BRCA1/2, ATM or other genes have been shown to play an important role in the development and progression of prostate cancer. The influence of such mutations on anti-tumor immunity in prostate cancer, however, is largely unknown. To better understand the correlation between BRCA1/2 mutations and the immune phenotype in prostate cancer, we characterized the immune infiltrate of eight BRCA2-mutated tumors in comparison with eight BRCA1/2 wild-type patients by T-cell receptor sequencing and immunohistochemistry for CD45, CD4, CD8, FOXP3, and CD163. In addition, we analyzed seven prostate cancer biopsies that were either BRCA2 or ATM-mutated in comparison with wild-type tumors. Whereas in BRCA1/2 wild-type tumors, immune cells were found predominantly extratumorally, most BRCA2-mutated tumors including one biopsy showed a significantly increased intratumoral immune cell infiltration. The ratio of intratumoral to extratumoral immune cells was considerably higher in BRCA2-mutated tumors for all markers and reached statistical significance for CD4 (p = 0.007), CD8 (p = 0.006), and FOXP3 (p = 0.001). However, the intratumoral CD8 to FOXP3 ratio showed a trend to be lower in BRCA2-mutated tumors suggesting a more suppressed tumor immune microenvironment. Our findings provide a rationale for the future use of immune oncological approaches in BRCA2-mutated prostate cancer and may encourage efforts to target immunosuppressive T-cell populations to prime tumors for immunotherapy.

Chemotherapy Toxicity in BRCA Mutation Carriers Undergoing First-Line Platinum-Based Chemotherapy.

BRCA mutations are the most frequent mutations causing homologous recombination defects in epithelial ovarian cancers (EOC). Germline mutation carriers are heterozygous for the mutation and harbor one defective allele in all cells. This has been hypothesized to cause increased susceptibility to DNA damage in healthy cells as well as neoplastic ones. Our objective was to assess chemotherapy-associated toxicities in patients with epithelial ovarian cancer with and without a germline BRCA mutation. A retrospective cohort study of patients with EOC receiving first-line platinum-based chemotherapy at a single center between 2006 and 2016. Indices of chemotoxicity, including blood counts, transfusion requirements, granulocyte colony-stimulating factor (gCSF) prescriptions, episodes of febrile neutropenia, and treatment delays were compared for BRCA mutation carriers and noncarriers. A total of 90 women met the inclusion criteria, including 31 BRCA mutation carriers (34%) and 59 noncarriers (66%). Mean hemoglobin, neutrophil count, and platelet counts during treatment were comparable for the two patient groups. There was a trend toward a higher frequency of hematological events in BRCA mutation carriers (neutropenia <1500 per mL: 6% vs. 0%, p = .12; thrombocytopenia <100,000 per mL: 23% vs. 9%, p = .07), but these differences were not statistically significant. Similarly, no significant differences were found in surrogates of bone marrow toxicity such as blood transfusions, use of gCSF, episodes of febrile neutropenia, or treatment delays. BRCA mutation carriers and noncarriers receiving first-line platinum-based chemotherapy for EOC have similar hematologic toxicity profiles. Clinicians treating these patients can be reassured that chemotherapy dosing or schedule do not require adjustment in patients carrying BRCA mutations. Patients with ovarian cancer carrying BRCA mutations are more likely to have serous tumors and present with higher CA125 levels. Germline BRCA mutation status is not associated with increased frequency of adverse hematologic events among patients with ovarian cancer being treated with first-line platinum-based chemotherapy. Germline BRCA mutations are also not associated with more treatment delays or a lower number of courses completed in this patient population. These findings should reassure practitioners engaged in care for patients with ovarian cancer that BRCA mutation status most likely will not affect chemotherapy dosing or schedule.

Association of Cytokeratin 5 and Claudin 3 expression with BRCA1 and BRCA2 germline mutations in women with early breast cancer

BackgroundIt is important to identify biomarkers associated with BRCA mutation in women with early breast cancer (BC) to improve early identification of mutation carriers. Thus, in this study, we examined the protein expression of claudin (CLDN) 3, CLDN4, CLDN7, and E-cadherin. Moreover, we analyzed additional histopathological variables and their associations in familial BC.MethodsImmunohistochemical analysis for CLDNs and E-cadherin was performed on 237 BC cases of three different subsets of BC tumors: 62 from BRCA1 mutation carriers, 59 from BRCA2 mutation carriers, and 116 tumors from patients with BRCA wild type (WT) as controls. Histopathological data were also analyzed in the different subgroups. Logistic regression and receiver operation characteristic (ROC) curve were conducted to investigate factors associated with BRCA tumors.ResultsExpression of CLDN3 positively correlated with BRCA-mutated BC. CLDN3 was expressed in 58% of BRCA1-mutated tumors compared to only 7% in BRCA2-mutated tumors (p < 0.001) and 1% in WT tumors (p < 0.001). CK5 and CK14 expression were also more likely to arise in BRCA1 tumors (44 and 16%, respectively) than in the control group (8 and 4%) (p < 0.001, p = 0.012, respectively). We also found a significantly higher proportion of CK5+ among BRCA1 tumors (44%) in comparison with BRCA2-related BC (8%) (p < 0.001). In addition, there was a significant difference between both groups regarding CK14: positive expression in 16 and 5%, respectively (p = 0.030). CK5 and CK14 did not differ between the BRCA2 group and the WT tumors significantly. In a multivariate regression model, expression of CK5 (Odds ratio (OR): 6.46; 95% confidence interval (CI): 1.52–27.43; p = 0.011), and CLDN3 (OR: 200.48; 95% CI: 21.52–1867.61; p < 0.001) were associated with BRCA1 mutation status.ConclusionsOur data suggests that CLDN3, CK5, and CK14 in combination with ER, PR and HER2 are associated with BRCA1 mutation status.

Impact of Taxanes, Endocrine Therapy, and Deleterious Germline BRCA Mutations on Anti-müllerian Hormone Levels in Early Breast Cancer Patients Treated With Anthracycline- and Cyclophosphamide-Based Chemotherapy.

Background: Limited evidence exists on the impact of adding a taxane, using endocrine therapy and carrying a deleterious germline BRCA mutation on ovarian reserve measured by anti-müllerian hormone (AMH) levels of young breast cancer patients receiving (neo)adjuvant cyclophosphamide- and anthracycline-based chemotherapy.Methods: This is a biomarker analysis including young (≤ 40 years) early breast cancer patients with known germline BRCA mutational status and available prospectively collected frozen plasma samples before and after chemotherapy. Chemotherapy consisted of either six cycles of FEC (5 fluorouracil 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2) or three cycles of FEC followed by three cycles of docetaxel (D, 100 mg/m2). Endocrine therapy consisted of tamoxifen (±GnRH agonists). AMH levels at baseline, 1 and 3 years after diagnosis were compared according to type of chemotherapy (FEC only vs. FEC-D), use of endocrine therapy (yes vs. no) and deleterious germline BRCA mutations (mutated vs. negative).Results: Out of 148 included patients, 127 (86%) received D following FEC chemotherapy, 90 (61%) underwent endocrine therapy, and 35 (24%) had deleterious germline BRCA mutations. In the whole cohort, AMH levels drastically dropped 1 year after diagnosis (p < 0.0001) with a slight but significant recovery at 3 years (p < 0.0001). One year after diagnosis, patients treated with FEC only had higher median AMH levels than those who received FEC-D (0.22 vs. 0.04 μg/L, p = 0.0006); no difference was observed at 3 years (0.06 and 0.18 μg/L, p = 0.47). Patients under endocrine therapy had significantly higher AMH levels than those who did not receive this treatment 1 year after diagnosis (0.12 vs. 0.02 μg/L; p = 0.008), with no difference at 3 years (0.11 and 0.20 μg/L, p = 0.22). AMH levels were similar between BRCA-mutated and BRCA-negative patients at baseline (1.94 vs. 1.66 μg/L, p = 0.53), 1 year (0.09 vs. 0.06 μg/L, p = 0.39) and 3 years (0.25 vs. 0.16 μg/L; p = 0.43) after diagnosis.Conclusions: In breast cancer patients receiving FEC chemotherapy, adding D appeared to negatively impact on their ovarian reserve in the short-term; no further detrimental effect was observed for endocrine therapy use and presence of a deleterious germline BRCA mutation.

Association between the cervicovaginal microbiome, BRCA1 mutation status, and risk of ovarian cancer: a case-control study.

Various factors-including age, family history, inflammation, reproductive factors, and tubal ligation-modulate the risk of ovarian cancer. In this study, our aim was to establish whether women with, or at risk of developing, ovarian cancer have an imbalanced cervicovaginal microbiome. We did a case-control study in two sets of women aged 18-87 years in the Czech Republic, Germany, Italy, Norway, and the UK. The ovarian cancer set comprised women with epithelial ovarian cancer and controls (both healthy controls and those diagnosed with benign gynaecological conditions). The BRCA set comprised women with a BRCA1 mutation but without ovarian cancer and controls who were wild type for BRCA1 and BRCA2 (both healthy controls and those with benign gynaecological conditions). Cervicovaginal samples were gathered from all participants with the ThinPrep system and then underwent 16S rRNA gene sequencing. For each sample, we calculated the proportion of lactobacilli species (ie, Lactobacillus crispatus, Lactobacillus iners, Lactobacillus gasseri, and Lactobacillus jensenii), which are essential for the generation of a protective low vaginal pH, in the cervicovaginal microbiota. We grouped samples into those in which lactobacilli accounted for at least 50% of the species present (community type L) and those in which lactobacilli accounted for less than 50% of the species present (community type O). We assessed the adjusted association between BRCA1 status and ovarian cancer status and cervicovaginal microbiota community type, using a logistic regression model with a bias reduction method. Participants were recruited between Jan 2, 2016, and July 21, 2018. The ovarian cancer set (n=360) comprised 176 women with epithelial ovarian cancer, 115 healthy controls and 69 controls with benign gynaecological conditions. The BRCA set (n=220) included 109 women with BRCA1 mutations, 97 healthy controls wild type for BRCA1 and BRCA2 and 14 controls with a benign gynaecological condition wild type for BRCA1 and BRCA2. On the basis of two-dimensional density plots, receiver-operating characteristic curve analysis, and age thresholds used previously, we divided the cohort into those younger than 50 years and those aged 50 years or older. In the ovarian cancer set, women aged 50 years or older had a higher prevalence of community type O microbiota (81 [61%] of 133 ovarian cancer cases and 84 [59%] of 142 healthy controls) than those younger than 50 years (23 [53%] of 43 cases and 12 [29%] of 42 controls). In the ovarian cancer set, women younger than 50 years with ovarian cancer had a significantly higher prevalence of community type O microbiota than did age-matched controls under a logistic regression model with bias correction (odds ratio [OR] 2·80 [95% CI 1·17-6·94]; p=0·020). In the BRCA set, women with BRCA1 mutations younger than 50 years were also more likely to have community type O microbiota than age-matched controls (OR 2·79 [95% CI 1·25-6·68]; p=0·012), after adjustment for pregnancy (ever). This risk was increased further if more than one first-degree family member was affected by any cancer (OR 5·26 [95% CI 1·83-15·30]; p=0·0022). In both sets, we noted that the younger the participants, the stronger the association between community type O microbiota and ovarian cancer or BRCA1 mutation status (eg, OR for community type O for cases aged <40 years in the ovarian cancer set 7·00 [95% CI 1·27-51·44], p=0·025; OR for community type O for BRCA1 mutation carriers aged <35 years in the BRCA set 4·40 [1·14-24·36], p=0·031). The presence of ovarian cancer, or factors known to affect risk for the disease (ie, age and BRCA1 germline mutations), were significantly associated with having a community type O cervicovaginal microbiota. Whether re-instatement of a community type L microbiome by using, for example, vaginal suppositories containing live lactobacilli, would alter the microbiomial composition higher up in the female genital tract and in the fallopian tubes (the site of origin of high-grade serous ovarian cancer), and whether such changes could translate into a reduced incidence of ovarian cancer, needs to be investigated. EU Horizon 2020 Research and Innovation Programme, EU Horizon 2020 European Research Council Programme, and The Eve Appeal.

Abstract 1409: Characterization of the LAR subtype triple negative breast cancer population

Abstract Background: The LAR subtype of triple negative breast cancer (TNBC) was defined using the Vanderbilt genomic signature in cell lines. The characteristics of this population remain unclear. Methods: We collected the clinicopathological, molecular and imaging characteristics of the LAR population who were enrolled in the ARTEMIS trial, a prospective trial to treat women with TNBC to receive neoadjuvant anthracycline therapy followed by experimental arms based on biomarker versus taxane. The ultrasonography-based response assessment was performed at baseline, after 2 and 4 cycles of anthracycline chemotherapy. The Vanderbilt genomic signature was used to classify the TNBC into the basal-like 1, basal-like 2, immunomodulatory, mesenchymal, mesenchymal stem-like and luminal androgen receptor (LAR) subtypes. The clinical data for this analysis included age, race, menopausal status, TNM stage and BRCA mutation status. Pathological and molecular characteristics included histologic subtype, nuclear grade, Ki67, vimentin expression, androgen receptor (AR) immunohistochemical (IHC) nuclear staining, stromal tumor infiltrating lymphocytes (TIL) percentage and residual cancer burden (RCB) at surgery. Results: Total 28 patients with the LAR signature were analyzed. The characteristics are showed in the table: AgeRaceno. (%)Clinical Stageno. (%)AR IHC StainingBRCA Mutationno. (%)Median (yr)55White19 (68)IA1 (4)Median (%)52No mutation16 (57)Distribution(%)no. (%)Asian3 (11)IIA6 (21)Distribution (%)no(%)Mutation present018-402 (7)Black2 (7)IIB10 (36)&amp;lt;259 (32)VUS1 (4)41-6012 (43)Hispanic3 (11)IIIA6 (21)25-505 (18)Test not indicated6 (21)&amp;gt;6014 (50)American Indian1 (3)IIIB051-751 (3,5)Unknown5 (18)IIIC5 (18)76-10012 (43)Not available1 (3,5)Menopauseno. (%)Histologic subtypeno. (%)Ki67Stromal TILno. (%)Vimentin expressionno. (%)Postmenopausal23 (82)IDC24 (87)Median (%)40&amp;lt;5%10 (36)&amp;lt; 1%24 (85)Perimenopausal2 (7)ILC2 (7)Distribution (%)no. (%)5% - &amp;lt;50 %16 (57)≥1%3 (11)Premenopausal3 (11)Apocrine Carcinoma1 (3)&amp;lt;205 (18)≥50%1 (3,5)N/A1 (4)Metaplastic carcinoma1 (3)≥2013 (46)N/A1 (3,5)N/A10 (36)T stageno. (%)Lymph node involvementno. (%)Nuclear gradeno. (%)Tumor reduction (%)no. (%)RCBno(%)T1c3 (11)Yes22 (79)11 (4)≥ 7012 (43)pCR-111 (39)T213 (46)No6 (21)26 (21)&amp;lt; 7014 (50)2-315 (54)T311 (39)321 (75)N/A2 (7)N/A2 (7)T41 (4)Experimental armno. (%)Enzalutamide8 (29)Atezolizumab4 (14)None16 (57) Relevant characteristics are: median age of 55 years, 82% postmenopausal, 89% breast tumor size &amp;gt; 2cm, 79% with lymph node involvement, no BRCA mutation detected, 75% nuclear grade III, 46% with Ki67 ≥ 20%, median AR IHC staining of 52%, 85% vimentin expression of &amp;lt;1%, 93% had stromal TIL &amp;lt;50%, 39% RCB 0-1 and 54% RCB 2-3. We found that 43% had ≥ 70% reduction in size after 4 cycles of AC. Univariate and multivariate analysis using characteristics did not reveal contributing factor to the RCB. Conclusion: The LAR subgroup harbors unique characteristics that require further confirmation in larger cohorts. Citation Format: James Crespo, Seth Sahil, Elizabeth Ravenberg, Lei Huo, Kenneth Hess, Lumarie Santiago, Beatriz Adrada, Gaiane Rauch, Damodaran Senthil, Rashmi Murthy, Jennifer Litton, Debu Tripathy, Naoto Ueno, Stacy Moulder, Bora Lim. Characterization of the LAR subtype triple negative breast cancer population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1409.

Abstract 4174: Familiality of ovarian cancer histotypes in the Utah Population Database

Abstract Introduction: Ovarian cancer is a heterogeneous disease; each histotype has distinct molecular origins, risk factors and outcomes. While it is well established that ovarian cancer has a familial risk component, the familiality of ovarian cancer histotypes has not been well described. The Utah Population Database (UPDB) captures over 10 million individuals, including more than 5 million with a minimum of three generations of genealogy data. By linking records from the UPDB to the Utah Cancer Registry (UCR) and other statewide data sources, we sought to describe the familiality of ovarian cancer histotypes. Methods: Our study includes all ovarian cancer cases in the UPDB and leverages clinical data reported to UCR for the case histotypes. Cases were matched to controls on age, birth cohort and at least three generations of UPDB data versus not. We quantified familiality by comparing the odds of ovarian cancer occurrence among family members of cases to the odds of ovarian cancer among family members of matched controls. We calculated odds ratios for first-degree relatives, second-degree relatives, and first cousins. Results: As of September 2018, the UPDB included 3,989 ovarian cancer cases. We observed an increased risk of epithelial ovarian cancer among first-degree relatives (OR=1.62, 95%CI=1.36-1.93), second-degree relatives (OR=1.53, 95%CI=1.34-1.74), and first cousins (OR=1.38, 95%CI=1.26-1.53) of ovarian cancer cases. When we analyzed epithelial ovarian cancers by histotype, familiality was most evident for high-grade serous, mucinous, and unclassified cancers. For example, we observed a 1.62-fold increased odds (95%CI=1.14-2.29) of high-grade serous ovarian cancer among the first-degree relatives of high-grade serous cases, and a 5.59-fold increased odds (95%CI=2.09-14.92) of mucinous ovarian cancer among first-degree relatives of mucinous ovarian cancer cases. Familiality patterns were less clear among endometrioid and clear cell cases. Conclusions: The UPDB has the potential to contribute greatly to family-based studies of the genetics of ovarian cancer histotypes. Despite the possible variations in quality of histotype data across generations, preliminary results suggest some histotypes may be particularly familial and good candidates for gene mapping studies. Work is ongoing to refine the histotype assignments for cases by performing pathology review using the 2014 World Health Organization guidelines. Analyses are also in progress to stratify analyses by BRCA mutation status, and to consider the potential for shared familiality across ovarian cancer histotypes and with cancers at other sites. Citation Format: Mollie E. Barnard, Nicola J. Camp, Jennifer A. Doherty. Familiality of ovarian cancer histotypes in the Utah Population Database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4174.

Can I Keep My Nipple? Factors Influencing the Surgical Decision between Skin-Sparing and Nipple-Sparing Mastectomy

Both skin-sparing mastectomy (SSM) and nipple-sparing mastectomy (NSM) are well accepted in the management of breast cancer. Factors that influence the decision of choosing one of these techniques over the other, however, remain to be well elucidated. From January 2010 to December 2017, 734 patients at our institution underwent one of these two procedures. Factors differentiating these patient cohorts were compared. In this study, 196 (26.7%) underwent NSM and 538 (73.3%) underwent SSM. The median age of patients at the time of surgery was 50 years (range, 22-78 years). On multivariate analysis, younger patient age, insurance type, BRCA+ mutation status, smaller breast size (by weight), and those who did not undergo neoadjuvant chemotherapy were more likely to undergo NSM. Surgeon also was an independent predictor of whether patients had NSM or SSM. There may be many factors that play into the decision to pursue NSM versus SSM, but younger patient age, BRCA mutation status, breast size, and whether the patient had neoadjuvant chemotherapy may be key among them. Insurance status may also be a factor for some patients. Aside from these factors, some surgeons may be more or less inclined to perform NSM.

Abstract 4178: Germline mutations in BRCA2 and pediatric/adolescent non-Hodgkin's lymphoma: A report from the St. Jude Lifetime (SJLIFE) and Childhood Cancer Survivor Study (CCSS) cohorts

Abstract Pathogenic or likely pathogenic (P/LP) monoallelic germline mutations in BRCA2 increase risk of developing breast, ovarian, prostate, and pancreatic cancers. In a prior report from the SJLIFE study, BRCA2 was the third most frequently mutated gene (14 occurrences) among 3006 survivors of childhood cancer with the highest number observed among lymphoma survivors (7/586). To further investigate BRCA2 as a potential predisposition gene for pediatric/adolescent lymphoma, we analyzed 781 additional lymphoma survivors in the SJLIFE and CCSS cohorts with whole-genome sequencing (30X coverage). In the combined set of 1367 survivors (808 Hodgkin’s lymphoma [HL], 559 non-Hodgkin’s lymphoma [NHL]; 54% male; median age at diagnosis 12.6 [range 1.1-22.7] years), 13 P/LP mutations in BRCA2 were identified, with 7 mapped to the breast or ovarian cancer cluster regions defined by the Consortium of Investigators of Modifiers of BRCA1/2. Compared to reference controls in the Genome Aggregation Database (gnomAD) (Table 1), a significant association was observed between lymphoma and mutations in BRCA2 (odds ratio [OR], 3.1; 95% CI, 1.7-5.5) but not BRCA1. When stratified by diagnosis, the association was significant for NHL (OR, 4.8; 95% CI, 2.0-9.6) but not for HL. BRCA2 mutation carriers included a broad spectrum of NHL histological subtypes. Our findings support inclusion of pediatric/adolescent NHL in the spectrum of cancers associated with germline BRCA2 mutations. Approximately 1.4% of survivors of pediatric/adolescent NHL are carriers of a P/LP mutation in BRCA2, which may be the underlying etiology of their primary diagnosis. Clinically, counselling regarding BRCA2 mutation status should be considered for pediatric/adolescent NHL patients. Large scale genetic studies of newly diagnosed pediatric/adolescent lymphoma patients are warranted to replicate and refine diagnosis-specific risk estimates. Table 1.Comparisons of Mutation Carriers for BRCA1/2 Genes Between Lymphoma Survivors and gnomAD ControlsLymphoma SurvivorsgnomAD Controls (Hu et al. JAMA 2018)Cancer Risk (Fisher''s Exact Test)GeneCancer DiagnosisCarriersNon-CarriersCarriersNon-CarriersOdds Ratio (95% CI)P ValueBRCA2HL+NHL1313543131024263.1 (1.7-5.5)0.00045HL58033131024262.0 (0.7-4.8)0.11NHL85513131024264.8 (2.0-9.6)0.00041BRCA1HL+NHL313642081039141.1 (0.2-3.3)0.76HL18072081039140.6 (0.02-3.5)1.0NHL25572081039141.8 (0.2-6.6)0.31 Citation Format: Zhaoming Wang, Ti-Cheng Chang, Carmen L. Wilson, Chimene A. Kesserwan, Todd M. Gibson, Nan Li, John Easton, Heather L. Mulder, Gang Wu, Michael N. Edmonson, Michael C. Rusch, James R. Downing, Kim E. Nichols, Smita Bhatia, Gregory T. Armstrong, Melissa M. Hudson, Jinghui Zhang, Yutaka Yasui, Leslie L. Robison. Germline mutations in BRCA2 and pediatric/adolescent non-Hodgkin's lymphoma: A report from the St. Jude Lifetime (SJLIFE) and Childhood Cancer Survivor Study (CCSS) cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4178.