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The 17th St Gallen International Breast Cancer Consensus Conference in 2021 was held virtually, owing to the global COVID-19 pandemic. More than 3300 participants took part in this important bi-annual critical review of the 'state of the art' in the multidisciplinary care of early-stage breast cancer. Seventy-four expert panelists (see Appendix 1) from all continents discussed and commented on the previously elaborated consensus questions, as well as many key questions on early breast cancer diagnosis and treatment asked by the audience. The theme of this year's conference was 'Customizing local and systemic therapies.' A well-organized program of pre-recorded symposia, live panel discussions and real-time panel voting results drew a worldwide audience of thousands, reflecting the farreaching impact of breast cancer on every continent. The interactive technology platform allowed, for the first time, audience members to ask direct questions to panelists, and to weigh in with their own vote on several key panel questions. A hallmark of this meeting was to focus on customized recommendations for treatment of early-stage breast cancer. There is increasing recognition that the care of a breast cancer patient depends on highly individualized clinical features, including the stage at presentation, the biological subset of breast cancer, the genetic factors that may underlie breast cancer risk, the genomic signatures that inform treatment recommendations, the extent of response before surgery in patients who receive neoadjuvant therapy, and patient preferences. This customized approach to treatment requires integration of clinical care between patients and radiology, pathology, genetics, and surgical, medical and radiation oncology providers. It also requires a dynamic response from clinicians as they encounter accumulating clinical information at the time of diagnosis and then serially with each step in the treatment plan and follow-up, reflecting patient experiences and treatment response.

Background This European phase IIIb, expanded-access multicenter trial evaluated the safety of EVE plus EXE in a patient population similar to BOLERO-2. Patients and methods Post-menopausal women aged ≥18 years with hormone receptor-positive, human epidermal growth factor-receptor-2–negative advanced breast cancer (ABC) recurring/progressing during/after prior non-steroidal aromatase inhibitors were enrolled. The primary objective was safety of EVE plus EXE based on frequency of adverse events (AEs), and serious AEs (SAEs). The secondary objective was to evaluate AEs of grade 3/4 severity. Results The median treatment duration was 5.1 months [95% confidence interval (CI) 4.8–5.6] for EVE and 5.3 months (95% CI 4.8–5.6) for EXE. Overall, 2131 patients were included in the analysis; 81.8% of patients experienced EVE- or EXE-related or EVE/EXE-related AEs (investigator assessed); 27.2% were of grade 3/4 severity. The most frequently reported non-hematologic AEs were (overall %, % EVE-related) stomatitis (52.8%; 50.8%) and asthenia (22.8%; 14.6%). The most frequently reported hematologic AEs were (overall %, % EVE-related) anemia (14.4%; 8.1%) and thrombocytopenia (5.9%; 4.6%). AE-related treatment discontinuations were higher in elderly (≥70 years) versus non-elderly patients (23.8% versus 13.0%). The incidence of EVE-related AEs in both elderly and non-elderly patients appeared to be lower in first-line ABC versus later lines. The incidence of AEs (including stomatitis/pneumonitis) was independent of BMI status (post hoc analysis). Overall, 8.5% of patients experienced at least one EVE-related SAE. Of the 121 on-treatment deaths (5.7%), 66 (3.1%) deaths were due to disease progression and 46 (2.2%) due to AEs; 4 deaths were suspected to be EVE-related. Conclusions This is the largest ever reported safety dataset on a general patient population presenting ABC treated with EVE plus EXE and included a sizeable elderly subset. Although the patients were more heavily pretreated, the safety profile of EVE plus EXE in BALLET was consistent with BOLERO-2. Clinical trial registration EudraCT Number: 2012-000073-23. This article has been accepted for publication in Annals of Oncology. Published by Oxford University Press.

Background In Spain luminal metastatic Breast Cancer accounts for more than 3000 deaths yearly. Ribociclib+letrozole has shown efficacy on prolonging progression free survival (PFS) vs placebo+letrozol in two phase 3 trials. However, data on efficacy and tolerability is lacking for a broader population. We present interim data from CompLEEment-1, an ongoing, open-label, phase 3b trial evaluating ribociclib+letrozole as first-line endocrine therapy in an expanded population of patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC). Methods Patients treated with ≤1 line of prior chemotherapy and no prior endocrine therapy for advanced disease received ribociclib 600 mg/day (3-weeks-on/1week-off) + letrozole (2.5 mg/day; plus monthly goserelin or leuprolide in men and premenopausal women). The primary objective was safety and tolerability. Here we report a sub-analysis of CompLEEment-1 for the Spanish population. Results 526 patients were evaluated over a median follow-up of 10.3 months. Baseline characteristics indicated a diverse population with median age of 55.6 years (range 24-85); 0.8% of patients were male, 34.6% female pre-menopausal and 64.6% female post-menopausal. 71% had visceral metastasis, in 8 cases at the CNS. 55.9% had measurable disease at baseline. The rate of all-grade and grade ≥ 3 treatment-related adverse events (AEs) was 98.5% and 70.0%, respectively. Treatment-related serious AEs occurred in 12.2% of patients. All-grade and grade ≥ 3 AEs leading to ribociclib discontinuation occurred in 13.7% and 8.2% of patients, respectively. Rates of ≥ 3 AEs of special interest (AESI) were 59.5% for neutropenia, 6.8% for increased alanine aminotransferase, 4.8% for increased aspartate aminotransferase, and 0.6% for QTcF prolongation. Patient health-related quality of life was maintained versus baseline. Conclusions Initial results from the Spanish cohort in CompLEEment-1 are consistent with previous data showing efficacy and a manageable safety profile of ribociclib plus letrozole as a first-line treatment option in a diverse group of patients with HR+, HER2– ABC. Acknowledgement: Dr. J. Gavila-Gregori, Dr. M.J. Martinez-Serrano and Dr. M. Perello contributed equally to this study. Clinical trial identification NCT02941926. Legal entity responsible for the study Novartis Pharmaceuticals Corporation. Funding Novartis Pharmaceuticals Corporation. Disclosure E.M. Ciruelos: Advisory / Consultancy, Speaker Bureau / Expert testimony, Speaker and ad.board honoraria: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Speaker and ad.board honoraria: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony, Speaker and ad.board honoraria: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Speaker and ad.board honoraria: Pfizer. R. Villanueva Vazquez: Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche. F. Moreno: Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Eisai; Advisory / Consultancy: MSD. I. Alvarez: Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche. S. Gonzalez-Santiago: Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): AstraZeneca. A. Barnadas: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Research grant / Funding (institution): Lilly; Advisory / Consultancy, Travel / Accommodation / Expenses: Eisai; Advisory / Consultancy, Travel / Accommodation / Expenses: Genomic Health; Advisory / Consultancy, Travel / Accommodation / Expenses: Pierre Fabre. B. Cantos: Research grant / Funding (institution), Study enrollment: Fundacion para la Investigacion del Hospital Puerta de Hierro de Majadahonda; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: Celgene; Advisory / Consultancy: AstraZeneca. M. Bellet Ezquerra: Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Lilly. M. Martin: Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy: Lilly; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Pharmamar; Advisory / Consultancy: Taiho Oncology; Advisory / Consultancy: Amgen; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Puma. N. Martinez: Research grant / Funding (institution): Roche; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): AstraZeneca. All other authors have declared no conflicts of interest.

Background Approximately 40% of patients (pts) with HR+, HER2– BC have mutations (mut) in PIK3CA with hyperactivation of the PI3K pathway and relative endocrine resistance. In the phase 3 SOLAR-1 trial, treatment with the α-selective PI3K inhibitor ALP with FUL significantly prolonged progression-free survival (PFS) vs placebo [PBO] + FUL in the PIK3CA-mut cohort (median PFS [mPFS], 11.0 vs 5.7 mo; HR 0.65; P Methods Pts with HR+, HER2– ABC with progression on/after aromatase inhibitor received ALP 300 mg QD (or PBO) + FUL 500 mg. Efficacy, including PFS and response, and safety were assessed. Pts were stratified according to presence of lung and/or liver metastases and prior CDK4/6 inhibitor treatment. Results Of 341 pts with PIK3CA mut, 193 (56.6%) had VM. Tumor responses were improved with ALP vs PBO in pts with or without VM (Table). The majority (n = 170; 88.1%) of pts with VM had lung and/or liver metastases and mPFS was 9.0 vs 3.7 mo in the ALP (n = 84) vs PBO (n = 86) arms (HR 0.62; 95% CI, 0.44-0.89). PFS HRs (95% CI) for ALP vs PBO in pts with presence of liver metastases (ALP, n = 49; PBO, n = 54) or lung involvement (ALP, n = 57; PBO, n = 68) were 0.58 (0.37-0.90) and 0.65 (0.42-1.01), respectively. PFS HRs (95% CI) for ALP vs PBO in pts without lung and/or liver metastases (ALP, n = 85; PBO, n = 86) and in pts with bone-only metastases (ALP, n = 42; PBO, n = 35) were 0.69 (0.47-1.01) and 0.62 (0.33-1.18), respectively. mPFS for pts with bone-only metastases in the ALP vs PBO arms was 19.1 vs 13.0 mo.. Table . 342P Visceral Metastases, includes pts with lung, liver, and other visceral metastases Nonvisceral Metastases, includes pts with bone-only metastases (n = 193) (n = 148) ALP+FUL PBO+FUL ALP+FUL PBO+FUL (n = 93) (n = 100) (n = 76) (n = 72) Best % change from baseline in sum of target lesion diameters 79% 43% 69% 45% Clinical Benefit Rate (CBR), n (%) 52 (56) 38 (38) 52 (68) 40 (56) Conclusions Treatment benefit from ALP + FUL was maintained across pt subgroups analyzed, including pts with VM and bone-only metastases, and was consistent with the benefit observed in the PIK3CA-mut cohort in SOLAR-1. Clinical trial identification NCT02437318. Editorial acknowledgement Medical editorial assistance was provided by Joe Hodgson and Amanda Vreeland, PhD, of Healthcare Consultancy Group, LLC, and funded by Novartis Pharmaceuticals Corporation. Legal entity responsible for the study Novartis Pharmaceutical Corporation. Funding Novartis Pharmaceutical Corporation. Disclosure M. Campone: Research grant / Funding (self), Grant: Novartis; Research grant / Funding (self), Personal fee: Roche; Research grant / Funding (self), Personal fee: AstraZeneca; Research grant / Funding (self), Personal fee: Pfzier; Advisory / Consultancy, Advisory board fees to the institution: Servier; Advisory / Consultancy, NA: Lilly; Advisory / Consultancy, Advisory board fees to the institution: Sanofi; Advisory / Consultancy, Advisory board fees to the institution: Accord; Research grant / Funding (self), Grant: Tessaro. H.S. Rugo: Research grant / Funding (self), Research: Pfizer, Merck, Novartis, Lilly, Genentech, OBI, Odonate, Daiichi, Eisai, Seattle Genetics and Macrogenics; Travel / Accommodation / Expenses, Travel: Lilly, Mylan, Pfizer, Amgen, Merck and Puma. G. Rubovszky: Advisory / Consultancy, Conduct of clinical trials as investigator: Novartis. F. Andre: Research grant / Funding (institution), Research: Novartis, AstraZeneca, Pfizer, Lilly, Roche. S. Loibl: Honoraria (institution), honorario: Novartis; Honoraria (institution), honorario: Pfzier; Honoraria (institution), honorario: Amgen; Honoraria (institution), honorario: Celgene; Honoraria (institution), honorario: Roche; Honoraria (institution), honorario: AstraZeneca; Honoraria (institution), honorario: Abbvie; Honoraria (institution), honorario: Lilly; Honoraria (institution), honorario: Daichi; Honoraria (institution), honorario: Eirgenix. H. Iwata: Honoraria (institution), Advisory / Consultancy, Support of parent study and funding of editorial support, honoraria and consulting: Novartis; Honoraria (institution), Advisory / Consultancy, Consulting: F. Hoffmann-La Roche via Chugai; Honoraria (institution), Advisory / Consultancy, Consulting: AstraZeneca; Honoraria (institution), Advisory / Consultancy, Consulting: Lilly; Honoraria (institution), Advisory / Consultancy, Consulting: Pfzier; Honoraria (institution), Advisory / Consultancy, Consulting: Daiichi-Sankyo. P.F. Conte: Speaker Bureau / Expert testimony, Speakers Bureau: Roche/Genentech; Novartis; AstraZeneca; Research grant / Funding (institution), Research: Roche Relationship (Institution); Novartis (Institution); Merck Serono (Institution); Travel / Accommodation / Expenses, Travel: Novartis; Celgene;AstraZeneca. I. Mayer: Research grant / Funding (institution), Institutional research funding and Ad board: Novartis; Research grant / Funding (institution), Institutional research funding and Ad board: Genentech; Research grant / Funding (institution), Institutional research funding: Pfzier; Advisory / Consultancy, Ad board: Eli-Lilly; Advisory / Consultancy, Ad board: AstraZeneca; Advisory / Consultancy, Ad board: GSK; Advisory / Consultancy, Ad board: Macrogenics; Advisory / Consultancy, Ad board: Seattle Genetics; Advisory / Consultancy, Ad board: Immunomedic. D. Juric: Advisory / Consultancy, Scientific Advisory Board: Novartis; Speaker Bureau / Expert testimony, Scientific Advisory Board: Genentech; Advisory / Consultancy, Scientific Advisory Board: Eisai; Advisory / Consultancy, Scientific Advisory Board: Ipsen; Advisory / Consultancy, Scientific Advisory Board: EMD Serono. T. Yamashita: Honoraria (self), Research grant / Funding (self): Chugai; Honoraria (self), Research grant / Funding (self): Nippon Kayaku; Honoraria (self), Research grant / Funding (self): Kyowa Kirin; Honoraria (self): Eisai, Novartis, Taiho, AstraZeneca, Pfzier Japan. I. Lorenzo: Full / Part-time employment, Employee: Novartis. A. Ridolfi: Full / Part-time employment, Employee: Novartis. E.M. Ciruelos: Honoraria (self), honorario: Consultancy for Novartis, Lilly, Roche, Pfizer; Advisory / Consultancy, Consulting: Novartis, Pfizer, Lilly, Roche; Speaker Bureau / Expert testimony, Speakers Bureau: Novartis, Pfizer, Lilly, Roche; Travel / Accommodation / Expenses, Travel: Roche, Pfizer.

Background PIK3CA mutations occur in ≈ 40% of HR+/HER2− breast cancers. In the phase III SOLAR-1 study (NCT02437318), ALP (PI3Kα inhibitor) + FUL significantly prolonged progression-free survival vs placebo (PBO) + FUL in patients (pts) with HR+/HER2− ABC, prior endocrine therapy, and PIK3CA mutations (HR 0.65; P Methods Pts received ALP + FUL (n=284) or PBO + FUL (n=287). Safety was assessed per CTCAE v4.03 and regardless of PIK3CA mutation status. We evaluated time to onset and management of key AESIs in patients receiving ALP. Results The median ALP treatment exposure was 5.5mo. As previously reported, the most common any-grade AESIs were hyperglycemia, diarrhea, and rash (Table). Rates of ALP discontinuation and median times to onset and improvement are presented in the table. Supportive medication was frequently used to manage hyperglycemia, diarrhea, and rash. In pts with anti-rash medication initiated prior to onset of rash (n=86), 60 (69.8%) received antihistamines. Use of anti-rash medication prior to onset of rash was associated with decreased frequency of rash (26.7% vs 53.9% in the overall population) and decreased reported grade (grade 3, 11.6% vs 20.1%). During the study, the implementation of more detailed AE management guidelines decreased treatment discontinuation due to any-grade AEs (29.2% vs 20.7%) and grade ≥ 3 events (18.1% vs 7.9%) between the first 50% of pts randomized and the last 50% of patients randomized.Table324PTableHyperglycemiaDiarrhea0010Rashn=284Pts with any-grade event, n (%)187 (65.8)164 (57.7)153 (53.9)-ALP discontinuation due to event, n (%)19 (10.2)8 (4.9)12 (7.8)-Received supportive medication, n (%)163 (87.2)104 (63.4)134 (87.6)-Most-common supportive medication for any-grade event, n (%)Metformin, 142 (87.1)Antipropulsives, 69 (66.3)Steroids, 113 (84.3)b,cPts with ≥ grade-3 event, n (%)110 (38.7)d19 (6.7)28 (9.9)e-Time to onset, median (range), days15 (5-395)d139 (10-470)13 (9-571)e-Time to improvement by≥1 grade, median (95% CI), days6 (4-7)d,f18 (9-45)11 (8-NE)eaBased on preferred term.bNote that this is for pts who already had developed rash, which is different from pts who received medication before the onset of rash.cIncludes both topical and systemic.dBased on fasting plasma glucose values.eBased on single preferred term.fRange. Conclusions Adverse events associatated with ALP were manageable, improved with appropriate intervention (medication and/or ALP dose interruptions/modifications), and were generally reversible upon treatment discontinuation. Use of anti-rash medication prior to rash onset reduced the frequency and grade of rash. Clinical trial identification NCT02437318. Editorial acknowledgement Tara Wabbersen of MediTech Media, LLC funded by Novartis. Legal entity responsible for the study Novartis. Funding Novartis Pharmaceuticals Corp. Disclosure H.S. Rugo: Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer Inc.; Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck Sharp & Dohme Corp.; Research grant / Funding (institution): Novartis International AG; Research grant / Funding (institution), Travel / Accommodation / Expenses: Eli Lilly and Company; Research grant / Funding (institution): Genentech, Inc.; Research grant / Funding (institution): Oklahoma Blood Institute; Research grant / Funding (institution): Odonate Therapeutics, Inc.; Research grant / Funding (institution): Daiichi Sankyo Company, Limited; Travel / Accommodation / Expenses: Mylan N.V.; Travel / Accommodation / Expenses: Amgen Inc.; Travel / Accommodation / Expenses: Puma Biotechnology, Inc. F. Andre: Research grant / Funding (institution): Novartis International AG; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Pfizer Inc.; Research grant / Funding (institution): Eli Lilly and Company; Research grant / Funding (institution): F. Hoffmann-La Roche Ltd. T. Yamashita: Honoraria (self), Research grant / Funding (institution): Chugai Pharma USA, Inc; Honoraria (self): Eisai Inc.; Honoraria (self): Novartis International AG; Honoraria (self): Taiho Oncology, Inc.; Honoraria (self), Research grant / Funding (institution): Nippon Kayaku Co.,Ltd.; Honoraria (self): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Kyowa Hakko Kirin Co., Ltd.; Honoraria (self): Pfizer Inc. J. Cruz Jurado: Honoraria (self): Novartis International AG; Honoraria (self): Genentech, Inc.; Honoraria (self): Elsai; Honoraria (self): Ipsen; Honoraria (self): EMD Serono. D. Juric: Honoraria (self): Novartis International AG; Honoraria (self): Genentech, Inc.; Honoraria (self): Eisai Inc.; Honoraria (self): Ipsen Pharma; Honoraria (self): EMD Serono, Inc. I. Mayer: Honoraria (self), Research grant / Funding (institution): Novarts International AG; Research grant / Funding (institution): Genentech, Inc.; Research grant / Funding (institution): Pfizer, Inc.; Honoraria (self): Eli Lilly and Company; Honoraria (self): AstraZeneca; Honoraria (self): GlaxoSmithKline plc.; Honoraria (self): MacroGenics, Inc. E.M. Ciruelos: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis International AG; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly and Company; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: F. Hoffmann-La Roche Ltd; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer Inc. H. Iwata: Honoraria (self), Research grant / Funding (institution): Novartis International AG; Honoraria (self): F. Hoffmann-La Roche via Chugai; Honoraria (self): AstraZeneca; Honoraria (self): Pfizer, Inc.; Honoraria (self): Eli Lilly and Company; Honoraria (self): Daiichi Sankyo Company, Ltd. P.F. Conte: Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis International AG; Speaker Bureau / Expert testimony, Research grant / Funding (institution): F. Hoffmann-La Roche Ltd; Speaker Bureau / Expert testimony: Genentech, Inc.; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Research grant / Funding (institution): EMD Serono, Inc.; Travel / Accommodation / Expenses: Celgene Corporation. M. Campone: Research grant / Funding (institution): Novartis International AG; Honoraria (self), Research grant / Funding (institution): F. Hoffmann-La Roche Ltd; Honoraria (self): AstraZeneca; Honoraria (self): Pfizer, Inc.; Honoraria (institution): Servier Laboratories; Honoraria (institution): Sanofy; Honoraria (institution): Accord; Research grant / Funding (institution): Tessaro. C. Wilke: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. D. Mills: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis International AG. M. Miller: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. S. Loibl: Honoraria (institution): Novartis International AG; Honoraria (institution): Pfizer, Inc.; Honoraria (institution): Celgene Corporation; Honoraria (institution): Amgen; Honoraria (institution): F. Hoffmann-La Roche Ltd; Honoraria (institution): AstraZeneca; Honoraria (institution): Abbvie; Honoraria (institution): Eli Lilly and Company; Honoraria (institution): Daiichi Sankyo Company, Ltd; Honoraria (institution): Eirgenix. All other authors have declared no conflicts of interest.

Background Approximately 40% of pts with HR+, HER2– ABC have mutations (mut) in PIK3CA, which encodes α-PI3K and leads to PI3K pathway hyperactivation and potentially ET resistance. ALP is a selective inhibitor of α-PI3K that, in combination with fulvestrant (FUL), significantly improved median progression-free survival (PFS) vs placebo + FUL in pts with PIK3CA-mut, HR+ HER2– ABC in the phase 3 SOLAR-1 trial (11.0 vs 5.7 mo, respectively; HR 0.65; 95% CI, 0.50-0.85; P Trial design BYLieve includes women (any menopausal status) and men with PIK3CA-mut, HR+, HER2– ABC and evidence of tumor progression on prior tx. Cohorts A and B comprise pts who received a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) + ET as their last tx. With the adoption of Amendment 3, a new cohort (C) enrolls pts who had systemic chemotherapy or ET as last prior tx and who failed aromatase inhibitor (AI) in the adjuvant or metastatic setting. In the advanced setting, ≤2 anticancer tx (including ≤1 chemotherapy) are allowed. Pts must have ≥1 measurable lesion per RECIST criteria or ≥ 1 predominantly lytic bone lesion. Key exclusion criteria include prior PI3Ki tx and type 1 or uncontrolled type 2 diabetes. Study tx comprises: Cohort A (prior CDK 4/6i + AI), ALP 300 mg once daily (qd) + FUL 500 mg Q28d + C1d15; Cohort B (prior CDK 4/6i + FUL), ALP 300 mg qd + LET 2.5 mg qd; Cohort C, ALP 300 mg qd + FUL 500 mg Q28d + C1d15. The primary endpoint is the proportion of pts free of progression at 6 mo per local investigator assessment for each cohort. Secondary endpoints include PFS, PFS2, ORR, and CBR. Safety and tolerability will also be assessed, including fasted or random blood glucose levels (non-fasted). Tumor tissue and circulating tumor DNA are collected for biomarker assessments. The study is ongoing and currently recruiting pts, with increase in planned overall enrollment from 160 to 340 pts. Clinical trial identification NCT03056755. Editorial acknowledgement Medical editorial assistance was provided by Joe Hodgson of Healthcare Consultancy Group, LLC, and funded by Novartis Pharmaceuticals Corporation. Legal entity responsible for the study Novartis Pharmaceuticals Corporation. Funding Novartis Pharmaceuticals Corporation. Disclosure E. Ciruelos: Advisory / Consultancy, Speaker and consultant fee: Novartis, Roche, Pfzier, Lilly. T. Bachelot: Research grant / Funding (self), Research grant: Novartis; Research grant / Funding (self): Roche; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Pfzier. S. Chia: Advisory / Consultancy, Research grant / Funding (institution), Payment to the institution for conducting clinical trials. Honorarium to myself for advisory boards.: Novartis; Advisory / Consultancy, Research grant / Funding (institution), Payment to the institution for conducting clinical trials. Honorarium to myself for advisory boards.: Pfzier. D. Juric: Advisory / Consultancy, Scientific Advisory Board: Novartis, Genentech, Eisai, Ipsen, EMD Serono. N. Turner: Advisory / Consultancy: AstraZeneca, BMS, Lilly, MSD, Novartis, Pfizer, Roche/Genentech, Tesaro, Bicycle Therapeutics; Research grant / Funding (self): AstraZeneca, BioRad, Pfizer, Roche/Genentech, Clovis, Guardant Health. A. Ridolfi: Full / Part-time employment: Novartis. N. Sophos: Full / Part-time employment: Novartis. B. Cooper: Full / Part-time employment: Novartis. A. Thuerigen: Full / Part-time employment: Novartis. H.S. Rugo: Research grant / Funding (institution): Pfizer, Merck, Novartis, Lilly, Genentech, OBI, Odonate, Daiichi, Eisai, Seattle Genetics and Macrogenics; Travel / Accommodation / Expenses: Lilly, Mylan, Pfizer, Amgen, Merck and Puma. All other authors have declared no conflicts of interest.

Background The purpose of this study was to determine the dose-limiting toxicity (DLT) and maximum tolerated dose of a combination of vinorelbine plus gemcitabine administered on a biweekly schedule in patients with advanced solid tumors. Patients and methods Patients with advanced or refractory solid tumors included in this phase I study were treated with vinorelbine followed by gemcitabine. Vinorelbine was given intravenously over 10 min, andgemcitabine was given intravenously at an fixed-dose infusion rate of 10 mg/m2/min. Six dose levels of vinorelbine/gemcitabine were explored: 20/2000, 25/2500, 25/3000, 30/3000, 30/3500 and 30/2500 mg/m2. Results Nineteen patients were included in the study. Fourteen patients were pretreated with chemotherapy and/or radiotherapy. A total of 123 cycles of chemotherapy were administered. DLTs were neutropenic fever and grade 3 asthenia at dose level 5 (30/3500 mg/m2); at dose level 4 (30/3000 mg/m2) they were grade 3 asthenia, and a radiation-recall reaction and pneumonitis. Sixteen patients were evaluable for efficacy. Five patients had an objective response (one complete response and four partial responses), for an overall response rate of 31%. Conclusions The recommended dose for phase II study is vinorelbine 30 mg/m2 and gemcitabine 2500 mg/m2 administered once every 2 weeks. This regimen is feasible and well-tolerated at this dose, and shows a good clinical activity in all levels explored.

Background: Metastatic breast cancer is a major cause of cancer death among women globally. In recent years, a better understanding of tumor biology, namely many molecular drivers of the disease, and the availability of high throughput technologies, has enabled the emergence of precision medicine bringing new expectations. Furthermore, the shift from single-biomarker focus to the simultaneous examination of large numbers of alterations in order to optimize drug development has resulted in the rise of molecular screening programs worldwide. In Spain, however, only a few institutions have implemented such initiatives. With this in mind, SOLTI, as collaborative network, aims to expand the access to enabling technologies and expertise to perform molecular screening of patients and facilitate their access to clinical trials with novel targeted agents. Objectives: During this pilot stage, our primary objective is to determine the success rate in including patients in trials based on their molecular profile. Additional aims are to identify technical and logistical barriers to the implementation of a nationwide program, to describe the genomic profiles of the tumors, and to assess patient outcomes. Patients and Methods: Up to 260 patients with metastatic breast cancer will be recruited in 8 participating sites in Spain. Mutation testing is performed in the genomics laboratories of Vall d'Hebron Institute of Oncology in Barcelona, Doce de Octubre University Hospital in Madrid, or the University Clinical Hospital of Valencia. Upon molecular characterization and collection of key clinical data, each case is reviewed by a multidisciplinary advisory board, which recommends potential experimental treatments. The patients, assisted by their oncologists, must consent to participate in any given clinical trial. Patient follow-up data is then collected periodically. Status and Future Perspectives: AGATA is the first multi-institutional molecular screening program ever implemented in Spain. Patient recruitment started in October 2014 and is expected to conclude in 30 months. Upon completion of the pilot stage, additional patients will be included in an expanded network of hospitals and laboratories. Acknowledgements: Funding provided by Novartis and Fundacion Mutua Madrilena.

Background Pertuzumab (P) inhibits downstream signaling of HER2 by preventing its heterodimerization with other HER family members. The epitope recognized by P is distinct from that bound by trastuzumab (H) and their complementary mechanisms of action lead to a more comprehensive HER2 blockade when combined. Data from the phase III trial CLEOPATRA showed significantly improved PFS in pts with HER2-positive 1L MBC given P + H + docetaxel (D). As H was not widely available in the (neo)adjuvant setting prior to CLEOPATRA recruitment, a relatively low proportion of pts in CLEOPATRA had previously received H. PERUSE will assess the safety and tolerability of P + H + one of a choice of taxanes (T) as 1L therapy for pts with HER2-positive metastatic or locally advanced BC. Efficacy endpoints will also be recorded in PERUSE, in a pt population likely to have experienced wider exposure to prior H therapy. Methods PERUSE is a phase IIIb, multicenter, open-label, single-arm study in pts with HER2-positive BC who have not been treated with systemic non-hormonal anticancer therapy for MBC. The planned sample size is 1500. Pts will receive, P: 840mg initial dose, 420mg q3w IV; H: 8mg/kg initial dose, 6mg/kg q3w IV, T: D, paclitaxel or nab-paclitaxel according to local guidelines. A planned protocol amendment will allow HR-positive pts to receive endocrine therapy in conjunction with P + H following completion of T in line with clinical practice. Treatment will be administered until disease progression or unacceptable toxicity. At baseline, pts must have an LVEF of ≥50%, ECOG PS of 0, 1 or 2 and must not have received prior anti-HER2 agents for MBC. Prior H and/or lapatinib in the (neo)adjuvant setting is allowed, provided there was no disease progression on-treatment. A disease-free interval of ≥6 months is required. The primary endpoint is safety and tolerability. Secondary endpoints include PFS, OS, ORR, CBR, duration of response, time to response and QoL. The final analysis will be carried out when pts have been followed up for ≥12 months. Interim analyses are planned after enrollment of ∼350, 700 and 1000 pts. Regular interim safety assessments by a DSMB will take place. Disclosure D. Miles: I have an interest in relation with one organisation that could be perceived as a possible conflict of interest in the context of the subject of this abstract. I have served on Advisory Board Meetings for Roche/Genentech. F. Puglisi: I have an interest in relation with one organisation that could be perceived as a possible conflict of interest in the context of the subject of this abstract. I participate in Advisory Board Meetings for Roche. A. Schneeweiss: I have an interest in relation with one organisation that could be perceived as a possible conflict of interest in the context of the subject of this abstract. I serve on Roche Advisory Boards and am in volved with corporate-sponsored research with Roche. L. Mitchell: I am currently an employee of F. Hoffmann-La Roche. A. Dunne: I have an interest in relation with one organisation that could be perceived as a possible conflict of interest in the context of the subject of this abstract. I am an employee of hoffmann-La Roche. T. Bachelot: I have an interest in relation with one organisation that could be perceived as a possible conflict of interest in the context of the subject of this abstract. I am involved with Roche sponsoredresearch and Roche advisory Board Meetings. All other authors have declared no conflicts of interest.

Aim: In CLEOPATRA, 808 pts with HER2-positive MBC were randomized to receive 1L placebo (Pla) + T + D or Ptz + T + D. At primary analysis, pertuzumab was shown to increase progression-free survival significantly, with a strong trend to OS benefit. At a second interim analysis (May 2012), OS was improved to a degree which was both statistically significant and clinically meaningful (HR = 0.66, 95% CI 0.52–0.84; P = 0.0008) but the median OS in pts who received Ptz was not reached. Here we report results of a subsequent prespecified OS analysis. Methods: This OS analysis was planned when ≥385 deaths were reported. The log-rank test, stratified by prior treatment status and geographic region, was used to compare OS between arms, applying the Lan-DeMets a-spending function with an O'Brien-Fleming threshold of p ≤ 0.0456. The Kaplan–Meier approach was used to estimate median OS in both arms; a stratified Cox proportional hazard model was used to estimate HR and 95% CIs. Subgroup analyses of OS were performed for stratification factors and other key baseline characteristics. Results: Median follow-up time was 50 months (mos) and the statistically significant improvement in OS in favor of Ptz + T + D was maintained (HR = 0.68, 95% CI 0.56–0.84; p = 0.0002). Median OS was 40.8 mos in the Pla arm and 56.5 mos in the Ptz arm, the difference at the medians being 15.7 mos. The OS benefit in predefined subgroups was consistent with previous observations. It is to be noted that following the previous report of OS benefit, cross-over therapy was allowed and 48 pts in the Pla arm crossed over to the Ptz arm. The safety profile of Ptz + T + D in the overall population and in pts who crossed over to the Ptz arm was consistent with the known safety profile of Ptz and the long-term cardiac safety profile was maintained. Conclusions: 1L treatment with Ptz + T + D significantly improved OS for pts with HER2-positive MBC compared with Pla + T + D, providing a 15.7 mo increase in the median values. The 56.5 mo median OS is unprecedented in 1L MBC and this substantial improvement confirms the Ptz regimen as 1L standard of care for pts with HER2-positive MBC. Disclosure: S. Swain: acts as an uncompensated consultant for Genentech/Roche. Her institution has received research funding from Genentech/Roche, Pfizer, Puma, Sanofi-Aventis and Bristol-Myers Squibb; S. Kim: has received research funding from Novartis; J. Cortes: has provided consultancy for Novartis, Celgene and Roche and has received honoraria from Novartis, Celgene, Eisai and Roche; M. Campone: has provided consultancy for Novartis/Servier and has received honoraria from Novartis; J. Ferrero: has provided consultancy for Sanofi and has received honoraria from Novartis and Roche; A. Schneeweiss: has provided consultancy for Medac, Celgene and Roche, has received honoraria from Novartis, Celgene, Eisai, Astrazeneca, GlaxoSmithKline, Pfizer and Roche and has received research funding from Roche and Celgene; S. Heeson and G. Ross: is an employee of and owns shares in Roche; E. Clark: is an employee of Roche and owns shares in AstraZeneca; M.C. Benyunes: is an employee of Genentech/Roche; J. Baselga: has provided consultancy for Roche. All other authors have declared no conflicts of interest.

Aim: Combining BEV with 1st- or 2nd-line chemotherapy (CT) improves progression-free survival (PFS) in HER2-negative LR/mBC. The open-label randomised phase III TANIA trial evaluated further BEV in BEV-pretreated LR/mBC. Methods: Patients (pts) whose HER2-negative LR/mBC had progressed during/after ≥12 weeks of 1st-line BEV + CT were randomised 1:1 to 2nd-line single-agent CT either alone or with BEV (15 mg/kg q3w or 10 mg/kg q2w). Stratification factors were: hormone receptor status; time to 1st-line progression (PD; 1.5 × upper normal limit). 2nd-line therapy was continued until PD, unacceptable toxicity or consent withdrawal. At PD, pts in the CT arm received 3rd-line CT without BEV (no crossover); pts initially randomised to CT + BEV received 3rd-line CT + BEV. The primary endpoint was PFS from randomisation to 2nd PD/death. Additional endpoints included 2nd-line PFS in prespecified subgroups, 2nd- and 3rd-line PFS (randomisation to 3rd PD/death), 2nd-line objective response rate, overall survival (OS), safety, QoL and biomarkers. Sample size was calculated based on a log-rank test assuming median PFS of 7 → 9.3 mo and a HR of 0.75. PFS events were required in 384 of 488 pts for 80% power at 2-sided a = 0.05. Results: From Jan 2011 to Apr 2013, 494 pts were enrolled (247 CT; 247 CT + BEV). Baseline characteristics, CT vs CT + BEV: median age 54 vs 56 y; triple negative 23% vs 20%; disease-free interval ≤12 mo 10% vs 7%. The most frequently chosen 2nd-line CT was capecitabine (59% vs 61%). CT (N = 247) CT + BEV (N = 247) Median follow-up, mo 15.9 16.1 2nd-line PFS (primary endpoint) Events, n (%) 203 (82) 204 (83) Median 2nd-line PFS, mo 4.2 6.3 Stratified HR (95% CI) 0.75 (0.61–0.93) p = 0.0068a Best objective response rate, % (95% CI) 16.8 (11.7–22.9) 20.9 (15.2–27.5) Difference (95% CI) 4.1 (–4.2 to 12.4) p = 0.3457b 2nd-line grade ≥3 adverse events of special interest, %c (N = 238) (N = 245) Hypertension 7.1 13.5 Proteinuria 0.4 6.9 Venous thromboembolic event 2.1 3.3 Febrile neutropenia 1.7 3.3 Congestive heart failure 0.4 2.0 Bleeding 1.7 0.4 Arterial thromboembolic event 1.3 0 Wound-healing complication 0 0.8 Gastrointestinal perforation 0 0.4 Fistula/abscess 0 0 a2-sided stratified log-rank test. b2-sided chi-squared test with Schouten correction. cBEV basket terms, MedDRA v16.1. Data cut-off: 20 Dec 2013. Conclusions: The primary objective was met, showing statistically significantly improved PFS with BEV after PD on 1st-line BEV-containing therapy. 2nd-line safety results were as expected from previous BEV trials in LR/mBC. Final OS, 2nd and 3rd-line PFS and 3rd-line safety results are due in 2015. Disclosure: G. von Minckwitz: is a paid member on Roche's advisory boards, and has received speaker honoraria and conducted Roche-sponsored research; F. Puglisi: has received honoraria from Roche; J. Cortes: has received honoraria from Roche, Celgene, Novartis and Eisai and has acted as a consultant for Roche and Celgene; E. Vrdoljak: is a member of Roche advisory boards and has received corporate sponsored research; N. Marschner:is a member of Roche advisory boards and has received corporate sponsored research; C. Zielinski: has received speaker honoraria Roche, Eli Lilly and Pfizer; G. Romieu: is a member of a Roche Advisory Board; M. De Laurentiis: has received honoraria for talks, seminars and Advisory Board participation from Roche; C. Veyret: is an expert member of Roche Boards; S. De Ducla: is an employee of, and holds stock in Roche; U. Freudensprung: is an employee of F. Hoffmann-La Roche Ltd S. Srock: SS is an employee of, and holds stock in Roche; J. Gligorov: has acted as a Consultant/Advisor for, and has received honoraria and research funding from Roche. All other authors have declared no conflicts of interest.

Background MicroRNAs (miRNAs) are small noncoding RNA molecules that post-transcriptionally regulate gene expression. In the present study, we describe miRNA expression in early node-positive BC and identify a 8-miRNA score that could contribute to prognosis assessment. Methods First, microarray analysis was performed using RNA samples extracted from primary breast cancer. The expression of miRNAs was analyzed by RT-qPCR using the TaqMan Arrays from Applied Biosystems. After a suitable normalization of the 677 miRNAs analyzed, 96 presented a good correlation between their expression in frozen and paraffin-embeded tissue. A supervised analysis was done in order to identify miR that could predict relapse. Results 172 patients with node-positive chemotherapy-treated early BC were included in the present study. The median age at diagnosis was (53.7) years, 128 cases (74.4%) had positive estrogen receptor, and 163 patients (94,7%) received adjuvant chemotherapy. After a median follow up of 8,1 years, 71p (41.2%) relapsed. Supervised analyses identified 8 microRNAs (has miR-30e, miR-30a, miR-21, miR-210, miR-93, miR-150, miR-99b, miR-572) associated with higher risk of relapse (5 year PFS 50% vs 90%, HR 3.75, 95% CI 2.27 – 6.19) and with estimated overall survival (median not reached, HR 4.51, 95% CI 2.36 – 8.61). Interestingly, miRNAs defined 2 prognostic groups (high and low risk) regardless of type of adjuvant chemotherapy (with or without anthracyclines) and histological subtype (luminal A, B or triple negative). Conclusions This study suggests that miRNA expression could contribute to assess molecular prognosis of breast cancer and identifies clusters of miRNAs that could improve outcome prediction. A validation study in node-negative and triple negative disease is planned. Disclosure All authors have declared no conflicts of interest.

Background Bevacizumab in combination with chemotherapy has demonstrated activity for ovarian cancer in first and second lines. The purpose of this study is to evaluate the efficacy and safety of bevacizumab plus metronomic cyclophosphamide in heavily pretreated ovarian cancer patients Methods We reviewed retrospectively 29 patients (p) with recurrent ovarian cancer treated with bevacizumab 10 mg/Kg IV every 14 days plus oral cyclophosphamide 50 mg daily between January 2007 and January 2012 at a single institution. P characteristics, tumour features, survival data and adverse events (AE) were collected. Results Twenty-nine p with a median age of 59 years old (31-79) and ECOG 1 (0-2) were analyzed. Fifteen (52%) and 14 (48%) p had stage IV and IIIC respectively before receiving bevacizumab-cyclophosphamide. The most frequent pathologic subtype was serous in 22 p (76%). The median of previous lines was 4 (2-9), including drugs as carboplatin 29p (100%), paclitaxel 29p (100%), pegylated liposomal doxorubicin 26p (90%), gemcitabine 20p (69%), altretamine 10p (34%), topotecan 9p (31%) or trabectedine 1p (3%). Twenty-three cases (79%) were platinum-resistant (progression free interval less than 6 months from last platinum treatment). The median of cycles administered was 9 (3-67). Twenty-six p were assessable for CA 125 marker evaluation: 4p (15%) had CA125 normalization, 7p (27%) partial response (PR), 8p (31%) stable disease (SD) and 7p (27%) progression disease (PD). The radiologic evaluation was performed in 23 patients: There were 6p (26%) with PR, 9p (39%) with SD and 8p (35%) with PD. Median progression free survival (PFS) and overall survival (OS) were 3.7 months and 12.1 months respectively. P with platinum-resistant disease had significantly worse PFS (3.2m vs 36.0m) p = 0.001 and OS (12m vs not reached) p = 0.009. P with ECOG >1 also had worse PFS (2.8m vs 4.7m) p = 0.047 and OS (5.4m vs 34.5m) p = 0.011). Severe AE were G3 arterial hypertension (1p), G3 mucositis (1p), G3 anaemia and G4 digestive bleeding (1p). No alopecia and neurotoxicity deterioration were observed. Conclusions This schedule consisting on bevacizumab plus metronomic cyclophosphamide shows activity in heavily pre-treated ovarian cancer with a well toxicity profile Disclosure All authors have declared no conflicts of interest.

Background Medical board interpretation of prognostic and predictive factors and quality of IHC analysis can substantially affect the adjuvant treatment advice, resulting in substantial differences in treatment recommendations; with risk of potential over- and under treatment. Introduction of a centralized multi-gene assay could potentially lead to more formalized treatment recommendations throughout Europe. The primary aim of this study was to measure the impact of MammaPrint on chemotherapy treatment advice for patient cohorts from 3 different European institutes. Methods Between 2008 and 2010, tumor samples from early stage breast cancer patients (T1-3, N0-1, M0, Results Treatment advice as assessed by the Spanish multidisciplinary team was changed in 27% of patients after disclosure of MammaPrint results, in 33% of patients as assessed by the Dutch team, in 26% of patients by the Italian team and in 22% of patients by the Belgian team. The inter-institutional agreement for the four multidisciplinary teams in treatment advice was 57% (prior to MammaPrint disclosure) and increased to 79% after disclosing MammaPrint results. Conclusion This study demonstrates high variability in adjuvant chemotherapy treatment advice between multidisciplinary teams from 4 different European hospitals based on traditional patient and tumor related parameters. MammaPrint would have modified adjuvant chemotherapy treatment advice in around 27% of patients and lead to a more consistent and objective treatment advice. Disclosure L. Stork-Sloots: I am an employee of Agendia. All other authors have declared no conflicts of interest.

Background In HER2+ MBC, central nervous system (CNS) metastases (mets) occur in 28 - 43% of cases. Systemic therapies with potential to prevent or reduce CNS mets are of current interest. Based on lapatinib promising activity in CNS mets, CEREBEL evaluated the prophylactic impact on CNS mets incidence in HER2+ MBC pts treated with Lapatinib plus capecitabine (LC) in comparison to Trastuzumab plus capecitabine (TC). Methods CEREBEL was a multicenter study in HER2+ MBC pts without CNS mets at baseline, confirmed centrally by MRI. Prior treatment must include anthracyclines or taxanes in (neo)adjuvant or metastatic setting. Pts were randomized to LC (L-1250 mg daily + C-2000 mg/m2/day for 14 days [21-day cycle]) or TC (T loading dose 8 mg/kg followed by 6 mg/kg q3weekly + C-2500 mg/m2/day for 14 days [21-day cycle]). Primary endpoint was incidence of CNS as first site of relapse. Secondary endpoints were progression free survival (PFS), overall survival (OS), CNS progression at any time, overall response rate (ORR), clinical benefit response rate, duration of response and safety. Results A pre-specified interim analysis (IA) including 475 pts was performed by an IDMC convened on June 2012. A total of 43% and 46% of pts had not received prior treatment for MBC, 38% and 40% of pts had not received prior T, in LC and TC arms, respectively. Adverse events were similar in both arms with the exception of diarrhoea, nausea and rash (higher with LC). The incidence of CNS metastasis as site of first relapse was 3% for LC versus 4% for TC (OR 95% CI = 0.75 (0.25, 2.20) in modified ITT population (N = 218 pts per arm). The median PFS was 6.6 and 8.0 months in LC and TC arms (HR: 1.3; 95% CI: 1.0, 1.7; ) and median OS was 22.4 and 27.3 months (HR:1.58; 95% CI:1.07,2.32)(ITT) Conclusions Based on these results, the IDMC recommended study termination. Final results and updated survival data will be presented at ESMO with the 535 patients included in CEREBEL. EudraCT number 2008-000673-38 Disclosure X. Pivot: I am consultant and I have received honorariums for the sponsor GSK. R. Allerton: Roche advisory boad for use of Pertuzumab in breast cancer. R. Parikh: Employee of GSK M. DeSilvio: Employee of GSK S. Santillana: Employees of GSK, Director Clinical Development R. Swaby: Employee of GSK. All other authors have declared no conflicts of interest.