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Background: The GeparOLA study was designed to evaluate the efficacy and safety of the combination of paclitaxel (P) plus olaparib (O) as part of neoadjuvant chemotherapy (NACT) in patients with human epidermal growth factor receptor 2 (HER2)-negative, either hormone receptor (HR)-positive or HR-negative and homologous recombination deficiency (HRD) defined as having a g/tBRCA mutation and/or a high HRD score. Primary analysis showed a pCR rate of 55.1% (90% CI 44.5%-65.3%) with PO and 48.6% (90% CI 34.3%-63.2%) with P plus carboplatinum (Cb). The PO combination could not exclude a pCR rate of ≤55% in the PO arm but was significantly better tolerated. Analysis on the stratified subgroups showed higher pCR rates with PO in the cohorts of patients < 40 years and HR-positive tumors (Fasching Ann Oncol 2020). Here, we report long-term data. Methods: GeparOLA (NCT02789332) was a non-comparative, multicenter, prospective, randomized, open-label, phase II trial. Patients with primary HER2-negative breast cancer, HRD and indication for chemotherapy (cT2-cT4a-d or cT1c and cN+ or cT1c and pNSLN+ or cT1c and TNBC or cT1c and Ki-67 >20%) were randomly assigned to receive either P 80 mg/m2 weekly plus O 100 mg twice daily for 12 weeks or P plus Cb area under the curve 2 (AUC2) weekly for 12 weeks, both followed by four cycles of either 2-weekly or 3-weekly epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2. Primary endpoint was pCR (ypT0/is ypN0) rate after NACT with PO followed by EC. Long-term efficacy endpoints included invasive disease-free survival (iDFS), distant disease-free survival (DDFS) and overall survival (OS). The time-to-event endpoints analysis is planned with median follow-up of at least 4 years and a follow-up completeness of at least 80%. Results: Between September 2016 and July 2018, 274 patients were screened, of whom 107 were randomized and 106 (PO N=69; PCb N=37) started treatment. The median age was 47.0 years (range 25.0-71.0); 32 patients were aged < 40 years; 36.2% of patients had cT1 tumors and 31.8% were cN-positive; the majority (86.8%) had grade 3 tumors and a Ki-67>20% (89.6%). Seventy-seven patients (72.6%) had TNBC. After a median follow-up of 49.8 months (range 0.1-69.1), 18 (15 in PO; 3 in PCb) iDFS events and 7 (6 in PO; 1 in PCb) deaths were reported. The 4-year survival rates are shown in the table below. iDFS (HR PO to PCb=2.86 [95%CI 0.83-9.9], log-rank p=0.081), DDFS (HR =3.03 [95%CI 0.67-13.67], log-rank p=0.129), and OS (HR=3.27 [95%CI 0.39-27.2], log-rank p=0.244) tended to be inferior with olaparib. Patients without g/tBRCA mutation seem to benefit from the use of carboplatinum (7/30 iDFS/DDFS events in PO; 0/16 in PCb, log-rank p=0.037, HR n.a.). Conclusions: In patients with HER2-negative and HRD breast cancer the use of olaparib instead of carboplatinum although showing comparable pCR rates, tended to result in an overall inferior outcome. This was mainly driven by the patients without a g/tBRCA mutation. In patients with a g/t BRCA mutation no difference between olaparib and carboplatinum was seen. Key words: Olaparib, HER2-negative breast cancer, HRD, survival Funding: The study was financially supported by AstraZeneca Citation Format: Peter A. Fasching, Sabine Schmatloch, Jan Hauke, Julia Rey, Christian Jackisch, Peter Klare, Theresa Link, Claus Hanusch, Jens Huober, Andrea Stefek, Sabine Seiler, Wolfgang D. Schmitt, Christoph Uleer, Gabriele Doering, Kerstin Rhiem, Andreas Schneeweiss, Carsten Denkert, Rita K. Schmutzler, Eric Hahnen, Michael Untch, Valentina Nekljudova, Jens-Uwe Blohmer, Sibylle Loibl. Neoadjuvant paclitaxel/olaparib in comparison to paclitaxel/carboplatinum in patients with HER2-negative breast cancer and homologous recombination deficiency – long-term survival of the GeparOLA study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-06-13.

IMPORTANCE: Adjuvant denosumab might improve disease-free survival in hormone receptor (HR)–positive primary breast cancer (BC). The optimal neoadjuvant nab-paclitaxel schedule in terms of efficacy and safety is unclear. OBJECTIVE: To determine whether adding denosumab to anthracycline/taxane-containing neoadjuvant chemotherapy (NACT) increases the pathological complete response (pCR) rate and which nab-paclitaxel schedule is more effective in the NACT setting. DESIGN, SETTING, AND PARTICIPANTS: The GeparX was a multicenter, prospective, open-label, phase 2b, 2 × 2 randomized clinical trial conducted by GBG and AGO-B at 38 German sites between February 2017 and March 2019. The analysis data set was locked September 4, 2020; analysis was completed November 13, 2020. Patients had unilateral or bilateral primary BC, stage cT2-cT4a-d or cT1c, with either clinically node-positive or pathologically node-positive or HR-negative disease, or Ki-67 proliferation index greater than 20%, or ERBB2 (formerly HER2)–positive BC. INTERVENTIONS: Patients were randomized to receive or not receive denosumab, 120 mg subcutaneously every 4 weeks for 6 cycles, and either nab-paclitaxel, 125 mg/m(2) weekly for 12 weeks or days 1 and 8 every 3 weeks for 4 cycles (8 doses), followed by 4 cycles of epirubicin/cyclophosphamide, 90/600 mg/m(2) (every 2 weeks or every 3 weeks). Carboplatin was given in triple-negative BC (TNBC), and trastuzumab biosimilar ABP980 plus pertuzumab was given in ERBB2-positive BC (ERBB2-positive substudy). MAIN OUTCOMES AND MEASURES: The primary outcome was pCR rates between arms for each randomization. RESULTS: A total of 780 female (n = 779) and male (n = 1) patients (median [range] age, 49.0 [22-80] years) were randomized to the 4 treatment groups. The pCR (ypT0 ypN0) rate was 41.0% (90% CI, 37%-45%) with denosumab vs 42.8% (90% CI, 39%-47%) (P = .58) without denosumab, irrespective of BC subtype. Nab-paclitaxel weekly resulted in a significantly (significance level of α = .10) higher pCR rate of 44.9% (90% CI, 41%-49%) vs 39.0% (90% CI, 35%-43%) (P = .06) with nab-paclitaxel days 1 and 8 every 3 weeks. The pCR rates for nab-paclitaxel schedules in subgroups were only significantly different for TNBC (60.4% vs 50.0%; P = .06). Grade 3 to 4 toxic effects did not differ with or without denosumab. Nonhematologic toxic effects of grade 3 to 4 were higher with nab-paclitaxel weekly (33.7% vs 24.1%; P = .004). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, denosumab added to anthracycline/taxane-based NACT did not improve pCR rates. Nab-paclitaxel at a dosage of 125 mg/m(2) weekly significantly increased the pCR rate compared with the days 1 and 8, every-3-weeks schedule overall and in TNBC, but generated higher toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02682693

Background: Neoadjuvant chemotherapy (NACT) is standard of care for patients with triple-negative breast cancer (TNBC). Treatment response, especially pathologic complete response (pCR), is a strong predictive factor for treatment outcome. In the setting of up-front surgery, retrospective data have suggested improved outcome in patients with early TNBC that received breast-conserving surgery with adjuvant radiotherapy (BCT) as compared to mastectomy. Methods: We identified 2632 patients with early TNBC from the German Breast Group meta-database. Patients with cT1-2 cN0 and ypN0, available surgery and follow-up data were eligible for this project. A total of 1074 patients from 8 prospective NACT trials were analyzed. Endpoints of interest were locoregional recurrence as first site of relapse (LRR, other sites of recurrence were considered competing events), disease-free survival (DFS) and overall survival (OS); analyses were performed using univariate and multivariate Fine-Gray (for LRR) and Cox models including study, age, cT, surgery type and pCR. For the analyses including pCR as covariable, only patients at risk at the landmark time were evaluated. Results: Median age was 48 years, 69.6% of patients had cT2 tumors and 85.3% underwent BCS. Of the 1074 analyzed patients, 48.8% achieved pCR. After a median follow-up of 64 months, there were 94 (8.8%) locoregional events as first site of relapse. Upon univariate analysis, absence of pCR (hazard ratio [HR]=2.28; 95%CI 1.44-3.61; p< 0.001) and ypT-stage (ypT0/is vs. ypT1-3, HR=0.61; 95%CI 0.40-0.95; p=0.028) were significantly associated with LRR, while type of surgery, age and cT-stage were not. Upon multivariate analysis, absence of pCR was the only factor associated with increased risk of LRR (HR=2.22; 95%CI 1.38-3.58; p=0.001). Patients that underwent mastectomy (N=158) were significantly younger (age ≤ 50 years 72.8% vs. 59.9% for BCT [N=916]; p=0.002) DFS and OS was significantly better in patients who underwent BCT compared to mastectomy (DFS: HR=0.47; 95%CI 0.34-0.66; p< 0.001 and OS: HR=0.40; 95%CI 0.26-0.63; p< 0.001). In multivariate analysis, BCT was associated with a significantly better DFS and OS as compared to mastectomy (DFS: HR=0.51; 95%CI 0.36-0.72; p< 0.001; and OS HR=0.43; 95%CI 0.27-0.68; p< 0.001), whereas absence of pCR was associated with significantly worse DFS and OS (DFS: HR=2.43; 95%CI 1.78-3.31; p< 0.001; and OS: HR=3.15; 95%CI 1.94-5.10; p< 0.001). Conclusions: In this retrospective analysis from the GBG meta-database, treatment response, e.g. pCR, was the main determinant of locoregional recurrence in patients with early stage TNBC treated with NACT. BCT was associated with improved DFS and OS compared to mastectomy, which may at least in part reflect favorable patient selection. Citation Format: David Krug, Valentina Vladimirova, Michael Untch, Thorsten Kühn, Andreas Schneeweiss, Carsten Denkert, Beyhan Ataseven, Christine Solbach, Bernd Gerber, Hans Tesch, Michael Golatta, Sabine Seiler, Jörg Heil, Valentina Nekljudova, Sibylle Loibl. PD15-06 Pathologic complete response and breast-conserving surgery are associated with improved prognosis in patients with early-stage triple-negative breast cancer treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD15-06.

Summary Background The development of anti-HER2 antibody–drug conjugates opens new therapeutic options for patients with breast cancer, including patients with low expression of HER2. To characterise this new breast cancer subtype, we have compared the clinical and molecular characteristics of HER2-low-positive and HER2-zero breast cancer, including response to neoadjuvant chemotherapy and prognosis. Methods In this pooled analysis of individual patient data, we evaluated a cohort of 2310 patients with HER2-non-amplified primary breast cancer that were treated with neoadjuvant combination chemotherapy in four prospective neoadjuvant clinical trials (GeparSepto, NCT01583426 ; GeparOcto, NCT02125344 ; GeparX, NCT02682693 ; Gain-2 neoadjuvant, NCT01690702 ) between July 30, 2012, and March 20, 2019. Central HER2 testing was done prospectively before random assignment of participants in all trials. HER2-low-positive status was defined as immunohistochemistry (IHC) 1+ or IHC2+/in-situ hybridisation negative and HER2-zero was defined as IHC0, based on the American Society of Clinical Oncology/College of American Pathologists guidelines. Disease-free survival and overall survival data were available for 1694 patients (from all trials except GeparX) with a median follow-up of 46·6 months (IQR 35·0–52·3). Bivariable and multivariable logistic regression models and Cox-proportional hazards models were performed based on a predefined statistical analysis plan for analysis of the endpoints pathological complete response, disease-free survival, and overall survival. Findings A total of 1098 (47·5%) of 2310 tumours were HER2-low-positive and 1212 (52·5%) were HER2-zero. 703 (64·0%) of 1098 patients with HER2-low-positive tumours were hormone receptor positive, compared with 445 (36·7%) of 1212 patients with HER2-zero tumours (p Interpretation Our results show that HER2-low-positive tumours can be identified as new subgroup of breast cancer by standardised IHC, distinct from HER2-zero tumours. HER2-low-positive tumours have a specific biology and show differences in response to therapy and prognosis, which is particularly relevant in therapy-resistant, hormone receptor-negative tumours. Our results provide a basis for a better understanding of the biology of breast cancer subtypes and the refinement of future diagnostic and therapeutic strategies. Funding German Cancer Aid (Deutsche Krebshilfe).

Background: The GeparOLA study was designed to evaluate the efficacy and safety of the combination of paclitaxel (P) plus olaparib (O) as part of neoadjuvant chemotherapy (NACT) in patients with human epidermal growth factor receptor 2 (HER2)-negative, either hormone receptor (HR)-positive or HR-negative and homologous recombination deficiency (HRD) defined as having a g/tBRCA mutation and/or a high HRD score. Primary analysis showed a pCR rate of 55.1% (90% CI 44.5%-65.3%) with PO and 48.6% (90% CI 34.3%-63.2%) with P plus carboplatinum (Cb). The PO combination could not exclude a pCR rate of ≤55% in the PO arm but was significantly better tolerated. Analysis on the stratified subgroups showed higher pCR rates with PO in the cohorts of patients < 40 years and HR-positive tumors (Fasching Ann Oncol 2020). Here, we report long-term data. Methods: GeparOLA (NCT02789332) was a non-comparative, multicenter, prospective, randomized, open-label, phase II trial. Patients with primary HER2-negative breast cancer, HRD and indication for chemotherapy (cT2-cT4a-d or cT1c and cN+ or cT1c and pNSLN+ or cT1c and TNBC or cT1c and Ki-67 >20%) were randomly assigned to receive either P 80 mg/m2 weekly plus O 100 mg twice daily for 12 weeks or P plus Cb area under the curve 2 (AUC2) weekly for 12 weeks, both followed by four cycles of either 2-weekly or 3-weekly epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2. Primary endpoint was pCR (ypT0/is ypN0) rate after NACT with PO followed by EC. Long-term efficacy endpoints included invasive disease-free survival (iDFS), distant disease-free survival (DDFS) and overall survival (OS). The time-to-event endpoints analysis is planned with median follow-up of at least 4 years and a follow-up completeness of at least 80%. Results: Between September 2016 and July 2018, 274 patients were screened, of whom 107 were randomized and 106 (PO N=69; PCb N=37) started treatment. The median age was 47.0 years (range 25.0-71.0); 32 patients were aged < 40 years; 36.2% of patients had cT1 tumors and 31.8% were cN-positive; the majority (86.8%) had grade 3 tumors and a Ki-67>20% (89.6%). Seventy-seven patients (72.6%) had TNBC. After a median follow-up of 49.8 months (range 0.1-69.1), 18 (15 in PO; 3 in PCb) iDFS events and 7 (6 in PO; 1 in PCb) deaths were reported. The 4-year survival rates are shown in the table below. iDFS (HR PO to PCb=2.86 [95%CI 0.83-9.9], log-rank p=0.081), DDFS (HR =3.03 [95%CI 0.67-13.67], log-rank p=0.129), and OS (HR=3.27 [95%CI 0.39-27.2], log-rank p=0.244) tended to be inferior with olaparib. Patients without g/tBRCA mutation seem to benefit from the use of carboplatinum (7/30 iDFS/DDFS events in PO; 0/16 in PCb, log-rank p=0.037, HR n.a.). Conclusions: In patients with HER2-negative and HRD breast cancer the use of olaparib instead of carboplatinum although showing comparable pCR rates, tended to result in an overall inferior outcome. This was mainly driven by the patients without a g/tBRCA mutation. In patients with a g/t BRCA mutation no difference between olaparib and carboplatinum was seen. Key words: Olaparib, HER2-negative breast cancer, HRD, survival Funding: The study was financially supported by AstraZeneca Citation Format: Peter A. Fasching, Sabine Schmatloch, Jan Hauke, Julia Rey, Christian Jackisch, Peter Klare, Theresa Link, Claus Hanusch, Jens Huober, Andrea Stefek, Sabine Seiler, Wolfgang D. Schmitt, Christoph Uleer, Gabriele Doering, Kerstin Rhiem, Andreas Schneeweiss, Carsten Denkert, Rita K. Schmutzler, Eric Hahnen, Michael Untch, Valentina Nekljudova, Jens-Uwe Blohmer, Sibylle Loibl. Neoadjuvant paclitaxel/olaparib in comparison to paclitaxel/carboplatinum in patients with HER2-negative breast cancer and homologous recombination deficiency – long-term survival of the GeparOLA study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS5-02.

515 Background: Overall a diagnosis of breast cancer during pregnancy (BCP) appears not to impact maternal prognosis if standard treatment is offered. However, caution is warranted as gestational changes in pharmacokinetics with respect to the distribution, metabolism and excretion of drugs may lead to reduced chemotherapy concentration in pregnant patients. This cohort study was designed to focus on the maternal prognosis of BCP patients that receive chemotherapy during pregnancy. Methods: The outcome of BCP patients treated with chemotherapy during pregnancy was compared to non-pregnant breast cancer patients treated with chemotherapy, diagnosed after 2000, excluding postpartum diagnosis and with an age limit of 45 years. The data was registered by two multicentric registries (the International Network of Cancer, Infertility and Pregnancy and the German Breast Cancer Group) that collect both retro-and prospectively breast cancer data. Cox proportional hazards regression was used to compare disease-free (DFS) and overall survival (OS) between both groups, adjusting for age, stage, grade, hormone receptor status, human epidermal growth factor 2 status and histology, weighted by propensity scoring in order to account for the differences in baseline characteristics between pregnant patients and controls. Results: In total, 662 pregnant and 2081 non-pregnant patients, were eligible for analysis. Median age at diagnosis was 34 (range 22-47) years for pregnant and 38 (range 19-45) years for non-pregnant patients. Pregnant patients were more likely to have stage II breast cancer (60.1% vs 56.1%, p = 0.035), grade 3 tumors (74.0% vs 62.2%, p < 0.001), hormone receptor-negative tumors (48.4% vs 34.0%, p < 0.001) or triple-negative breast cancer (38.9% vs 26.9%, p < 0.001). Median follow-up was 66 months. DFS and OS were comparable for pregnant and non-pregnant patients (DFS: HR 1.02, 95%CI 0.82-1.27, p = 0.83; OS: HR 1.08, 95% CI 0.81-1.45, p = 0.59). A subgroup analysis of 339 women that received more than 60% of chemotherapy during pregnancy (cut-off at median) revealed a comparable survival compared to non-pregnant women (DFS: HR 0.81, 95%CI 0.62-1.06, p = 0.13; OS: HR 0.85 95% CI 0.58-1.23, p = 0.39). Conclusions: Pregnancy-induced alternations in chemotherapy concentration do not seem to affect maternal prognosis in breast cancer patients. These results support initiation of chemotherapy for BCP where indicated for oncological reasons.

ObjectivesTo characterise factors associated with permanent vision loss (PVL) and potential reasons for the therapeutic delay contributing to PVL in giant cell arteritis (GCA).MethodsRetrospective analysis of GCA patients diagnosed at the University Hospital Basel between December 2006 and May 2021.ResultsOf 282 patients with GCA (64% females), 49 (17.4%) experienced PVL. In 43/49 (87.8%) PVL occurred before treatment. Of these, 24 (55.8%) patients had first non-ocular symptoms and eventually sought consultation when PVL occurred in a median of 21 (IQR 14.75–31.0) days after the first symptoms. Only five of the 24 patients had consulted a physician before PVL, but GCA diagnosis was missed. Treatment was initiated rapidly after diagnosis (median 1 day (IQR 0.0–7.0)). PVL on therapy occurred in six patients in a median of 40 (IQR 20.5–67.3) days after treatment started. In two of those, glucocorticoids were tapered too quickly.In multivariable analysis, patients with PVL were older (OR 1.17, 95% CI 1.07 to 1.29, p=0.001) and reported more frequently jaw claudication (OR 3.52, 95% CI 1.02 to 13.16, p=0.051). PVL was present in 18 (42.9%) of the 42 patients with vasculitic ultrasound findings in all six temporal artery segments. The incidence of PVL over 15 years did not decline (Spearman rank=0.3, p=0.68).ConclusionThe prevalence of GCA-associated PVL remains high. Associated factors were advanced age, jaw claudication and ultrasound findings consistent with vasculitis in all six temporal artery segments. Despite preceding non-ocular GCA symptoms weeks before the onset of PVL, most patients were not seen by a rheumatologist before PVL occurred.

Background: TNBC is associated with higher percentages of pathological complete response (pCR) to neoadjuvant chemotherapy (NAC), and women with a pCR have a favorable prognosis. However, previous studies have found that women with residual disease have a substantially higher risk of recurrence than women with other subtypes of breast cancer. Additionally, other recent studies have found that therapeutic blockade of PD-L1 binding by atezolizumab has resulted in relevant anti-tumor efficacy. Design This is a phase III, double blind, placebo-control trial evaluating neoadjuvant atezolizumab with NAC followed by adjuvant atezolizumab in TNBC. Pts are stratified by region (North America; Europe), tumor size (1.1-3.0cm; >3.0cm), AC/EC schedule (q2w; q3w), nodal status (positive; negative), and PD-L1 status (positive; negative or indeterminate) then randomized 1:1 to receive atezolizumab/placebo 1200 mg IV every 3 wks concurrently with both sequential regimens of weekly paclitaxel 80 mg/m2 IV for 12 doses with every 3-wk carboplatin AUC of 5 IV for 4 doses followed by AC/EC every 2-3 wks (per investigator discretion) for 4 cycles. Following surgery, pts resume atezolizumab/placebo 1200 mg IV every 3 wks as adjuvant therapy for 6 months. Radiotherapy based on local standards is co-administered with atezolizumab/placebo. Eligibility criteria Centrally-confirmed ER-neg, PR-neg, HER2-neg invasive breast cancer by ASCO/CAP guidelines. Primary tumor must be stage T2 or T3 if cN0 or cN1 with negative biopsy or T1c, T2, or T3 if cN1 with positive biopsy or cN2 or cN3. LVEF >55% and no significant cardiac history. Statistical methods Co-primary endpoints are event-free survival (EFS) and pCR breast/nodes. Secondary endpoints include pCR breast, overall survival, distant disease-free survival, safety and toxicity. Trial is an academic collaboration between NSABP and GBG with support from Genentech/Roche. As of 7-8-19, 279/1,520 pts have been randomized. NCT03281954 Support: Genentech/Roche. Citation Format: Charles E Geyer Jr., Sibylle Loibl, Priya Rastogi, Sabine Seiler, Joseph P Costantino, Valentina Nekljudova, Patricia Cortazar, Peter C Lucas, Carsten Denkert, Eleftherios P Mamounas, Christian Jackish, Norman Wolmark. A randomized double-blind phase III clinical trial of neoadjuvant chemotherapy (NAC) with atezolizumab or placebo in patients (pts) with triple negative breast cancer (TNBC) followed by adjuvant atezolizumab or placebo: NSABP B-59/GBG 96-GeparDouze [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 OT2-04-08.

Introduction Breast cancer diagnosed in young women who are 40 years (yrs) or younger is a relatively rare disease. However, it represents the most common cause of cancer-related deaths in this age-group. Furthermore, young age at diagnosis is associated with an increased risk of recurrence and worse survival. To date, general concepts concerning oncological cancer management should be driven by clinicopathological tumor characteristics and should adhere to standardized protocols for patients in general, but little is known about the oncological cancer treatment and outcome of this very young women in today's clinical practice. Patients and Methods The breast cancer in pregnancy registry study (BCP/GBG29/BIG 03-02) is a multicenter, international, observational study. BCP was established to investigate the oncological management and outcome of breast cancer in pregnancy. Since 2014 non-pregnant patients who are 40 yrs or younger are eligible if diagnosed with histological confirmed invasive breast cancer, independent of the type of treatment as control cohort. All patients received oncological treatment according to local standards. In this study the following endpoints will be analyzed descriptively for the young non-pregnant women cohort: breast cancer staging at diagnosis, biological characteristics of breast cancer at diagnosis, diagnostic procedures, treatment modalities, toxicity, pathological complete response after neoadjuvant chemotherapy, disease-free survival and overall survival. Results From February 2014 until June 2018, 969 non-pregnant patients ≤40 yrs have been registered. The median age at diagnosis was 35 yrs (range 19-40). Overall, 90.1% of patients had a stage T1-2 at diagnosis and 67.1% of patients had negative lymph nodes. 86.7% of tumors were invasive ductal carcinomas and 4.1% lobular carcinomas. Grading (G) 3 was reported in 55.5%. 26.6% of tumors were luminal A-like (ER- and/or PgR-positive, HER2-negative, G1-2), 40.0% luminal B-like (ER- and/or PgR-positive, HER2-negative, G3 or ER- and/or PgR-positive, HER2-positive, any G), 7.7% HER2 positive non-luminal-like, and 25.7% triple negative breast cancers. 3.8% of young non-pregnant patients had metastatic disease at primary diagnosis. Conclusion This registry comprises a large cohort of young non-pregnant patients with breast cancer diagnosed at the age of 40 yrs or younger and provides important data about a modern breast cancer treatment as well as oncological outcome in this setting of young women. Further results including oncological management, toxicity, and survival will be presented at the meeting. Citation Format: Seiler S, Schmatloch S, Reinisch M, Neunhöffer T, Schmidt M, Bechtner C, Marmé F, Wagner M, Möbus V, Reimer T, Kleine-Tebbe A, Sinn B, Stickeler E, Untch M, Janni W, Seither F, Loibl S. Cancer management and outcome of very young non-pregnant patients with breast cancer diagnosed at 40 years or younger– GBG 29 [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 P1-17-07.

Young women receiving chemotherapy for early breast cancer (EBC) have a high probability for ovarian failure, defined by chemotherapy-induced amenorrhea (CIA) as a surrogate. CIA is insufficiently reliable and reproducible. We analysed chemotherapy-induced ovarian failure (CIOF) by assessing hormone parameters, CIA, and antral follicle count (AFC).Blood samples of women aged ≤45 years treated with anthracycline/taxane-based chemotherapy for EBC from four neoadjuvant/adjuvant trials were collected at baseline, at the end of treatment (EOT), and at 6, 12, 18, and 24 months after EOT. Centrally assessed oestradiol (cutoff52.2 ng/L) and follicle-stimulating hormone (cutoff12.4IU/L) were used to define CIOF for patients with baseline premenopausal hormone levels, anti-Müllerian hormone (AMH), and AFC to assess ovarian reserve. Further analyses included CIA, regain of premenopausal hormone levels, and disease-free survival (DFS) also in subgroups.Six hundred ninety-six patients aged ≤45 years had premenopausal hormone levels at baseline. Overall, 85.1% (592/696) experienced CIOF at EOT, and 147 of 592 had further hormone measurements after EOT. Of those, 32.7% (48/147) regained premenopausal hormone levels after 6 months, 57.9% (66/114) regained premenopausal hormone levels after 12 months, 83.0% (73/88) regained premenopausal hormone levels after 18 months, and 89.2% (74/83) regained premenopausal hormone levels after 24 months. After 24 months, 72.4% (21/29) of patients without CIOF and 100% (14/14) with CIOF had low AMH levels. Four-year DFS without CIOF versus CIOF was 65.9% versus 84.6% (hazard ratio [HR] = 2.09, 95% confidence interval [CI]: 1.37-3.19; P 0.001); in hormone receptor positive 61.8% versus 87.5% (HR = 2.69, 95% CI: 1.57-4.60; P 0.001); in30 years 68.3% versus 92.6% (HR = 4.87, 95% CI: 1.05-22.63; P = 0.026).Most premenopausal women experienced CIOF after chemotherapy for EBC. After 2 years, nearly all regain premenopausal hormone levels. CIOF was associated with better DFS, especially in patients with hormone receptor-positive EBC or aged30 years.

IMPORTANCE: The extent of changes in estradiol levels in male patients with hormone receptor–positive breast cancer receiving standard endocrine therapies is unknown. The sexual function and quality of life related to those changes have not been adequately evaluated. OBJECTIVE: To assess the changes in estradiol levels in male patients with breast cancer after 3 months of therapy. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, phase 2 randomized clinical trial assessed 56 male patients with hormone receptor–positive breast cancer. Patients were recruited from 24 breast units across Germany between October 2012 and May 2017. The last patient completed 6 months of treatment in December 2017. The analysis data set was locked on August 24, 2018, and analysis was completed on December 19, 2018. INTERVENTIONS: Patients were randomized to 1 of 3 arms: tamoxifen alone or tamoxifen plus gonadotropin-releasing hormone analogue (GnRHa) or aromatase inhibitor (AI) plus GnRHa for 6 months. MAIN OUTCOMES AND MEASURES: The primary end point was the change in estradiol levels from baseline to 3 months. Secondary end points were changes of estradiol levels after 6 months, changes of additional hormonal parameters, adverse effects, sexual function, and quality of life after 3 and 6 months. RESULTS: In this phase 2 randomized clinical trial, a total of 52 of 56 male patients with a median (range) age of 61.5 (37-83) years started treatment. A total of 3 patients discontinued study treatment prematurely, 1 in each arm. A total of 50 patients were evaluable for the primary end point. After 3 months the patients’ median estradiol levels increased by 67% (a change of +17.0 ng/L) with tamoxifen, decreased by 85% (−23.0 ng/L) with tamoxifen plus GnRHa, and decreased by 72% (−18.5 ng/L) with AI plus GnRHa (P

Background The efficacy and toxicity of olaparib as combination therapy in early breast cancer (BC) patients with homologous recombinant deficiency (HRD) [score high and/or germline (g) or tumour (t) BRCA1/2 mutation] is not well described. GeparOLA ( ClinicalTrials.gov , NCT02789332 ) investigated olaparib in combination with paclitaxel in HER2-negative early BC with HRD. Patients and methods Patients with untreated primary HER2-negative cT2-cT4a-d or cT1c with either cN+ or pNSLN+ or cT1c and triple-negative breast cancer (TNBC) or cT1c and Ki-67>20% BC with HRD were randomised either to paclitaxel (P) 80 mg/m2 weekly plus olaparib (O) 100 mg twice daily for 12 weeks or P plus carboplatinum (Cb) area under the curve 2 weekly for 12 weeks, both followed by epirubicin/cyclophosphamide (EC). Stratification factors were hormone receptor (HR) status (HR+ versus HR−) and age ( Results A total of 107 patients were randomised between September 2016 and July 2018; 106 (PO N = 69; PCb N = 37) started treatment. Median age was 47.0 years (range 25.0-71.0); 36.2% had cT1, 61.0% cT2, 2.9% cT3, and 31.8% cN-positive tumours; grade 3 tumours: 86.8%; Ki-67>20%: 89.6%; TNBC: 72.6%; confirmed gBRCA1/2 mutation: 56.2%. The pCR rate with PO was 55.1% [90% confidence interval (CI) 44.5% to 65.3%] versus PCb 48.6% (90% CI 34.3% to 63.2%). Analysis for the stratified subgroups showed higher pCR rates with PO in the cohorts of patients Conclusion GeparOLA could not exclude a pCR rate of ≤55% in the PO arm. PO was significantly better tolerated and the combination merits further evaluation.

Allied to the current tendency to postpone childbearing to the later reproductive years, the incidence rate of pregnancy-associated breast cancer is increasing. Delayed diagnosis and suboptimal therapy worsen prognosis. General concepts concerning local and systemic treatment and staging workup should adhere as much as possible to those of young nonpregnant female patients. Clinicopathological tumor characteristics determine the appropriate treatment. Most diagnostic methods and treatments options including imaging, surgery, and chemotherapy are feasible during pregnancy depending on the gestational stage at diagnosis. However, the selection and timing of local and systemic therapies must be adapted to ensure safety of both the fetus and the mother. Treatment strategies should be established in a multidisciplinary team and the pregnant woman and the family should be clearly informed and involved in the decision-making progress. Premature delivery should be avoided, whenever possible. Radiotherapy, endocrine and anti-HER2 therapies as well as new breast cancer treatments are contraindicated during pregnancy and lactation. Since randomized studies are not feasible in patients with breast cancer during pregnancy, register studies need to be supported and international collaborations to be continued.

Background Over 90% of male breast cancer (BC) patients (pts) have hormone receptor (HR) positive disease. Until today tamoxifen is considered to be the standard of care in male BC pts. Due to the low incidence of male BC, there is a lack of data regarding efficacy and safety. Therapeutic strategies are extrapolated from the standard of care of female BC. However, no prospectively randomized study in male BC pts has been conducted so far. The Male-GBG54 study is the first prospective, randomized, multicenter trial evaluating the efficacy and safety of different endocrine treatment options in male BC patients. Patients and Methods In the phase II Male-GBG54 trial (NCT01638247), pts were randomized to receive either tamoxifen 20 mg/day per os (p.o.) or tamoxifen 20mg/day p.o. + GnRHa subcutaneous (s.c.) q3m or exemestane 25 mg/day p.o. + GnRHa s.c. for 6 months as (neo)adjuvant or metastatic therapy. Further treatment was conducted as per local guidelines. Primary objective was the suppression of oestradiol in the three treatment arms after 3 months of therapy. Secondary objectives comprised oestradiol suppression after six months, compliance and safety of the three therapies, the level of different steroidal hormones (testosterone, dihydrotestosterone, SHBG, FSH, LH) and osteocalcin in the three arms. Quality of Life was assessed using the Aging Male Symptom Score, International Index of Erectile function and International Prostate Symptom Score. Tissue and blood was collected for translational research. Male BC pts with a Karnofsky Index ≥60%, normal blood lipids, and no history or evidence of prostate cancer were eligible. 14 pts per group were needed for the F-test to have 80% power to detect a difference in mean oestradiol decrease between the three therapeutic groups at the 5% significance level. The final sample size was calculated as 48 patients, as a non-parametric test (Kruskal-Wallis) was chosen in case the oestradiol levels are not normally distributed within the study population. Results Between October 2012 and May 2017, 55 pts were randomized within 24 centers in Germany. 52 pts were included in the adjuvant and 2 pts in the metastatic setting of whom 48 pts were fully evaluable and comprised the analysis set. The median age was 62 years (range 37-83 years). The baseline characteristics were well balanced between the 3 treatment groups. Karnofsky Index ranged from 60%-100%, 36.4% had received prior chemotherapy and 12.7% had HER2-positive BC. The majority had a pT2 (52%), pN0 (58.0%) BC. 3 serious adverse events were reported, none was related to the study treatment. Conclusion This is the first prospective randomized trial worldwide evaluating the impact of three different endocrine treatments in male breast cancer. The therapy was well tolerated without safety signals. At the meeting, final results of the primary and secondary endpoints will be present. Citation Format: Reinisch M, Seiler S, Hauzenberger T, Schmatloch S, Strittmatter HJ, Zahm DM, Thode C, Jackisch C, Furlanetto J, Strik D, Stickeler E, Marmé F, Janni W, Schmidt M, Kamischke A, Rudlowski C, Nekljudova V, von Minckwitz G, Loibl S. Male-GBG54: A prospective, randomised multi-centre phase II study evaluating endocrine treatment with either tamoxifen +/- gonadotropin releasing hormone analogue (GnRHa) or an aromatase inhibitor + GnRHa in male 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 PD7-10.

Background A new subcutaneous (s.c.) formulation of trastuzumab became available in 2013 based on equivalent efficacy, pharmacokinetic (PK) profile and safety with the standard intravenous (i.v.) administration, where the s.c. trastuzumab was administered only into the thigh. As an s.c. injection into the abdominal wall (abdw) might be more convenient for patients (pts) and health care professionals, the PK profile of s.c. trastuzumab injected into the thigh vs the abdw in pts with HER2+ early BC needs to be evaluated. Methods GAIN-2 study compared two intense dose-dense (idd) anthracycline/taxane containing regimens. After completion of the anthracycline and i.v. trastuzumab given concurrently with taxanes, HER2+ BC pts were randomized in a 1:1 ratio to continue adjuvant s.c. trastuzumab 600mg fixed dose injected every 3 weeks either into the thigh or the abdw. Randomization was stratified according to CT arm [(iddEnPC) vs tailored dd CT (dtEC-dtD)] and age (≤50 vs >50). Pts in the EnPC arm received 14 and in the dtEC-dtD arm 15 cycles of s.c. trastuzumab. For the PK profile of s.c. trastuzumab serum samples collected before cycle 7, on days 2, 4, 8, 15 and 21 of cycle 7 are evaluated. With a total sample size of 30 (15 per group), the simulated 90% two-sided CI for the area under the plasma concentration (AUC0-last) will be (0.79-1.27) and for the peak drug concentration (Cmax) will be (0.77-1.30). Allowing for a dropout rate of 15%, 18 pts per group will be included in the PK analysis. The primary objective was to assess the PK profile of s.c. trastuzumab injected into the thigh vs the abdw. The secondary objectives included safety and tolerability. Results The per-protocol (pp) set consists of 30 pts (17 in the thigh group and 13 in the abdw group). Baseline characteristics were well balanced between the groups. The log-transformed Geometric Least Square Means (GLSM) for Cmax were 11.77 and 11.52 in the thigh and the abdw group, respectively. The geo-mean ratio (on the original scale) for Cmax was 1.29 (90% CI 1.05-1.58). The log-transformed GLSM for AUC0-last were 14.54 and 14.28 in the thigh and the abdw group, respectively. The geo-mean ratio for AUC0-last was 1.29 (90% CI 1.02-1.63). Overall 29 pts (96.7%) reported any grade and 5 pts (16.7%) high grade adverse events (AEs). The incidence of any grade AEs was similar between the two groups. The most common AEs were anemia (70.6% for the thigh vs 61.5% for the abdw group, p=0.705), leukopenia (80.0% for both groups, p=1.000) and fatigue (47.1% for the thigh vs 76.9% for the abdw group, p=0.141). 6 serious AEs were reported (2 in the thigh vs 4 in the abdw group). The final PK results of s.c. trastuzumab will be presented at the meeting. Conclusions Bioavailability of s.c. trastuzumab as reflected by peak and total exposure measured in cycle 7 was approx. 30% higher if administered into the thigh than into the abdw in pts with HER2+ primary BC treated after dose-dense CT plus i.v. trastuzumab. However, no increased toxicity was observed. Study limitations were that no cross-over design was used and number of pts satisfying criteria for pp-set were different in the arms. Citation Format: Möbus V, Mahlberg R, Janni W, Tomé O, Marmé F, Forstbauer H, Reimer T, von der Assen A, Reinisch M, Lorenz R, Schmatloch S, Schmidt M, Sinn B, Klutinus N, Stickeler E, Untch M, Seiler S, Burchardi N, von Minckwitz G, Loibl S. Pharmacokinetic results of a subcutaneous injection of trastuzumab into the thigh versus into the abdominal wall in patients with HER2-positive primary breast cancer (BC) treated within the neo-/adjuvant GAIN-2 study [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 P5-20-09.

Background: TNBC is associated with higher percentages of pathological complete response (pCR) to neoadjuvant chemotherapy (NAC), and women with a pCR have a favorable prognosis. However, Liedtke (2008) and Loibl (2017) found that women with residual disease have a substantially higher risk of recurrence than women with other subtypes of breast cancer. Additionally, Adams (2017) and Schmid (2017) found that therapeutic blockade of PD-L1 binding by atezolizumab has resulted in relevant anti-tumor efficacy. Methods: Design This is a phase III, double blind, placebo-control trial evaluating neoadjuvant atezolizumab with NAC followed by adjuvant atezolizumab in TNBC. Pts are stratified by region (North America; Europe), tumor size (1.1-3.0cm; >3.0cm), AC/EC schedule (q2w; q3w), and nodal status (positive; negative), then randomized 1:1 to receive atezolizumab/placebo 1200 mg IV every 3 wks concurrently with both sequential regimens of weekly paclitaxel 80 mg/m2 IV for 12 doses with every 3-wk carboplatin AUC of 5 IV for 4 doses followed by AC/EC every 2-3 wks (per investigator discretion) for 4 cycles. Following surgery, pts resume atezolizumab/placebo 1200 mg IV every 3 wks as adjuvant therapy for 6 months. Radiotherapy based on local standards is co-administered with atezolizumab/placebo. Eligibility criteria Centrally-confirmed ER-neg, PR-neg, HER2-neg invasive breast cancer by ASCO/CAP guidelines. Primary tumor must be stage T2 or T3 if cN0 or cN1 with negative biopsy or T1c, T2, or T3 if cN1 with positive biopsy or cN2 or cN3. LVEF >55% and no significant cardiac history. Statistical methods Co-primary endpoints are event-free survival (EFS) and pCR breast/nodes. Secondary endpoints include pCR breast, overall survival, distant disease-free survival, safety and toxicity. Trial is an academic collaboration between NSABP and GBG with support from Genentech/Roche. NCT03281954 Support: Genentech/Roche Citation Format: Geyer, Jr. CE, Loibl S, Rastogi P, Seiler S, Costantino JP, Nekljudova VN, Cortazar P, Lucas PC, Denkert C, Mamounas EP, Jackisch C, Wolmark N. A randomized double-blind phase III clinical trial of neoadjuvant chemotherapy (NAC) with atezolizumab or placebo in patients (pts) with triple negative breast cancer (TNBC) followed by adjuvant atezolizumab or placebo: NSABP B-59/GBG 96-GeparDouze [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 OT3-05-01.

Background: About one third of patients with hormone-receptor-positive (HR+), HER2- primary breast cancer with residual invasive disease after neoadjuvant chemotherapy will relapse despite adjuvant endocrine therapy. The risk of relapse can be assessed more accurately using the CPS-EG scoring system (Mittendorf et al. JCO 2011). Therapeutic inhibition of cyclin-dependent kinase 4 and 6 (CDK 4/6) by palbociclib combined with endocrine therapy demonstrated highly relevant efficacy in metastatic breast cancer. Thus, we hypothesize that palbociclib may also be active in these high-risk patients with primary breast cancer. Methods: PENELOPE-B (NCT01864746) is a double-blind, placebo-controlled, phase III study in women with centrally confirmed HR+, HER2- primary breast cancer without a pathological complete response after taxane-containing neoadjuvant chemotherapy and at high-risk of relapse (CPS-EG score ≥3 or 2 and ypN+). After completion of neoadjuvant chemotherapy and locoregional therapy, patients were randomized (1:1) to receive 13 cycles of palbociclib 125mg daily or placebo on days 1-21 in a 28d cycle in addition to standard endocrine therapy. Randomization was stratified by lymph node status (at surgery), age, Ki-67, global region, and CPS-EG score. Primary endpoint is invasive disease-free survival (iDFS). Final analysis was planned after 290 iDFS events with efficacy boundary p15% in 27.7 %; 54.7% of patients had risk status CPS-EG score ≥3. 1118 patients (89%) completed at least 7 cycles of therapy. 50.1% of patients received aromatase inhibitor (AI), 49.8% tamoxifen, 6.6% AI + gonadotropin-releasing hormone (GnRH) and 9.7% tamoxifen + GnRH. Most common related serious adverse events (SAEs) were infections and vascular disorders. 8 fatal SAEs were reported. Conclusions: PENELOPE-B evaluates the effect of palbociclib for 1 year compared to placebo in addition to endocrine therapy in high-risk primary breast cancer patients. The database was locked with 308 events on September 25th 2020. After breaking the blind for analysis, top line results will be available as of mid October 2020. Results of the final iDFS analysis will be presented at the meeting. Citation Format: Sibylle Loibl, Frederik Marmé, Miguel Martin, Michael Untch, Hervé Bonnefoi, Sung-Bae Kim, Harry Bear, Nicole Mc Carthy, Mireia Melé Olivé, Karen Gelmon, José García Sáenz, Catherine M Kelly, Toralf Reimer, Masakazu Toi, Hope S Rugo, Sabine Seiler, Valentina Nekljudova, Carsten Denkert, Michael Gnant, Andreas Makris, Nicole Burchardi, Gunter von Minckwitz. Phase III study of palbociclib combined with endocrine therapy (ET) in patients with hormone-receptor-positive (HR+), HER2-negative primary breast cancerand with high relapse risk after neoadjuvant chemotherapy (NACT): First results from PENELOPE-B [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS1-02.

Background Pre-clinical data and initial results from clinical studies point to the added benefit of CDK4/6 inhibition when combined with anti-HER2 tx. The current study is designed to evaluate the added benefit of palbociclib when given in combination with anti-HER2 and endocrine tx maintenance in the 1st†line setting of metastatic HER2+HR+ breast cancer. Trial design PATINA is an international, open-label, pivotal Phase III study. Primary objective is to demonstrate that the combination of palbociclib with anti-HER2 plus endocrine tx is superior to anti-HER2 plus endocrine tx in prolonging PFS. Sample size is 496 pts. The study starts after completion of 6-8 cycles of chemotherapy-containing anti-HER2 tx for metastatic breast cancer in the 1st line setting. Pts are eligible provided they are without evidence of disease progression by local assessment (i.e. CR, PR or SD). To account for the need for less intense tx regimens for a subset of pts diagnosed with HER2+ER+ disease, clinicians may recommend the combination of trastuzumab with either a taxane or vinorelbine prior to study initiation. Clinicians might also choose a non-pertuzumab option for pts previously treated with pertuzumab in the neo(adjuvant) setting. Secondary objectives include measures of tumor control (OR, CBR, DOR), OS, safety and QOL. The translational science main objective is to compare PFS estimates according to PIK3CA mutation status assessed by cfDNA analysis. Endocrine tx options are AI or fulvestrant. Premenopausal pts must receive ovarian suppression. The study has a 90% power to detect a hazard ratio of 0.667 in favor of the palbociclib arm. Pts approached to participate in AFT-38 will be asked to indicate on the informed consent forms whether remaining biospecimens and clinical data from the control arm of the study can be shared with the Mastering Breast Cancer (MBC) Initiative. The overarching purpose of the MBC is to create a mechanism for understanding the natural history of metastatic breast cancer by cataloguing longitudinally studied tumor-specific markers and treatment effects. ClinicalTrials.gov Identifier: NCT02947685 Citation Format: Metzger-Filho O, Mandrekar S, Loibl S, Ciruelos E, Gianni L, Lim E, Miller K, Huang C, Koehler M, Francis P, Valagussa P, Goel S, Prat A, Goetz M, Loi S, Krop I, Carey L, Lanzillotti J, Winer E, Tripathy D, DeMichele A. PATINA: A randomized open label phase III trial to evaluate the efficacy and safety of palbociclib + anti HER2 therapy + endocrine therapy vs anti HER2 therapy + endocrine therapy after induction treatment for hormone receptor positive, HER2 positive metastatic breast cancer [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 OT3-05-07.

Background: Although endocrine therapy (ET) is recommended as first-line therapy for hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (MBC) up to 50% of patients receive chemotherapy in this setting. Meanwhile new targeted treatment options for combination with ET have been developed and endocrine-based therapy with the CDK4/6 inhibitor Palbociclib (P) improves the progression free survival (PFS) of ET alone by about 50%. So far, there is no data comparing chemotherapy with or without maintenance ET and ET in combination with P as first-line therapy. Patients included in clinical trials are often criticized not to mirror the general breast cancer population and every-day clinical practice due to rigid inclusion and exclusion criteria, limited number of treatment options, strict monitoring intervals and study assessments. Methods: PADMA trial is a so called low intervention trial with no rigid inclusion and exclusion criteria, and study assessments.Patients with first-line HR+/HER2- MBC who are candidate for mono-chemotherapy will be eligible to receive either P plus ET per label or mono-chemotherapy per investigator´s choice with or without maintenance ET (1:1 randomization). Primary objective is to compare the time-to-treatment failure (TTF) for patients randomized to receive the mono-chemotherapy treatment strategy versus those randomized to receive P and ET. TTF is defined as time from randomization to discontinuation of treatment due to disease progression, treatment toxicity, patient's preference, or death. Main secondary objectives are progression free survival, overall survival at 36 months, amongst other time to event endpoints as well as toxicity and compliance. All patients receive a specific mobile device (PADMA-Phone) and a validated wearable device (ActiWatch) in order to collect data regarding sleep and activity levels, patient well-being and health care utilization (number and duration of phone calls, and patient visits to investigator site) for assessment of daily monitoring treatment impact (DMTI). Results: Overall, 360 patients will be accrued to show an improved TTF for P in combination with ET compared to mono-chemotherapy of investigator´s choice with or without maintenance ET. Recruitment will start in QIII/2017 and is planned for approximately 18 months in 100 sites in Germany, Spain, Poland, Italy, France, UK and Canada. Conclusions: The aim of PADMA is to demonstrate that an endocrine-based strategy consisting of ET plus P is superior to a chemotherapy-based strategy as first-line therapy in women with HR+/HER2- MBC in a real world setting. Assessment of patient-reported outcome, health care utilization, and sleep and activity levels will deliver important information on the differences between endocrine-based and chemotherapy-based treatment. Citation Format: Loibl S, Barinoff J, Seiler S, Decker T, Denkert C, Hardy-Bessard A-C, Senkus-Konefka E, Cognetti F, Palmieri C, Gelmon K, Luebbe K, Furlanetto J, Mueller V, Mundhenke C, Schmidt M, von Minckwitz G, Uhlig M, Burchardi N, Thill M. A randomized, open-label, multi-center phase IV study evaluating palbociclib plus endocrine treatment versus a chemotherapy-based treatment strategy in patients with hormone receptor-positive, HER2-negative metastatic breast cancer in a real world setting (PADMA) [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 OT3-05-04.

The E-VITA study evaluated the efficacy and tolerability of two schedules of eribulin and lapatinib in patients with trastuzumab-pretreated HER-2-positive metastatic breast cancer. This multicenter, open-label phase II trial, randomly assigned patients with trastuzumab-pretreated HER-2-positive metastatic breast cancer to lapatinib 1000 mg daily with eribulin 1.23 mg/m (equivalent to 1.4 mg/m eribulin mesylate) days 1+8 every 21 days (split-dose arm) or eribulin 1.76 mg/m (equivalent to 2.0 mg/m eribulin mesylate) day 1 every 21 days (3-weekly arm). Time to progression and tolerability were defined as primary end points; no sample size calculation for formal comparison of efficacy data has been performed. Secondary end points included objective response rate, clinical benefit rate, and overall survival. Overall, 43 patients of a planned number of 80 patients were recruited. At a median follow-up of 28.7 months, the median time to progression was 8.1 months [95% confidence interval (CI): 4.8-9.4] in the split-dose arm and 6.5 months (95% CI: 4.6-13.4) in the 3-weekly arm. Objective response rate was 52.4% (95% CI: 31.0-73.7) in the split-dose arm and 45.0% (95% CI: 23.2-66.8) in the 3-weekly arm, and clinical benefit rate was 71.4% (95% CI: 52.1-90.8) and 75.0% (95% CI: 56.0-94.0), respectively. Overall survival was also similar in both arms. The most frequent grade 3-4 adverse events were neutropenia (58.5%) and leukopenia (39.0%). The combination of eribulin and lapatinib showed an acceptable safety profile with less toxicity observed in the eribulin 1.23 mg/m day 1+8 group. This might be an alternative regimen when other treatment options are exhausted. Therefore, further clinical studies are warranted.

518 Background: PENELOPE-B assessed efficacy of the CDK4/6 inhibitor 1-year palbociclib versus placebo added to endocrine therapy (ET) as post-neoadjuvant treatment in a high-risk breast cancer population. Palbociclib did not improve invasive disease-free survival (iDFS) compared to placebo (3-year iDFS 81.3% vs 77.7%) (Loibl et al. J Clin Oncol 2021). Here we report results from the subpopulation of premenopausal women. Methods: Patients with hormone receptor positive, HER2-negative breast cancer without pathological complete response after taxane‐containing neoadjuvant chemotherapy and at high risk of relapse (CPS‐EG score ≥3 or 2 and ypN+) were randomized (1:1) to receive 13 cycles of palbociclib 125mg daily or placebo on days 1-21 in a 28d cycle in addition to standard endocrine treatment including tamoxifen (TAM) +/- gonadotropin-releasing hormone analogue (GnRH) and aromatase inhibitor (AI) +/- GnRH. Randomization was stratified by nodal status at surgery, age ( < 50 vs ≥50 years), Ki-67, region, and CPS-EG score. Results: 616/1250 patients were premenopausal at the time of enrollment, 185 of these patients (30.0%) were younger than 40 years of age. 95.2% had ypN+ after surgery; 42.8% had ypT2 and 46.8% a CPS-EG score of 3. 23.1% of the premenopausal women had a Ki67 of > 15% in residual disease. 66.1% started with TAM alone; 19.3% with TAM and ovarian function suppression (OFS); and 13.6% received an AI+OFS. There was no difference in iDFS between palbociclib and placebo in the premenopausal women HR 0.948 (0.693-1.30). The 3-year iDFS was 80.6% and 78.3%, respectively. Palbociclib vs placebo in subgroups by endocrine treatment: TAM alone HR 1.05 (0.715-1.53) p = 0.817; TAM+GnRH HR 0.52 (0.267-1.02) p = 0.057 and AI+GnRH HR 1.58 (0.548-4.56) p = 0.397; pinteraction0.124. Hematologic toxicity was significantly more common with palbociclib. Non-hematological toxicity any grade palbociclib vs placebo were: fatigue 67.4% vs 51.3%; hot flushes 52.2% vs 54.8%; bone pain 15.6% vs 16.6%; and vaginal dryness 11.0% vs 11.5%. When receiving palbociclib fewer patients in the AI+GnRH group vs the TAM +/- GnRH cohort experienced anemia (54.1% vs 80.5%) and thrombocytopenia (37.8% vs 65.1%). Fatigue (75.7% vs 66.3%) and nausea (40.5% vs 24.9%) were more common with AI+GnRH than TAM +/-GnRH when palbociclib was added. Thromboembolic events were low with overall 9 events (4 vs 5; AI+GnRH 2.4% vs 1.3% TAM+/-GnRH). Conclusions: The addition of palbociclib to endocrine therapy did not improve iDFS in premenopausal women. These are the first safety results from a phase III study for the combination tamoxifen +/-GnRH and palbociclib. The addition of palbociclib to tamoxifen +/-GnRH in premenopausal women did not increase side effects compared to AI+GnRH and seems to be an alternative to AI+GnRH. Clinical trial information: NCT01864746.

Purpose The role of temporary ovarian suppression with gonadotropin-releasing hormone agonists (GnRHa) during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal women remains controversial. This systematic review and meta-analysis using individual patient–level data was conducted to better assess the efficacy and safety of this strategy in patients with early breast cancer. Methods The trials in which premenopausal women with early breast cancer were randomly assigned to receive (neo)adjuvant chemotherapy alone or with concurrent GnRHa were eligible for inclusion. Primary end points were premature ovarian insufficiency (POI) rate and post-treatment pregnancy rate. Disease-free survival and overall survival were secondary end points. Because each study represents a cluster, statistical analyses were performed using a random effects model. Results A total of 873 patients from five trials were included. POI rate was 14.1% in the GnRHa group and 30.9% in the control group (adjusted odds ratio, 0.38; 95% CI, 0.26 to 0.57; P < .001). A total of 37 (10.3%) patients had at least one post-treatment pregnancy in the GnRHa group and 20 (5.5%) in the control group (incidence rate ratio, 1.83; 95% CI, 1.06 to 3.15; P = .030). No significant differences in disease-free survival (adjusted hazard ratio, 1.01; 95% CI, 0.72 to 1.42; P = .999) and overall survival (adjusted hazard ratio, 0.67; 95% CI, 0.42 to 1.06; P = .083) were observed between groups. Conclusion Our findings provide evidence for the efficacy and safety of temporary ovarian suppression with GnRHa during chemotherapy as an available option to reduce the likelihood of chemotherapy-induced POI and potentially improve future fertility in premenopausal patients with early breast cancer.

Background There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group. Methods The study comprised 802 women (median age 40 years, range 19–76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation. Results A total of 127 women with TNBC (15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1.1%). The mutation prevalence was 32.9% in the age group 20–29 years compared to 6.9% in the age group 60–69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95%CI 1.50–2.32, p 10% for women diagnosed below approximately 50 years. Conclusions Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation.

Background Use of parenteral (IV) ferric carboxymaltose (FCM) has been shown to be an efficient treatment of iron deficiency anaemia that can prevent blood transfusion. This substudy compared use of FCM with physician’s choice (PhCh) anaemia therapy in breast cancer (BC). Methods In GeparOcto trial pts with primary BC were randomised to receive sequential, intensified, dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddEPC) or weekly paclitaxel/liposomal doxorubicin +/- carboplatin (PM(Cb)) (Schneeweiss et al. Eur J Cancer). Pts with anaemia grade ≥2 (haemoglobin (Hb) Results Less than anticipated pts had CT-induced anaemia. 125 pts were randomised (62 in FCM, 63 in PhCh arm). Median age was 46 years (range 26-66); median levels of Hb, serum ferritin and TSAT were 9.6 (7.6-11.8)g/dl, 201 (3.0-551)ng/ml and 14.0% (4.0%-76.0%), respectively. After 6 wks, overall 40 (32.0%) pts (22 in FCM and 18 in PhCh arm; p = 0.447) reached Hb ≥ 11g/dl. Median time to achieve Hb ≥ 11g/dl was 9.0 wks with FCM vs 10.6 wks by PhCh. Median Hb changes vs baseline were comparable in both arms during the treatment. 2 pts in FCM and 5 in PhCh arm (p = 0.246) received blood transfusions until 6 wks of therapy. Conclusions This is the first study investigating IV iron treatment for dose-dense CT-induced anaemia in BC. 32% of pts reached Hb ≥ 11g/dl at 6 wks. FCM treatment was not different than PhCh for anaemia therapy. Clinical trial identification NCT02125344. Legal entity responsible for the study German Breast Group (GBG). Funding The anaemia supportive treatment substudy was financially supported by Vifor Pharma Ltd and the GeparOcto trial by Amgen, Roche and TEVA. Disclosure H. Tesch: Honoraria (self): Vifor; Honoraria (self): Roche; Honoraria (self): Amgen. S. Loibl: Honoraria (institution), Research grant / Funding (institution): Roche; Honoraria (institution), Research grant / Funding (institution): Amgen GmbH; Honoraria (institution), Research grant / Funding (institution): AstraZeneca; Honoraria (institution), Research grant / Funding (institution): Celgene; Honoraria (institution), Research grant / Funding (institution): Novartis; Honoraria (institution), Research grant / Funding (institution): Pfizer; Honoraria (institution), Research grant / Funding (institution): Seattle Genetics; Honoraria (institution), Research grant / Funding (institution): Teva; Honoraria (institution), Research grant / Funding (institution): Vifor; Honoraria (institution), Research grant / Funding (institution): PRIME; Honoraria (institution), Research grant / Funding (institution): Daiichi; Licensing / Royalties: EP14153692.0 pending. V. Mobus: Honoraria (self): Amgen; Honoraria (self): Celgene; Honoraria (self): Myelotherapeutics; Honoraria (self): AstraZeneca. M. Untch: Honoraria (institution), Non-remunerated activity/ies: Abbvie; Honoraria (institution), Non-remunerated activity/ies: Amgen GmbH; Honoraria (institution), Non-remunerated activity/ies: AstraZeneca; Honoraria (institution): BMS; Honoraria (institution), Non-remunerated activity/ies: Celgene GmbH; Honoraria (institution), Non-remunerated activity/ies: Daiji Sankyo; Honoraria (institution), Non-remunerated activity/ies: Eisai GmbH; Honoraria (institution), Non-remunerated activity/ies: Janssen Cilag; Honoraria (institution), Non-remunerated activity/ies: Lilly; Honoraria (institution), Non-remunerated activity/ies: MSD Merck; Honoraria (institution), Non-remunerated activity/ies: Mundipharma; Honoraria (institution), Non-remunerated activity/ies: Myriad Genetics; Honoraria (institution), Non-remunerated activity/ies: Odonate; Honoraria (institution), Non-remunerated activity/ies: Pfizer GmbH; Honoraria (institution): PUMA Biotechnology; Honoraria (institution), Non-remunerated activity/ies: Novartis; Honoraria (institution), Non-remunerated activity/ies: Roche Pharma AG; Honoraria (institution), Non-remunerated activity/ies: Sanofi Aventis Deutschland GmbH; Honoraria (institution), Non-remunerated activity/ies: Sividon Diagnostics; Honoraria (institution), Non-remunerated activity/ies: TEVA Pharmaceuticals Ind Ltd. C. Hanusch: Honoraria (self): Roche; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): Celgene; Honoraria (self): Lilly; Honoraria (self): AstraZeneca. S. Seiler: Honoraria (self), presentations: Roche; Honoraria (self), Advisory / Consultancy: Amgen GmbH; Honoraria (self), Advisory / Consultancy: Hexal; Honoraria (self), Advisory / Consultancy: Mundipharma; Advisory / Consultancy: Novartis. P.A. Fasching: Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Biontech; Honoraria (self): Novartis; Honoraria (self): Roche; Honoraria (self): Pfizer; Honoraria (self): Celgene; Honoraria (self): Daiichi-Sankyo; Honoraria (self): TEVA; Honoraria (self): AstraZeneca; Honoraria (self): Merck Sharp & Dohme; Honoraria (self): Myelo Therapeutics; Honoraria (self): Macrogenics; Honoraria (self): Eisai; Honoraria (self): PUMA; Research grant / Funding (institution): Cepheid. K. Rhiem: Honoraria (self): Tesaro; Honoraria (self): AstraZeneca; Honoraria (self): Pfizer. J. Huober: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy: Hexal; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: MSD Oncology; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Celgene; Honoraria (self), Travel / Accommodation / Expenses: Abbvie. C. Denkert: Shareholder / Stockholder / Stock options: Sividon Diagnostics; Honoraria (self): Teva; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Roche; Honoraria (self), Advisory / Consultancy: Amgen; Advisory / Consultancy: MSD Oncology; Advisory / Consultancy: Daiichi Sankyo; Licensing / Royalties: VMScope digital pathology software; Licensing / Royalties: Patent application: EP18209672 - cancer immunotherapy; Licensing / Royalties: Patent application EP20150702464 - therapy response; Licensing / Royalties: Patent application EP20150702464 - therapy response. T. Link: Honoraria (self): Amgen; Non-remunerated activity/ies: AstraZeneca; Honoraria (self), Non-remunerated activity/ies: Pfizer; Non-remunerated activity/ies: Pharma Mar; Non-remunerated activity/ies: Daiichi Sankyo; Honoraria (self): MSD Oncology; Honoraria (self): Novartis; Honoraria (self): Teva; Honoraria (self): Tesaro; Honoraria (self), Non-remunerated activity/ies: Roche. A. Schneeweiss: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Celgene; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Molecular Partner; Honoraria (self), Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (self), Travel / Accommodation / Expenses: Pfizer; Honoraria (self): MSD Oncology; Honoraria (self): Tesaro; Honoraria (self): Lilly. All other authors have declared no conflicts of interest.

Background LRR after neoadjuvant chemotherapy (NACT) for BC may impact patient's outcome. This study aimed to evaluate the rates of LRR as first event after NACT and to identify independent predictors of LRR. Methods A total of 10075 women with primary BC and available follow-up from 9 prospective neoadjuvant trials were included in the pooled analysis. The main endpoint was cumulative incidence rates of LRR as first event after NACT; distant recurrence, secondary malignancy or death was defined as competing event. To identify predictors of LRR, surgery type, pathological complete response (pCR=ypT0 ypN0), BC subtypes and other risk factors were evaluated using Fine-Gray's regression model. The two-sided significance level was set to α=0.05. Results After a median follow-up in the entire cohort of 67 months (range 0-215 months), 959 (9.5%) LRRs as first event were observed. Age ( 50 years; p Conclusions Young age, node-positive and G3 tumours as well as non-pCR status and TNBC were found to significantly increase the risk of LRR as first event after NACT. Pts with HR-/HER2+ and TNBC not achieving pCR were at highest risk of LRR. Hence, these BC subtypes might be considered for additional post-neoadjuvant treatment approaches. Legal entity responsible for the study German Breast Group (GBG). Funding Has not received any funding. Disclosure M. Untch: Honoraria (institution), non-financial support: Abbvie; Honoraria (institution), non-financial support: Amgen GmbH; Honoraria (institution), non-financial support: AstraZeneca; Honoraria (institution): BMS; Honoraria (institution), non-financial support: Celgene GmbH; Honoraria (institution), non-financial support: Daiji Sankyo; Honoraria (institution), non-financial support: Eisai GmbH; Honoraria (institution), non-financial support: Janssen Cilag; Honoraria (institution), non-financial support: TEVA Pharmaceuticals Ind Ltd; Honoraria (institution): Lilly Deutschland; Honoraria (institution), non-financial support: Sividon Diagnostics; Honoraria (institution), non-financial support: MSD Merck; Honoraria (institution), non-financial support: Mundipharma; Honoraria (institution), non-financial support: Myriad Genetics; Honoraria (institution), non-financial support: Odonate; Honoraria (institution), non-financial support: Pfizer GmbH; Honoraria (institution): PUMA Biotechnology; Honoraria (institution), non-financial support: Novartis; Honoraria (institution), non-financial support: Roche Pharma AG; Honoraria (institution), non-financial support: Sanofi Aventis Deutschland GmbH. C. Hanusch: Honoraria (self), Outside the submitted work: Roche; Honoraria (self), Outside the submitted work: Pfizer; Honoraria (self), Outside the submitted work: Novartis; Honoraria (self), Outside the submitted work: Celgene; Honoraria (self), Outside the submitted work: Lilly; Honoraria (self), Outside the submitted work: AstraZeneca. P.A. Fasching: Research grant / Funding (institution), The Work Under Consideration for Publication: Novartis; Research grant / Funding (institution), The Work Under Consideration for Publication: Biontech; Honoraria (self), The Work Under Consideration for Publication: Novartis; Honoraria (self), The Work Under Consideration for Publication: Roche; Honoraria (self), The Work Under Consideration for Publication: Pfizer; Honoraria (self), The Work Under Consideration for Publication: Celgene; Honoraria (self), The Work Under Consideration for Publication: Daiichi-Sankyo; Honoraria (self), The Work Under Consideration for Publication: TEVA; Honoraria (self), The Work Under Consideration for Publication: AstraZeneca; Honoraria (self), The Work Under Consideration for Publication: Merck Sharp & Dohme; Honoraria (self), The Work Under Consideration for Publication: Myelo Therapeutics; Honoraria (self), The Work Under Consideration for Publication: Macrogenics; Honoraria (self), The Work Under Consideration for Publication: Eisai; Honoraria (self), The Work Under Consideration for Publication: Puma; Research grant / Funding (institution), The Work Under Consideration for Publication: Cepheid. S. Seiler: Honoraria (self), presentations: Roche; Advisory / Consultancy: Amgen GmbH; Advisory / Consultancy: Hexal; Honoraria (self): Mundipharma; Non-remunerated activity/ies: Novartis. C. Denkert: Shareholder / Stockholder / Stock options: Sividon Diagnostics; Honoraria (self): Teva; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Roche; Honoraria (self), Advisory / Consultancy: Amgen; Advisory / Consultancy: MSD Oncology; Advisory / Consultancy: Daiichi Sankyo; Licensing / Royalties: VMScope digital pathology software; Licensing / Royalties: Patent application: EP18209672 - cancer immunotherapy; Licensing / Royalties: Patent application EP20150702464 - therapy response; Licensing / Royalties: Patent application EP20150702464 - therapy response. H. Tesch: Honoraria (self): Vifor; Honoraria (self): Roche; Honoraria (self): Amgen. C. Jackisch: Honoraria (self), Travel / Accommodation / Expenses: Celgene; Honoraria (self): Roche. A. Schneeweiss: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Celgene; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Molecular Partner; Honoraria (self), Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (self), Travel / Accommodation / Expenses: Pfizer; Honoraria (self): Novartis; Honoraria (self): MSD; Honoraria (self): Tesaro; Honoraria (self): Lilly. T. Link: Honoraria (self): Amgen; Non-remunerated activity/ies: AstraZeneca; Honoraria (self), Non-remunerated activity/ies: Pfizer; Non-remunerated activity/ies: Pharma Mar; Non-remunerated activity/ies: Daiichi Sankyo; Honoraria (self): MSD; Honoraria (self): Novartis; Honoraria (self): Teva; Honoraria (self): Tesaro; Honoraria (self), Non-remunerated activity/ies: Roche. J. Huober: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy: Hexal; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: MSD Oncology; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Celgene; Honoraria (self), Advisory / Consultancy: Abbvie. K. Rhiem: Honoraria (self): Tesaro; Honoraria (self): Pfizer; Honoraria (self): AstraZeneca. S. Loibl: Honoraria (institution), Research grant / Funding (institution), The Work Under Consideration for Publication: Roche; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: AbbVie; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: Amgen; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: AstraZeneca; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: Celgene; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: Novartis; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: Pfizer; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: Seattle Genetics; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: Teva; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: Vifor; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: PRIME; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: Daiichi; Licensing / Royalties, Intellectual Property - Patents & Copyrights: EP14153692.0 pending. All other authors have declared no conflicts of interest.

Several studies have demonstrated the feasibility of molecular screening of tumour samples for matching patients with cancer to targeted therapies. However, most of them have been carried out at institutional or national level. Herein, we report on the pilot phase of AURORA (NCT02102165), a European multinational collaborative molecular screening initiative for advanced breast cancer patients. Forty-one patients were prospectively enroled at four participating centres across Europe. Metastatic tumours were biopsied and profiled using an Ion Torrent sequencing platform at a central facility. Sequencing results were obtained for 63% of the patients in real-time with variable turnaround time stemming from delays between patient consent and biopsy. At least one clinically actionable mutation was identified in 73% of patients. We used the Illumina sequencing technology for orthogonal validation and achieved an average of 66% concordance of substitution calls per patient. Additionally, copy number aberrations inferred from the Ion Torrent sequencing were compared to single nucleotide polymorphism arrays and found to be 59% concordant on average. Although this study demonstrates that powerful next generation genomic techniques are logistically ready for international molecular screening programs in routine clinical settings, technical challenges remain to be addressed in order to ensure the accuracy and clinical utility of the genomic data., info:eu-repo/semantics/published

TPS605 Background: TNBC is associated with higher percentages of pathological complete response (pCR) to neoadjuvant chemotherapy (NAC), and women with a pCR have a favorable prognosis. However, Liedtke (2008) and Loibl (2017) found that women with residual disease have a substantially higher risk of recurrence than women with other subtypes of breast cancer. Additionally, Adams (2017) and Schmid (2017) found that therapeutic blockade of PD-L1 binding by atezolizumab has resulted in relevant anti-tumor efficacy. Methods: Design: This is a phase III, double blind, placebo-control trial evaluating neoadjuvant atezolizumab with NAC followed by adjuvant atezolizumab in TNBC. Pts are stratified by region (North America; Europe), tumor size (1.1-3.0cm; >3.0cm), AC/EC schedule (q2w; q3w), nodal status (positive; negative), and PD-L1 status (positive; negative or indeterminate) then randomized 1:1 to receive atezolizumab/placebo 1200 mg IV every 3 wks concurrently with both sequential regimens of weekly paclitaxel 80 mg/m2 IV for 12 doses with every 3-wk carboplatin AUC of 5 IV for 4 doses followed by AC/EC every 2-3 wks (per investigator discretion) for 4 cycles. Following surgery, pts resume atezolizumab/placebo 1200 mg IV every 3 wks as adjuvant therapy for 6 months. Radiotherapy based on local standards is co-administered with atezolizumab/placebo. Eligibility criteria: Centrally confirmed ER-neg, PR-neg, HER2-neg invasive breast cancer by ASCO/CAP guidelines. Primary tumor must be stage T2 or T3 if cN0 or cN1 with negative biopsy or T1c, T2, or T3 if cN1 with positive biopsy or cN2 or cN3. LVEF >55% and no significant cardiac history. Statistical methods: Co-primary endpoints are event-free survival (EFS) and pCR breast/nodes. Secondary endpoints include pCR breast, overall survival, distant disease-free survival, safety and toxicity. Trial is an academic collaboration between NSABP and GBG with support from Genentech/Roche. Support: Genentech/Roche. Clinical trial information: NCT03281954.

TPS603Background: TNBC is associated with higher percentages of pathological complete response (pCR) to neoadjuvant chemotherapy (NAC), and women with a pCR have a favorable prognosis. However, Lie...

Background The role of temporary ovarian suppression with gonadotropin-releasing hormone analogs (GnRHa) during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal early breast cancer patients remains highly controversial. This option is considered experimental by the ASCO and ESMO guidelines on fertility preservation in cancer patients. The present pooled analysis aimed at elucidating the efficacy and safety of temporary ovarian suppression with GnRHa during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal early breast cancer patients. Patients and methods This study included individual patient data from 5 trials (PROMISE-GIM6, POEMS/SWOG S0230, Anglo Celtic Group OPTION, GBG-37 ZORO, Moffitt-led trial) in which premenopausal women with early breast cancer were randomized to receive (neo)adjuvant chemotherapy alone or with concurrent administration of GnRHa. Efficacy endpoints were premature ovarian insufficiency (POI, according to the definition used as primary endpoint in the included trials), 1- and 2-year amenorrhea rates and post-treatment pregnancy rate. Safety endpoints were disease-free survival (DFS) and overall survival (OS). Odds ratio (OR), incidence rate ratio (IRR) and hazard ratio (HR) with 95% confidence intervals (CI) were calculated for the effect of adding GnRHa to chemotherapy alone. As each study represents a cluster, statistical analysis has been performed using a random effects model. The study is registered with the PROSPERO registration number CRD42014015638. Results A total of 873 patients from 5 randomized trials were included. Median age was 38 years (interquartile range: 34-42 years). POI rate was 14.1% in the GnRHa group and 30.9% in the control group (adjusted OR 0.38; 95% CI 0.26-0.57; p < 0.001). The incidence of 1-year amenorrhea was 36.8% in the GnRHa group and 40.4% in the control group (adjusted OR 0.92; 95% CI 0.66-1.28; p = 0.623). The incidence of 2-year amenorrhea was 18.2% in the GnRHa group and 30.0% in the control group (adjusted OR 0.51; 95% CI 0.31-0.85; p = 0.009). A total of 37 patients had at least one post-treatment pregnancy in the GnRHa group and 20 in the control group (IRR 1.83; 95% CI 1.06-3.15; p = 0.030). There were no significant differences in DFS (adjusted HR 1.01; 95% CI 0.72-1.42; p = 0.999) or OS (adjusted HR 0.67; 95% CI 0.42-1.06; p = 0.083) between the GnRHa and control groups. Subgroup analyses of both efficacy and safety endpoints according to age of the patients, hormone receptor status, type and duration of chemotherapy will be presented at the conference. Conclusions This study provides level 1A of evidence for the efficacy and safety of temporary ovarian suppression with GnRHa during chemotherapy in premenopausal early breast cancer patients. Given the findings of this pooled analysis, temporary ovarian suppression with GnRHa during chemotherapy should be considered as a new standard option to reduce the likelihood of chemotherapy-induced POF and possibly improve future fertility in premenopausal early breast cancer patients. Citation Format: Lambertini M, Moore HCF, Leonard RCF, Loibl S, Munster P, Bruzzone M, Boni L, Unger JM, Anderson RA, Mehta K, Minton S, Poggio F, Albain KS, Adamson DJA, Gerber B, Cripps A, Bertelli G, Seiler S, Ceppi M, Partridge AH, Del Mastro L. Pooled analysis of five randomized trials investigating temporary ovarian suppression with gonadotropin-releasing hormone analogs during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal early 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 GS4-01.

TPS1115 Background: Although endocrine based therapy is recommended as first-line treatment in metastatic breast cancer (MBC) in patients with an HER2-/HR+ tumour up to 50% of the patients receive chemotherapy. Palbociclib (P) a CDK4/6 inhibitor improves PFS by 42% in endocrine sensitive and resistant HER2-/HR+ MBC when added to an endocrine therapy (ET). Patients included in clinical trials are often criticised not to be representative for real world breast cancer patients. Methods: Patients with first-line HER2-/HR+ MBC who are candidate for mono-chemotherapy will be eligible to be randomised 1:1 to receive either P plus ET per label or mono-chemotherapy per investigator´s choice with or without maintenance ET. In both study arms, treatment will be given until disease progression, unacceptable toxicity, withdrawal of consent of the patient or change of initial treatment plan (either planned six chemotherapy cycles followed by maintenance ET or chemotherapy until disease progression). Primary objective is to compare the time-to-treatment failure (TTF), defined as time from randomization to discontinuation of treatment for any reason, including disease progression, treatment toxicity and death. Secondary objectives are progression free survival, overall survival at 36 months, amongst other time to event endpoints; investigator assessed overall clinical response; toxicity and compliance; patient well-being and health care utilization by daily monitoring treatment impact. Aim: 360 patients will be accrued to show an improved TTF for P in combination with ET. Recruitment will start in QII/2017 and is planned for approximately 18 months in 100 sites in Germany, Spain, Poland, Italy, France, UK and Canada. Conclusions: The aim of the trial is to demonstrate that an endocrine based strategy consisting of ET plus P is superior to a chemotherapy based strategy as first-line therapy in women with HER2-/HR+ breast cancer in a real world setting.

571 Background: Time interval from diagnostic biopsy to neoadjuvant chemotherapy (NACT) start (TBC) and from last chemotherapy application to surgery (TCS) are influenced by many factors. It is unclear whether a delay of systemic therapy or surgery impacts patients (pts) outcome. Methods: 9127 pts with early BC from 6 German neoadjuvant trials receiving an anthracycline-taxane based NACT were included. pCR (ypT0/is ypN0), disease free survival (DFS) and overall survival (OS) were compared according to TBC and TCS length (cut-off of ≤4 vs >4weeks (w)), overall and in subgroups (BC subtypes [luminal, HER2+, triple-negative breast cancer (TNBC)] and pCR [yes vs no] for survival endpoints) adjusted by study. Results: Data on TBC were available for 8072 pts, on TCS for 6420, on follow-up (FU) for 7889. Median age was 49 yrs, 25.6% had cT3-4, 48.6% N+, 44.1% G3, 46.0% luminal, 26.4% TNBC, 27.6% HER2+ tumors. Median (m) FU-time was 65 months [0-201]. mTBC was 23 days [0-228] (67.5% ≤4w vs 32.5% >4w), mTCS was 28d [0-204] (53.7% ≤4w vs 46.3% >4w), with inter-study variability for mTBC ranging from 14 to 32d and for mTCS ranging from 24 to 29d from the oldest to the most recently conducted study. TBC did not influence the pCR rate, neither in all patients nor in subgroups. At multivariable logistic regression analysis TBC length did not independently predict pCR. TBC did not influence DFS or OS, neither in all patients nor in subgroups. TCS4w did not independently influence DFS or OS. Conclusions: A delay in starting NACT does not impact the pCR rate, DFS or OS and results are independent of the subgroup. However, early surgery after NACT in pts without pCR seems to influence outcome. Our analysis is explorative, but indicates for the first time, that time interval of starting NACT and undergoing surgery might be uncritical. Further research is ongoing.

Oral mucositis (OM) is a clinically important and frequent adverse event (AE) associated with cancer treatment with conventional chemotherapy as well as new targeted agents. Incidence and severity of OM vary from treatment to treatment and from patient to patient. The pathogenesis of chemotherapy-induced OM can be divided into 5 phases. OM induced by targeted therapies differs among other things in appearance, course, concomitant AEs and toxicity, and thus could be perceived as an entity distinct from chemotherapy-induced OM with an innate pathogenic mechanism. OM has a severe impact on a patient's quality of life (QoL) by causing complications such as pain and discomfort. Even more important are associated restrictions in nutrition and hydration. Thus, the efficacy of cancer therapy might be impaired due to the necessity of dose delays and dose reductions. Numerous preventive and therapeutic approaches have been evaluated, but currently no single agent has changed the standard of care in preventing and treating OM. Thus, the current management has evolved from clinical experience rather than clinical evidence. This article will review the AE ‘OM' induced by breast cancer treatment with chemotherapy and targeted agents in order to provide practical guidance for management and prevention.