BRCA1 Mutations In Breast Cancer Patients Research Articles

Abstract 2013: Extracellular vesicles transfer miR-181a to confer PARP inhibitor resistance and induce STING degradation in BRCA-mutated triple-negative breast and ovarian cancers cells

Abstract Background: Patients with BRCA-mutated breast cancer (BC), including triple-negative BC (TNBC), and ovarian cancer (OvCa) are treated with poly (ADP-ribose) polymerase inhibitors (PARPi). BC and OvCa tumors develop similar mechanisms of resistance to platinum-based agents and PARPi. This study aimed to identify microRNAs (miRs) inducing PARPi resistance in cancer cells that can be transferred by extracellular vesicles (EV). Methods: Olaparib-resistant (OlaR) cell lines were analyzed for 2,083 miRs using HTG miRNA Whole Transcriptomic Analysis (WTA) and NGS. Functional assays were performed in BRCA1-mutated TNBC and OvCa cell lines. In-silico analysis were performed using TCGA, GTEx, CCLE, GDSC, and GEO databases. Results: The miR-181 family (including miR-181a, p=0.001) was significantly upregulated in OlaR TNBC cell lines. High miR-181a levels occurred in tumor tissues of TNBC patients (p=0.001). miR-181a binds to the stimulator of interferon genes (STING) mRNA to promote STING mRNA degradation in OvCa. We hypothesized that miR-181a downregulates STING and downstream proinflammatory cytokines, to mediate PARPi resistance. miR-181a-overexpression induced olaparib resistance and STING downregulation in BRCA1-mutated TNBC cell lines. EV isolated from OlaR TNBC cell lines horizontally transferred miR-181a to non-resistant parental cell lines, which conferred PARPi-resistance and decreased STING. In clinical settings, STING levels were positively correlated with interferon gamma (IFNG) response scores (p=0.01). Low-IFNG response scores in HER2-negative BC patients showed a worse response to neoadjuvant treatment (p=0.001). Consistently, OlaR TNBC cell lines showed resistance to platinum-based drugs. OvCa cell lines resistant to cisplatin showed resistance to olaparib; but miR-181a knockout significantly improved olaparib sensitivity (p=0.001). Conclusions: High levels of miR-181a decrease STING pathway, correlate with IFNG scores, drive PARPi and platinum-based drug resistance. Horizontal miR-181a EVs transfer can facilitate drug resistance in cells. The miR-181a-STING axis can be used for predicting PARPi responses in TNBC and OvCa tumors. Citation Format: Matias A. Bustos, Takamichi Yokoe, Yoshiaki Shoji, Yuta Kobayashi, Shodai Mizuno, Tomohiro Murakami, Sreeja C. Sekhar, Matthew Knarr, Steven A. Vasilev, Analisa DiFeo, Ronny Drapkin, Dave S. Hoon. Extracellular vesicles transfer miR-181a to confer PARP inhibitor resistance and induce STING degradation in BRCA-mutated triple-negative breast and ovarian cancers cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2013.

MiR-181a targets STING to drive PARP inhibitor resistance in BRCA- mutated triple-negative breast cancer and ovarian cancer

BackgroundPoly (ADP-ribose) polymerase inhibitors (PARPi) are approved for the treatment of BRCA-mutated breast cancer (BC), including triple-negative BC (TNBC) and ovarian cancer (OvCa). A key challenge is to identify the factors associated with PARPi resistance; although, previous studies suggest that platinum-based agents and PARPi share similar resistance mechanisms.MethodsOlaparib-resistant (OlaR) cell lines were analyzed using HTG EdgeSeq miRNA Whole Transcriptomic Analysis (WTA). Functional assays were performed in three BRCA-mutated TNBC cell lines. In-silico analysis were performed using multiple databases including The Cancer Genome Atlas, the Genotype-Tissue Expression, The Cancer Cell Line Encyclopedia, Genomics of Drug Sensitivity in Cancer, and Gene Omnibus Expression.ResultsHigh miR-181a levels were identified in OlaR TNBC cell lines (p = 0.001) as well as in tumor tissues from TNBC patients (p = 0.001). We hypothesized that miR-181a downregulates the stimulator of interferon genes (STING) and the downstream proinflammatory cytokines to mediate PARPi resistance. BRCA1 mutated TNBC cell lines with miR-181a-overexpression were more resistant to olaparib and showed downregulation in STING and the downstream genes controlled by STING. Extracellular vesicles derived from PARPi-resistant TNBC cell lines horizontally transferred miR-181a to parental cells which conferred PARPi-resistance and targeted STING. In clinical settings, STING levels were positively correlated with interferon gamma (IFNG) response scores (p = 0.01). In addition, low IFNG response scores were associated with worse response to neoadjuvant treatment including PARPi for high-risk HER2 negative BC patients (p = 0.001). OlaR TNBC cell lines showed resistance to platinum-based drugs. OvCa cell lines resistant to platinum showed resistance to olaparib. Knockout of miR-181a significantly improved olaparib sensitivity in OvCa cell lines (p = 0.001).ConclusionmiR-181a is a key factor controlling the STING pathway and driving PARPi and platinum-based drug resistance in TNBC and OvCa. The miR-181a-STING axis can be used as a potential marker for predicting PARPi responses in TNBC and OvCa tumors.

P-426 In vitro and in vivo toxicity of carboplatin and paclitaxel regimen on BRCA-mutated ovarian tissue fragments

Abstract Study question Does carboplatin and paclitaxel regimen have a toxic cumulative impact on the ovarian reserve of young breast cancer patients with germline Breast Cancer (BRCA) mutation? Summary answer Based on follicle classification and survival through apoptosis and DNA repair mechanism recruitment analyses, gonadotoxic but no cumulative effect was observed in BRCA-mutated ovarian tissue. What is known already Ovarian function recovery and fertility issues remain major concerns for young patients diagnosed with cancer. Breast cancer is the first cancer diagnosed among women under 40 years and around 10% of them are BRCA germline mutation carriers. Beside their predisposition to breast and ovarian cancers, BRCA carriers might be more sensitive to chemotherapy-induced gonadotoxicity due to the role of BRCA in DNA repair mechanism. Current therapies for BRCA-mutated breast cancer patients often include carboplatin and paclitaxel, drugs that are both considered as moderately gonadotoxic. However, the effect of combined therapy in BRCA-mutated ovarian tissue is unknown. Study design, size, duration Ovarian tissue cryopreserved for fertility preservation before chemotherapy and donated for research by breast cancer patients with or without BRCA1/2 mutation (< 35 years at diagnosis) were used in this study. Two models were investigated: 3 days in vitro culture with carboplatin (10 µg/mL) and/or paclitaxel (1 µM) and ovarian tissue xenograft into mice followed by 3 weeks injections of carboplatin (50mg/kg/week) and paclitaxel (10mg/kg every 3 days). Control conditions were performed for each model. Participants/materials, setting, methods Ovarian tissue from 3 BRCA-mutated and 3 non-mutated patients were thawed and exposed in vitro and in vivo to chemotherapy. Follicle density (number of follicles/mm²) as well as ratios of quiescent/activated and healthy/atretic follicles were evaluated following haematoxylin-eosin staining. Apoptosis and DNA repair mechanisms were analysed using TUNEL/GDF9 co-staining and phosphorylated H2A histone family member X (γH2AX)/ZP-3 co-staining, respectively. Genes expression level will be evaluated on isolated follicles to assess the activation process. Main results and the role of chance First, the impact of in vitro culture and in vivo xenotransplantation was evaluated by follicle counting and classification. A decrease of follicular density (5 to 95% irrespective of patient, model, nor condition) and an increase of activated and atretic follicles was observed after both in vitro and in vivo experiments in all conditions. However, a slight increase of quiescent follicle pool was observed in the in vitro control condition, with no difference between mutated and non-mutated fragments. Then, immunofluorescence staining was performed to evaluate follicle damage. For quantification, 30 to 150 follicles per patient were counted within each condition and classified as positive if at least one cell was stained. Apoptosis was assessed with TUNEL/GDF9 co-staining. In both models, the ratio of positive follicles was higher in fragments treated with chemotherapy (40-60%) compared to control conditions (15-20%). Recruitment of DNA repair complex was analysed using γH2AX/ZP3 co-staining. In both models, an increase in positive follicles ratio was observed in treated fragments (15-40%) compared to control conditions (5-10%). Interestingly, the positive follicles ratio was lower in BRCA-mutated (15-18%) than in non-mutated fragments (25-40%) after 3-days in vitro culture, irrespective of the treatment used. Limitations, reasons for caution Reasons of caution include the high inter-variations between patients as well as intra-variations in one patient regarding follicular density within ovarian tissue. Moreover, BRCA-mutated patients included (27.67 ± 2.08) are younger than control ones (33.67 ± 1.53). Ongoing experiments with additional patients should support the results already obtained. Wider implications of the findings Carboplatin and paclitaxel combined exposure in vitro or in vivo does not seem to have a cumulative deleterious impact on ovarian reserve. Ovarian tissue with BRCA-mutation did not appear to be more sensitive to chemotherapy exposure. Further investigations focusing on DNA repair mechanisms will be performed in both models. Trial registration number Not applicable

Survival outcomes of BRCA1/BRCA2 mutated breast cancers: Study from a tertiary care cancer centre in India.

e22546 Background: There exists a discrepancy amongst various studies over the years on survival outcomes of BRCA (Breast cancer susceptibility gene) mutated breast cancers. Prevalence of BRCA mutation varies from 10 to 18% among Indian population and there is a paucity of data on the survival outcomes of this population. Methods: This ambispective observational study assessed the survival outcomes of 71 BRCA mutated breast cancer patients, treated with uniform protocol at AIIMS New Delhi between January 2014 to December 2022, using survival analysis and cox regression methods. Results: Amongst the 71 patients, BRCA1 and BRCA2 mutated cases were 52 (73.2%) and 19 (26.8%) respectively. The median age was 39 years (24-63 years) in both the groups. Positive family history for malignancy (BRCA1- 69.2% vs BRCA2- 36.8%) and incidence of Triple negative histology (BRCA1-82.7% VS 36.8%) were more commonly associated with BRCA1 positivity. Eight patients (11.3%) had synchronous cancer, most common being a contralateral breast primary. 4 patients (5.6%) developed metachronous cancer. Eighty percent of patients were premenopausal at presentation. There was no difference in stage at presentation, incidence of synchronous and metachronous cancers across both the groups. Of 71 patients, 18 (25%) and 17 (24%) patients underwent risk reducing mastectomy and risk reducing oophorectomy respectively. Thirty five (49.3%) presented with stage I & II disease, while 28 (34.4%) and 7 (9.9%) presented with stage III and metastatic disease respectively. Forty seven patients (67.1%) received neoadjuvant chemotherapy with pathologic complete response rate of 42.5% which was uniform among both the groups. Over the study period, 10 (14.1%) patients had disease relapse with 7 (70%) being metastatic and 3 patients died of the disease. With a median follow up of 36.9 months, 3-year disease free survival (DFS) was 84.2% (BRCA1: 81.1% vs BRCA2: 93.1%) and overall survival (OS) was 94.7% for both groups. Median DFS and OS were not achieved. BRCA type, receptor status, age and menopausal status were not predictors of survival in our study. Conclusions: In our study population of BRCA1/BRCA2 mutated breast cancer, survival outcomes were comparable to historical cohorts of Indian breast cancer patients. Thus, BRCA mutation positivity doesn’t seem to have any prognostic significance in breast cancer outcome.

P-484 Oocytes quality assessment in breast cancer: implications for fertility preservation

Abstract Study question Does the breast cancer (BC) influence the oocyte quality and ovarian response to controlled ovarian hyperstimulation (COH) for fertility preservation (FP) in female oncology patients? Summary answer The diagnosis of breast cancer does not seem to be associated with an impairment of ovarian reserve, but with a worsening of oocyte quality. What is known already Fertility preservation in female oncology patients should be integrated as part of management of cancer patient to improve their quality of life. Every day in Italy about 30 new cases of cancer are diagnosed in patients with age under 40 years and BC is the most common malignancy in women undergoing fertility preservation. Currently mature oocyte cryopreservation is a standard technique for fertility. The studies on the outcome of ovarian response after ovarian stimulation in specific cancer patients are limited. Only few reports have suggested a deleterious impact of the oncological disease on quality of follicular growth and ovarian function. Study design, size, duration This is a retrospective single-center case-control study carried out in the IVF (in vitro fertilization) Unit at the Sandro Pertini Hospital in Rome between 2016 and 2021. The aim of this study is to investigate the effect of BC on number, above all on quality of oocyte and on dysmorphic oocyte ratio, in oncology patients compared to women age- and date-matched controls undergoing COH for IVF for male or tubal factor infertility. Participants/materials, setting, methods A total of 294 women were enrolled in the study: 105 women affected by breast cancer in the case group and 189 healthy women in the control group. Boths groups were comparable in terms of age, body mass index (BMI) and antimulleran hormone (AMH) value, E2 level at triggering day, total FSH cumulative dose, stage, histotype, BRCA status and hormone receptors. The primary outcome was number and quality of retrievd oocyte from ovarian pick-up (OPU). Main results and the role of chance There were no significant differences in terms of basal fertility indices between the 2 groups: median AMH levels were 2.3 ng/mL in BC patients and 2.8 ng/mL in control group (p = 0.103). The median length of stimulation was 11 days in both groups. The median of total immature oocytes (oocytes MI + germinal vesicle) was 2 in cancer patients and 0 in control group (p < 0.0001). Finally, the median of total dysmorphic oocytes were 1 in cancer group vs 0 (p < 0.0001). The multivariable analysis identified the cancer as risk factors of presence of dysmorphic oocytes (OR (95%CI):3.92 (1.84-8.35). Moreover either in the case and control group age, BMI, AMH, duration of stimulation, E2 level at triggering day, total FSH cumulative dose and, only for BC patients, stage, histotype, BRCA status and hormone receptors were not statistical significantly associated with the presence of dysmophic oocytes. Finally, our data confirmed that the cancer is the only risk factors not only for the presence of dysmorphic oocytes, but also respect to the number of dysmorphic oocytes and to the percentage of dysmorphic oocytes respect to the total number of retrieved oocytes for patient. Two patients have had a spontaneous pregnancy. Limitations, reasons for caution The limitations concern the paucity of specific cancer group especially BRCA mutated BC patients and the different triggers for induction of final maturation. We still have not a follow up data to evaluate the competence of vitrified MII oocytes for oncology patients and we cannot report information on spontaneous births. Wider implications of the findings The BC diagnosis is a four times greater risk factor in retrieving dysmorphic oocytes, but the stage of BC does not influence the number of retrieved dysmorphic oocytes. Further studies are necessary to evaluate the etiopathogenetic mechanisms underlying oocyte abnormalities in specific group of female oncology patients. Trial registration number 0104898/2020

Abstract CT562: PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of Olaparib to Platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients

Abstract Background: Triple Negative Breast Cancers (TNBC) are a biologically diverse and aggressive subgroup lacking targeted therapy. TNBC and Germline BRCA (gBRCA) breast cancer share certain phenotypic and molecular similarities, with gBRCA mutations seen in 10% to 20% of TNBC patients. Homologous recombination deficient tumours, especially those caused by germline or somatic BRCA mutations, are thought to be particularly sensitive to PARP inhibitors. Aim: To establish if the addition of Olaparib to neoadjuvant Platinum-based chemotherapy in the treatment of basal TNBC and/or gBRCA breast cancer is safe and increases efficacy. Trial design: 3-stage open label randomised phase II/III trial of neoadjuvant Paclitaxel and Carboplatin +/- Olaparib, followed by clinicians' choice of Anthracycline regimen. Stages 1 and 2: Randomisation (1:1:1) to control (3-weekly carboplatin AUC5/weekly with paclitaxel 80mg/m2 for 4 cycles), or to one of two research arms. These use an identical chemotherapy regimen and also include different treatment schedules of Olaparib 150mg BD for 12 days. Stage 3: Randomisation (1:1) to either the control or research arm chosen following stage 2. End-points: Stage 1: Safety; Stage 2: Schedule selection based on pCR rate and Olaparib completion rate using a “pick-the-winner” design. Stage 3: pCR rate. This trial includes an optional pathway (PARTNERING) for patients with evidence of residual disease after six chemotherapy cycles. This aims to establish if the addition of new agents (ATR inhibitor and PD-L1 inhibitor) improves treatment response. Eligibility criteria: Aged 16-70; histologically confirmed invasive breast cancer; ER-negative, HER2-negative with TNBC basal phenotype or gBRCA positive, HER2-negative irrespective of hormone status; stage T1-4 N0-2; performance status 0-1; treatment within 6 weeks of diagnostic biopsy; biomarker scores: TILs, CK 5/6, EGFR +/- AR. Statistical methods: The recruitment of TNBC non-gBRCA and gBRCA patients is independent. Enrichment design is applied with an overall significance level 0.05(α) and 80% power. A minimum of 780 patients will be included to detect an absolute improvement of 15% (all patients and TNBC non-gBRCA cohort) and 20% (gBRCA patients) by combining Olaparib with Platinum based chemotherapy. A minimum of 478 TNBC non-gBRCA and 188 gBRCA patients will be recruited. Each PARTNERING cohort will consist of 15 patients. Current Enrollment: Since May 2016, 756 patients from 30 sites have been enrolled. Stages 1 and 2 are completed. An IDSMC review identified no safety concerns and Research Arm 2 was selected. This arm involves Olaparib administration on days 3-14. Stage 3 Phase I (recruitment of non-gBRCA and gBRCA patients) completed in December 2021. Stage 3 Phase II (recruitment of gBRCA patients only) remains open to patients to UK and internationally. 5 patients have been enrolled in PARTNERING. ClinicalTrials.gov Identifier: NCT03150576 Citation Format: Lynsey Drewett, Karen A. Pinilla, Louise Grybowicz, Jerome Wulff, Alimu Dayimu, Nikolaos Demiris, Rebecca Lucey, Anne-Laure Vallier, Wendi Qian, Andrea Machin, PARTNER Research Team, Karen McAdam, Rebecca Roylance, Ellen R. Copson, Anne Armstrong, Nicola Levitt, Elena Provenzano, Marc Tischkowitz, Emma McMurtry, Helena Earl, Jean E. Abraham. PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of Olaparib to Platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT562.

Abstract OT2-24-01: PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients

Abstract Background: Triple Negative Breast Cancers (TNBC) are a biologically diverse and aggressive subgroup lacking targeted therapy. Germline BRCA (gBRCA) breast cancer and TNBC share some phenotypic and molecular similarities, with 10%-20% of TNBC patients having gBRCA mutations. Homologous recombination deficient tumours are particularly sensitive to PARP inhibitors such as olaparib (Lynparza). It has been shown that adjuvant olaparib for patients with high-risk, HER2-negative early breast cancer and gBRCA pathogenic or likely pathogenic variants after adjuvant or neoadjuvant chemotherapy significantly improves 3-year invasive and distant disease-free survival compared to placebo (OlympiA). Aim: To establish if the addition of olaparib to neoadjuvant platinum based chemotherapy for basal TNBC and/or gBRCA breast cancer is safe and improves efficacy (pathological complete response (pCR) rate). Trial design: 3-stage open label randomised phase II/III trial of neoadjuvant paclitaxel and carboplatin +/- olaparib, followed by clinicians' choice of anthracycline regimen. Stage 1 and 2: Randomisation (1:1:1) to either control (3 weekly carboplatin AUC5/weekly paclitaxel 80mg/m2 for 4 cycles) or one of two research arms with the same chemotherapy regimen but with two different schedules of olaparib 150mg BD for 12 days. Stage 3: Randomisation (1:1) to either control arm or to the research arm selected in stage 2. End-points: Stage 1: Safety; Stage 2: Schedule selection using pCR rate and completion rate of olaparib using a “pick-the-winner” design. Stage 3: pCR rate. This trial includes an optional pathway (PARTNERING) aiming to establish if the addition of new agents (ATR inhibitor and PDL1 inhibitor) can improve response in those patients with evidence of residual disease before surgery. Eligibility criteria: Aged 16-70; histologically confirmed invasive breast cancer; ER-negative, HER2-negative with TNBC basal phenotype or gBRCA positive, HER2-negative irrespective of hormone status; clinical stage T1-4 N0-2; performance status 0-1; treatment commenced within 6 weeks of diagnostic biopsy; biomarker scores: TILs, CK 5/6, EGFR +/- AR. Statistical methods: The recruitment of TNBC non-gBRCA and gBRCA patients is independent. Enrichment design is applied with an overall significance level 0.05(α) and 80% power. A minimum of 780 patients will be included to detect an absolute improvement of 15% (all patients and the TNBC non-gBRCA cohort) and 20% (gBRCA patients) by adding olaparib to platinum based chemotherapy. It is planned to recruit a minimum of 188 gBRCA patients. A maximum of 15 patients will be allocated into each PARTNERING cohort. Present accrual: Recruitment commenced 27 May 2016 and 678 patients from 30 sites have been accrued to date. The IDSMC reviewed the trial after Stages 1 and 2 and recommended to continue the trial without change. Data analysis for Stage 2 revealed no safety concerns and research arm 2 (olaparib on day 3 to day 14) was selected. Stage 3 Phase I recruitment is in progress (recruiting TNBC non-gBRCA and gBRCA patients) and we anticipate moving to Phase II (recruiting gBRCA patients only) by early 2022. Four patients have been accrued to the PARTNERING optional pathway to date. The trial is open and enrolling patients to UK and international sites. Contact information: partner@addenbrookes.nhs.uk Citation Format: Lynsey M Drewett, Karen A Pinilla, Louise Grybowicz, Jerome Wulff, Alimu Dayimu, Nikolaos Demiris, Jessica Martin, Camila Maida de Pontes, Nicola Johnson, Caron Harvey, Erdem Demir, Kimberley St John Green, James Jones, Gemma Young, Anne-Laure Vallier, Wendi Qian, Andrea Machin, Karen McAdam, Rebecca Roylance, Ellen R Copson, Anne Armstrong, Nicola Levitt, Elena Provenzano, Marc Tischkowitz, Emma McMurtry, Helena Earl, Jean E Abraham. PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-24-01.

Abstract PD5-06: Safety of assisted reproductive technologies (ART) following treatment completion in young women with germline BRCA pathogenic variants having a pregnancy after breast cancer

Abstract BACKGROUND: Young breast cancer (BC) survivors are at risk of infertility. Ovarian stimulation for fertility preservation before (neo)adjuvant chemotherapy is standard of care. Research efforts have shown no negative prognostic effect of pregnancy following BC therapy, also among BRCA carriers. Currently, poor evidence is available on the safety to undergo ART following BC treatment, with no data in carriers of germline BRCA pathogenic variants. To provide evidence on the safety of fertility treatments in this specific population, we assessed the outcomes of a cohort of BRCA-mutated BC survivors who had a pregnancy after prior BC history by comparing the group of patients who underwent ART to achieve pregnancy to the group with spontaneous pregnancy. METHODS: We conducted a multicenter retrospective cohort study across 30 centers worldwide including women diagnosed at ≤ 40 years with stage I-III BC, between January 2000 and December 2012, bearing germline BRCA1/2 pathogenic variants. Survivors with a pregnancy (any outcome) after BC, with no disease-free survival (DFS) event before pregnancy, were assigned to the ART and non-ART group if their pregnancy was achieved through ART or spontaneously, respectively. ART procedures included ovulation induction, ovarian stimulation for in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), and embryo transfer under hormonal replacement therapy (HRT). RESULTS: Of 1,424 patients registered in the study, 168 with a pregnancy after BC were included in the present analysis. A total of 22 patients were included in the ART group and 146 in the non-ART group. Before BC diagnosis, 18.2% patients in the ART group had at least one child, compared to 38.4% in the non-ART group (P=0.030). Patients had a median age at BC diagnosis of 33.0 vs 30.2 years old in the ART group and in the non-ART group, respectively (P=0.004); 45.4% and 17.1% had grade 1-2 tumors, respectively (P=0.008), and 59.1% vs 31.5% had hormone receptor-positive tumors, respectively (P=0.016). Both cohorts had similar tumor size and nodal stage characteristics. Type and duration of endocrine therapy were comparable between groups. The type of ART was not specified in 5 survivors (22.7%). Ovulation induction was used in 1 patient (4.5%), ovarian stimulation in 7 patients (31.8%), embryo transfer under HRT following oocyte donation in 5 patients (22.7%), and embryo transfer under HRT following oocyte and/or embryo cryopreservation for fertility preservation in 4 patients (18.2%). Median age at conception among survivors was 39.7 years in the ART group versus 35.4 years in the non-ART group (P<0.001). Overall, no differences in obstetrical outcomes were observed between groups, although there were more delivery complications in the ART group vs the non-ART group (22.1% vs 4.1%, respectively, P=0.011). Median follow-up from pregnancy was 3.4 years (range: 0.8-8.6) for patients in the ART group vs 5.0 years (range: 0.8-17.6) in the non-ART group (P=0.009). In the ART group, 2 patients (9.1%) experienced a DFS event (both were loco-regional recurrences) as compared to 40 patients (27.4%) in the non-ART group (P=0.182). No patients died in the ART group compared to 10 patients (6.9%) in the non-ART group. CONCLUSIONS: To our knowledge, this is the first study assessing the safety of ART in BC survivors bearing germline BRCA pathogenic variants. Even though the exposed cohort was small, results showed that the use of ART does not appear to increase the relapse risk at short-term follow-up. Further reproductive studies in BRCA-mutated BC patients are warranted. Citation Format: Margherita Condorelli, Marco Bruzzone, Marcello Ceppi, Alberta Ferrari, Albert Grinshpun, Anne-Sophie Hamy, Evandro de Azambuja, Estela Carrasco, Fedro A. Peccatori, Antonio Di Meglio, Shani Paluch-Shimon, Philip D. Poorvu, Marta Venturelli, Christine Rousset-Jablonski, Claire Senechal, Luca Livraghi, Riccardo Ponzone, Laura De Marchis, Katarzyna Pogoda, Amir Sonnenblick, Cynthia Villarreal-Garza, Octavi Córdoba, Luis Teixeira, Florian Clatot, Kevin Punie, Rossella Graffeo Galbiati, Maria Vittoria Dieci, Alejandro Pérez-Fidalgo, Francois P. Duhoux, Fabio Puglisi, Arlindo R. Ferreira, Eva Blondeaux, Tamar Peretz-Yablonski, Olivier Caron, Claire Saule, Lieveke Ameye, Judith Balmaña, Ann H. Partridge, Hatem A. Azim, Jr, Isabelle Demeestere, Matteo Lambertini. Safety of assisted reproductive technologies (ART) following treatment completion in young women with germline BRCA pathogenic variants having a pregnancy after breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD5-06.

Tumour-infiltrating CD4-, CD8- and FOXP3-positive immune cells as predictive markers of mortality in BRCA1- and BRCA2-associated breast cancer.

The prognostic value of tumour-infiltrating lymphocytes (TILs) in breast cancer is well-established. However, the investigation of specific T-cell subsets exclusively in BRCA-associated breast cancer is sparse. Tumour tissues from 414 BRCA-mutated breast cancer patients were analysed by immunohistochemistry and digital image analysis for expression of CD4, CD8 and FOXP3 immune markers. Distribution of CD4-, CD8- and FOXP3-positive cells and clinicopathological characteristics were assessed according to groups of low or high expression. The prognostic value was evaluated as continuous variables in univariate and multivariate analyses of overall survival and disease-free survival. Both CD4 and CD8 expression are associated with histological diagnosis, tumour grade and oestrogen and progesterone receptor expression status. CD4 expression is associated with BRCA gene status. A high percentage of tumour-infiltrating CD4-, CD8- or FOXP3-positive cells is significantly associated with lower mortality in BRCA1- and BRCA2-associated breast cancer and CD8-positive cells areassociated with disease-free survival. No heterogeneity according to BRCA gene status was found for the prognostic value of the immune markers. The results support a prognostic role of specific T-cell subsets in BRCA-associated breast cancer and the promising potential of targeting the immune system in the treatment of these patients.

Abstract 12: Localized delivery of the PARP inhibitor Talazoparib for chemoprevention of breast cancer

Abstract Mutations in BRCA genes are the leading cause of hereditary breast cancer and dramatically increase the lifetime risk of developing breast cancer. Anti-estrogen drugs are approved to reduce the risk of developing invasive breast cancer, but they are not effective for women with germline BRCA mutations and are limited by undesirable toxicities. Radical mastectomy provides a surgical option for high-risk patients for cancer prevention, but the physical and emotional challenges of such a radical surgery confirm that alternative approaches are needed. Our goal is to develop novel chemopreventive agents that are effective and safe for BRCA carriers. PARP inhibitors are effective for treating BRCA-mutated breast cancer patients, and we have shown that these drugs significantly delayed tumor development in BRCA-deficient mice. Here, we developed a novel implantable formulation of the PARP inhibitor Talazoparib for local delivery and thus provide a new therapeutic strategy for prevention of breast cancer. Talazoparib (TLZ) was encapsulated into spacer implants (InCeT-TLZ, 25 μg/mm) and is released in a linear manner from the implant over 30 days. When BRCA-deficient breast cancer cells were treated with the InCeT-TLZ implant in vitro, 83.1%±1.4% of the cells were dead after 7 days of treatment. To determine in vivo efficacy, age-matched BRCACo/Co;MMTV-Cre;p53+/-mice were randomized into three groups: empty spacers (2 mm), oral TLZ (50 μg given over 4 weeks), and InCeT-TLZ (50 μg, 2 mm). Using brachytherapy needles, spacers were implanted into mammary glands of the BRCA-deficient mice at 12, 16 and 20 weeks of age, before tumors had developed, and tissues were harvested 4 weeks after implantation. InCeT-TLZ significantly (p<0.05) increased DNA damage by 6.9 fold and decreased proliferation by 51.9% in the mammary gland, determined by γH2AX and PCNA staining, respectively, compared to empty spacer control. Notably, the number of mice (N=33-35/group) that developed hyperplasia in the mammary glands were significantly (p<0.05) lower with InCeT-TLZ spacers (22.9%) compared to the empty spacer group (63.6%) or oral TLZ (57.6%). Moreover, significantly (p<0.05) lower red blood cell counts were observed after oral TLZ treatment but not with InCeT-TLZ. Oral TLZ treatment also induced a significantly lower number of white blood cells (9.6±0.4 K cells/μl) compared to InCeT-TLZ group (11.4±0.6 K cells/μl). This study provides proof of concept for a novel and safe chemopreventive strategy using localized delivery of a PARP inhibitor for high risk individuals. Additional studies will be done to directly evaluate the effects of InCeT-TLZ for preventing tumor development. Work supported by Breast Cancer Research Foundation and HHSN261201800026C. Citation Format: Di Zhang, Bijay Singh, Jessica Moerland, Owen Mitchell, Lizbeth Lockwood, Sarah Carapellucci, Srinivas Sridhar, Karen Liby. Localized delivery of the PARP inhibitor Talazoparib for chemoprevention of breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 12.

Fertility preservation in patients with BRCA mutation.

Evidence suggests a likely negative impact of deleterious BRCA mutations on female fertility. Hence, different studies have aimed to address the reproductive potential and performance of fertility preservation strategies in BRCA-mutated breast cancer patients with a prime focus on their safety and efficacy. However, several uncertainties exist in many domains of this field. The aim of the current paper is to overview the reproductive potential and fertility preservation options in breast and ovarian cancer patients harbouring a BRCA mutation. We also discuss pre-implantation genetic testing in an attempt to help physicians during oncofertility counselling of these patients.

Abstract P3-10-05: Preliminary safety data from stage 1 and 2 of the phase II/III PARTNER trial: Addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients

Abstract Background: Triple negative breast cancers (TNBCs) are an aggressive and diverse subgroup with no specific targeted therapies currently available. Basal TNBCs show some phenotypic and molecular similarities with germline BRCA mutated BC (gBRCA). In gBRCA patients, and potentially other homologous recombination deficiencies, these already compromised pathways may allow PARP inhibitors (olaparib) to work more effectively. PARTNER was designed to establish if the addition of olaparib to neoadjuvant platinum-based chemotherapy for gBRCA and/or basal TNBC is safe and improves efficacy (pathological complete response (pCR)). This is the first time a clinical trial provides safety data of the combination of olaparib with platinum and taxane chemotherapy in an early breast cancer setting. Methods: PARTNER is a 3-stage open label randomised Phase II/III trial of neoadjuvant Carboplatin AUC5 with weekly Paclitaxel 80mg/m2 (CP) +/- olaparib (O) 150mgBD for 12 days x 4 cycles, followed by clinicians' choice of anthracycline regimen x 3 cycles. Basal-TNBC and/or gBRCA patients are eligible for inclusion. Primary endpoints are defined by stage: Stage 1 - Safety, Stage2 - Schedule selection, and Stage 3 - Efficacy (pCR rate). The trial is now powered for efficacy analysis in the BRCA and non-BRCA population independently. Stage 1 and 2 randomization was(1:1:1) to CP: CP + O from day (D) -2: or CP + O from D 3. G-CSF was mandatory during the first 4 cycles of treatment. We present a pooled-safety analysis from Stage 1 and 2 of the two research arms only. Recruitment continues into Stage 3. Results: Between June 2016 and April 2018, 159 patients were recruited among the three arms. Overall, median age was 48.2 [range 22.3- 70.9]; 12% had Tumours >5cm, 34% had Axillary involvement; 17% were gBRCA. Adverse events (AE) that were reported as common (in at least 10% of patients) were Anaemia 23%, Neutropenia 18% and Infection 10%. Fatigue and Diarrhoea were next most prevalent with 9% and 6% respectively. The most common AE Grade >=3 were haematological events. These include Neutropenia 19%, Anaemia 15%, and Thrombocytopenia 5%. Febrile Neutropenia and Haemorrhage were reported in only 2% and 1% of cases. Grade 3 Non- haematological events were Fatigue 7%, Hypertension 3%, Headache 3% and Diarrhoea 2%. Grade 3 Sensory neuropathy was present in 2% of patients. No grade 4 sensory or motor neuropathy events were described. Serious adverse reactions related to investigational regimen were reported in 17% of patients and include fever and infection with 8 and 4 events respectively. No toxicity related deaths were reported. As per July 8th 2019, 373 patients have been recruited from which 58 were gBRCA. Conclusions: Combinations of olaparib with neoadjuvant CP chemotherapy showed an acceptable and manageable toxicity profile. Although haematological events were the most common, they did not exceed historical frequencies reported for standard chemotherapy regimens. Final safety analysis will be performed once recruitment is complete and will include detailed long-term neuropathy data. Citation Format: Karen Pinilla Alba, Emma McMurtry, Anne-Laure Vallier, Louise Grybowicz, Ellen Copson, Anne Armstrong, Rebecca Roylance, Wendi Qian, Nikolaos Demiris, Stanly Thomas, Caron Harvey, Luke Hughes-Davies, Karen McAdam, Paula del Rosario, Bryony Harrop, Elena Provenzano, Marc Tischkowitz, Helena M Earl, Jean E Abraham. Preliminary safety data from stage 1 and 2 of the phase II/III PARTNER trial: Addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-10-05.

316P - Clinicopathologic features of BRCA mutated breast cancer patients: Hacettepe experience

BackgroundImpaired DNA damage response (DDR) mechanisms and subsequent genomic instability is associated with carcinogenic process itself, but it also results in sensitivity of tumor cells to certain drugs and can be exploited to treat cancer by inducing deadly mutations or mitotic catastrophe. As a result, BRCA1/2 testing is recommended for a group individuals with breast/ovarian cancer. MethodsIn this study, we retrospectively invesitigated clinicopathologic features of 303 breast cancer patients tested for BRCA 1/2 mutation in an oncology institute. NCCN recommendations are used to select patients to be tested for BRCA mutations. ResultsA total of 303 patients were analysed for BRCA 1/2 mutations. Median age of the patients at diagnoses were 40 (21-65). Family history for BRCA related cancers were detected in 120 patients (39.6%). BRCA 1/2 mutations have been shown in 98 of 303 patients (32.3%). Of 98 BRCA mutated patients, 43 had pathogenic BRCA1 mutation, 39 had pathogenic BRCA2 mutation, 11 had variant of uncertain significance (VUS) BRCA2 mutation, 3 had VUS BRCA1 mutation and 2 had pathogenic BRCA1 and 2 mutations. Molecular subtypes of tumors have been shown in Table.Table316P Molecular subtypes of tumorsTableBRCA StatusHR(+)/ HER2(-), N(%)HR(+)/ HER2(+), N(%)HR(-)/ HER2(+), N (%)Triple(-), N (%)N/A,N(%)BRCA118 (41.8%)2 (4.6%)022 (51.1%)1 (2.3%)BRCA225 (64.1%)3 (7.7%)06 (15.3%)5 (12.8%)BRCA1 VUS2 (66.7%)001 (33.3%)0BRCA2 VUS11 (100%)0000BRCA1+201 (50%)01 (50%)0BRCA mut (-)126 (61.4%)25 (12.1%)12 (5.8%)32 (15.6%)10 (4.8%)TOTAL182 (60%)31 (10.2%)12 (3.9%)62 (20.4%)16 (5.2%)Twelve of 98 BRCA mutated patients (12.2%) were de novo metastatic while 15 patients (15.3%) faced with metastatic disease during follow-up. In the BRCA mutated group there was significantly high rate of metastatic disease has been detected comparing BRCA non-mutated group (27.5% vs %16.5% respectively, p=0.026). Metastatic BRCA mutant patients showed worse OS numerically but data is not statistically significant (P=0.894). Nine patients were diagnosed with contralateral breast cancer, and 3 patients was diagnosed with BRCA-related cancers during follow-up. Prophylactic surgery (contralateral mastectomy and/or oophorectomy) was performed in 32 of 98 patients. ConclusionsAccording to this retrospective study, BRCA mutant patients tend to have worse clinical and pathological features comparing age-matched controls. Legal entity responsible for the studySercan Aksoy. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

A systematic review of international guidelines and recommendations for the genetic screening, diagnosis, genetic counseling, and treatment of BRCA-mutated breast cancer.

PurposeTo conduct a systematic review of international guidelines on screening and management of patients with BRCA-mutated breast cancer (BC).MethodsMajor electronic databases (MEDLINE and Embase; N=8) and gray literature sources were searched (January 2007 to February 2018). Latest guideline recommendations on genetic screening, counseling, and BC treatment of BRCA mutation carriers were summarized. Guidelines specific to germline BRCA (gBRCA) mutation were captured where available.ResultsA total of 3,775 records were retrieved and 32 guidelines were included; Europe (n=16), USA (n=11), Canada (n=3), Australia (n=1), and Japan (n=1) were included. Across and within guidelines, genetic counseling was recommended at multiple points in the care pathway, though the format was not always clearly defined. US guidelines emphasized that BRCA mutation testing should occur after specialized genetic counseling; other European guidelines are less prescriptive. BRCA testing eligibility criteria differed, with some guidelines being less restrictive; US National Comprehensive Cancer Network (NCCN) BC guidelines specified that HER2-negative BC patients eligible for single-agent therapy are eligible for gBRCA testing. Fast-track BRCA testing is recommended in the Netherlands if treatment choice will affect survival, but in the UK only as part of clinical trials. More recent European (European School of Oncology–European Society for Medical Oncology 3rd International Consensus Guidelines for Breast Cancer in Young Women 2017, Arbeitsgemeinschaft Gynäkologische Onkologie 2017 in Germany) and US (NCCN) guidelines have updated recommendations regarding gBRCA-targeted poly(ADP-ribose) polymerase (PARP) inhibitor therapy in BC.ConclusionRegional and organizational guidelines differ for genetic screening, counseling, and treatment of patients with BRCA-mutated BC. Guideline harmonization would optimize identification and management of these patients.

Abstract OT3-03-03: PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients

Abstract Background: No specific targeted therapies are available for Triple Negative Breast Cancers (TNBC), an aggressive and diverse subgroup. The basal TNBC sub-group share some phenotypic and molecular similarities with germline BRCA (gBRCA) tumours. In gBRCA patients, and potentially other homologous recombination deficiencies, these already compromised pathways may allow drugs called PARP inhibitors (Olaparib) to work more effectively. Aims: To establish if the addition of olaparib to neoadjuvant platinum based chemotherapy for basal TNBC and/or gBRCA breast cancer is safe and improves efficacy (pathological complete response (pCR)). Methods: Trial design: 3-stage open label randomised phase II/III trial of neoadjuvant paclitaxel and carboplatin +/- olaparib, followed by clinicians' choice of anthracycline regimen. Stage 1 and 2: Randomisation (1:1:1) to either control (3 weekly carboplatin AUC5/weekly paclitaxel 80mg/m2 for 4 cycles) or one of two research arms with the same chemotherapy regimen but with two different schedules of olaparib 150mg BD for 12 days. Stage 3: Patients are randomised (1:1) to either control arm or to the research arm selected in stage 2. End-points: Stage 1: Safety; Stage 2: Schedule selection using pCR rate and completion rate of olaparib using a “pick-the-winner” design. Stage 3: pCR rate. Enrichment design is applied with an overall significance level 0.05(α) and 80% power. A total of 527 patients will be included to detect an absolute improvement of 15% (all patients) and 20% (gBRCA patients) by adding olaparib to platinum based chemotherapy. Trial Progress: PARTNER has been recruiting in UK since 27th May 2016. IDSMC recommended to continue the trial without change after reviewing the Stage 1 safety data. The recruitment of stage 2 was completed in April 2018 and results to be reviewed by the IDSMC in early 2019. The trial is open and enrolling patients to national and international sites. Citation Format: Abraham J, Vallier A-L, Qian W, Machin A, Grybowicz L, Thomas S, Weiss M, Harvey C, McAdam K, Hughes-Davies L, Roberts A, Roylance R, Copson E, Pinilla K, Armstrong A, Provenzano E, Tischkowitz M, McMurty E, Earl H. PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-03-03.

Knowledge, attitudes and practice of physicians towards fertility and pregnancy-related issues in youngBRCA-mutated breast cancer patients.

This study explored the knowledge, attitudes and practice of physicians towards fertility and pregnancy-related issues in young BRCA-mutated breast cancer patients. Physicians attending two international breast cancer conferences completed a 26-item questionnaire exploring fertility preservation, pregnancy during (BCP) or after breast cancer. A statistical comparison was carried out of the responses exploring the same issues in young breast cancer patients overall or specifically in those with BRCA mutations. The survey was completed by 273 physicians. Ovarian tissue cryopreservation (33% versus 40%; P=0.009) and gonadotrophin-releasing hormone analogues during chemotherapy (74% versus 81%; P=0.001) were less commonly suggested in BRCA-mutated patients than in the overall breast cancer population. 42% of respondents agreed or were neutral on the statement that ovarian stimulation should not be considered safe in BRCA-mutated breast cancer patients. 45% and 30% agreed or were neutral on the statement that pregnancy in breast cancer survivors may increase the risk of recurrence in BRCA-mutated patients or in the overall breast cancer population, respectively (P<0.001). 15% and 3% disagreed that transplanting the cryopreserved ovarian tissue can be considered safe in BRCA-mutated patients or in the overall breast cancer population, respectively (P<0.001). 33.3% were against the addition of platinum agents as neoadjuvant chemotherapy in BRCA-mutated patients with BCP. Several misconceptions on fertility preservation and pregnancy-related issues in breast cancer patients persist even among physicians directly involved in breast cancer care. Focused research efforts to address these issues in BRCA-mutated breast cancer patients and education to improve physicians' knowledge and adherence to available guidelines are urgently needed.

Subtypes in BRCA-mutated breast cancer

Approximately 3% to 5% of breast cancer patients are BRCA1 or BRCA2 germline mutation carriers. In this study, we correlated the distribution of intrinsic molecular subtypes according to failure pattern in a Danish cohort of BRCA germline–mutated breast cancer patients. Tumor tissues from 425 BRCA germline–mutated breast cancer patients were analyzed by immunohistochemistry for hormone receptor status, proliferation index (Ki-67), and HER2. Surrogate intrinsic molecular subtypes were assigned according to approximated St Gallen criteria. Annual hazard rates (AHR) were calculated for death and local or distant relapse, contralateral breast cancer, new primary cancer other than breast cancer, or death as first event (disease-free event). Luminal A–like subtype was observed with a frequency of 9% and 35% for BRCA1 and BRCA2, respectively, and for both BRCA1 and BRCA2 patients, the luminal B–like subtype was more frequent than the luminal A–like subtype (BRCA1 21% and BRCA2 40% luminal B–like). No events or deaths were observed for luminal A–like subtype during the first 2.5 and 0 to 5 years, respectively. AHRs for luminal B–like tumors were 5.34% (95% confidence interval [CI], 1.49-1.19) and 1.76% (95% CI, 0.36-3.16) for disease-free event and death, respectively, and those for basal-like were 6.58% (95% CI, 2.98-10.18) and 4.54% (95% CI, 2.69-6.40). A substantial proportion of BRCA carriers had luminal A–like subtype, and these were mainly BRCA2 carriers. Luminal A–like subtype was significantly associated with low AHR the first 5 years after surgery. This study warrants further exploration of the impact of the molecular intrinsic subtypes on survival in BRCA-mutated breast cancer patients.

PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients.

PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients.

Abstract OT3-04-03: PARTNER randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients

Abstract Background: No specific targeted therapies are available for Triple Negative Breast Cancers (TNBC), an aggressive and diverse subgroup. The basal TNBC subgroup show some phenotypic and molecular similarities with germline BRCA (gBRCA). In gBRCA patients, and potentially other homologous recombination deficiencies, these already compromised pathways may allow drugs called PARP inhibitors (olaparib) to work more effectively. Aims: To establish if the addition of olaparib to neoadjuvant platinum based chemotherapy for basal TNBC and/or gBRCA breast cancer is safe and improves efficacy (pathological complete response (pCR)). Trial design: 3 stage open label randomised phase II/III trial of neoadjuvant paclitaxel and carboplatin +/olaparib, followed by clinicians' choice of anthracycline regimen. Stage 1 and 2: Patients are randomised (1:1:1) to either control (3 weekly carboplatin AUC5/weekly paclitaxel 80mg/m2 for 4 cycles) or one of two research arms with the same chemotherapy regimen but with two different schedules of olaparib 150mg BD for 12 days. Stage 3: Patients are randomised (1:1) to either control arm or to the research arm selected in stage 2. Methods: Stage 1 Safety: both research arms combined. Stage 2 Schedule selection criteria: pCR rate and completion rate of olaparib protocol treatment. It is a “pickthewinner” design with 53 patients in each research arm. This allows a 90% power, 5% onesided significance level to test null hypothesis of pCR ≤35% versus an alternative hypothesis of pCR ≥55% in each of the research arms. Stage 3 Efficacy:anticipated pCR ˜55-60% for all trial patients and ˜60-65% for gBRCA patients. The trial is powered to detect an absolute improvement of 15% (all patients) and 20% (gBRCA patients) by adding olaparib to chemotherapy (enriched design). TNBC patient recruitment will be capped, to ensure required gBRCA patients are enrolled. Enrichment design is applied with overall significance level 0.05(α) = 0.025(αall)+ 0.025(αgBRCA) and 80% power. Target accrual: 527 [gBRCA 220] Current accrual: 56 Sites activated: 15 [expected number of sites 30-50]. Citation Format: Abraham J, Vallier A-L, Qian W, Grybowicz L, Thomas S, Machin A, Harvey C, Chiu E, McAdam K, Hughes-Davies L, Roylance R, Copson E, Armstrong A, Provenzano E, Tischkowitz M, McMurtry E, Earl H. PARTNER randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-04-03.

Reproductive potential and performance of fertility preservation strategies in BRCA-mutated breast cancer patients

Preclinical evidence suggests a possible negative impact of deleterious BRCA mutations on female fertility. However, limited and rather conflicting clinical data are available. This study assessed the reproductive potential and performance of fertility preservation strategies in BRCA-mutated breast cancer patients. This was a retrospective analysis of two prospective studies investigating oocyte cryopreservation and ovarian tissue cryopreservation in newly diagnosed early breast cancer patients. In the current analysis, baseline anti-Mullerian hormone (AMH) and performance of cryopreservation strategies were compared between patients with or without germline deleterious BRCA mutations. Out of 156 patients included, 101 had known BRCA status of whom 29 (18.6%) were BRCA-mutated and 72 (46.1%) had no mutation. Median age in the entire cohort was 31 years [interquartile range (IQR) 28-33). Median AMH levels were 1.8 μg/l (IQR 1.0-2.7) and 2.6 µg/l (IQR 1.5-4.1) in the BRCA-positive and BRCA-negative cohorts, respectively (P = 0.109). Among patients who underwent oocyte cryopreservation (N = 29), women in the BRCA-positive cohort tended to retrieve (6.5 versus 9; P = 0.145) and to cryopreserve (3.5 versus 6; P = 0.121) less oocytes than those in the BRCA-negative cohort. Poor response rate (i.e. retrieval of ≤4 oocytes) was 40.0% and 11.1% in the BRCA-positive and BRCA-negative cohorts, respectively (P = 0.147). Among patients who underwent ovarian tissue cryopreservation (N = 72), women in the BRCA-positive cohort tended to have a numerically lower number of oocytes per fragment (0.08 versus 0.14; P = 0.193) and per square millimeter (0.33 versus 0.78; P = 0.153) than those in the BRCA-negative cohort. Two BRCA-mutated patients were transplanted after chemotherapy and one delivered at term a healthy baby. No difference between BRCA1- and BRCA2-mutated patients was observed in any of the above-mentioned outcomes. A consistent trend for reduced reproductive potential and performance of cryopreservation strategies was observed in BRCA-mutated breast cancer patients. Independent validation of these results is needed.