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Background: NATALEE assessed efficacy and tolerability of 3 years of adjuvant ribociclib plus a nonsteroidal aromatase inhibitor (NSAI) compared with an NSAI alone in a broad population of patients with hormone receptor (HR)-positive/human epidermal growth factor 2 (HER2)-negative early breast cancer, including a select group without nodal involvement. This is the final preplanned analysis of invasive disease-free survival (iDFS)., Patients and Methods: Premenopausal/postmenopausal women and men were randomized 1 : 1 to ribociclib (n = 2549; 400 mg/day, 3 weeks on/1 week off for 36 months) plus NSAI (letrozole 2.5 mg/day or anastrozole 1 mg/day for 60 months) or NSAI alone (n = 2552). Men and premenopausal women also received goserelin (3.6 mg once every 28 days). Patients had anatomical stage IIA (N0 with additional risk factors or N1), IIB, or III disease. The primary endpoint was iDFS. Secondary efficacy endpoints were recurrence-free survival (RFS), distant DFS, and overall survival. This final iDFS analysis was planned after ∼500 events., Results: At data cut-off (21 July 2023), ribociclib was stopped for 1996 patients (78.3%); 1091 (42.8%) completed 3 years of ribociclib, and ribociclib treatment was ongoing for 528 (20.7%). Median follow-up for iDFS was 33.3 months. Overall, 226 and 283 iDFS events occurred with ribociclib plus NSAI versus NSAI alone, respectively. Ribociclib plus NSAI demonstrated significant iDFS benefit over NSAI alone [hazard ratio 0.749, 95% confidence interval (CI) 0.628-0.892; P = 0.0012]. The 3-year iDFS rates were 90.7% (95% CI 89.3% to 91.8%) versus 87.6% (95% CI 86.1% to 88.9%). A consistent benefit was observed across prespecified subgroups, including stage (II/III) and nodal status (positive/negative). Distant DFS and RFS favored ribociclib plus NSAI. Overall survival data were immature. No new safety signals were observed., Conclusions: With longer follow-up and most patients off ribociclib, NATALEE continues to demonstrate iDFS benefit with ribociclib plus NSAI over NSAI alone in the overall population and across key subgroups. Observed adverse events remained stable., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Overall survival (OS) is a universally accepted measure of clinical benefit; however, prolonged follow-up is needed to observe sufficient events. Disease-free survival (DFS) has been widely adopted as a primary endpoint for early breast cancer (EBC) trials, as follow-up is comparatively shorter. Here, we present an analysis evaluating DFS as a surrogate for OS for adjuvant treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) EBC., Methods: A systematic literature review which included randomized controlled trials (RCTs) with ≥80% of adult patients with HR+/HER2- EBC was conducted. The RCTs evaluated various systemic therapeutic categories; key inclusion criteria included reporting of DFS and OS hazard ratios (HRs) and mature OS data. Spearman rank correlation and weighted linear regression analyses evaluated DFS and OS HR correlation. A scenario analysis tested base-case analysis robustness, and a parallel analysis using patient-level data was conducted., Results: The base case (N = 14 RCTs) showed an unweighted Spearman coefficient of 0.81 between OS and DFS (weighted: 0.81), with 84% of the variability in OS explained by DFS differences (R 2 from weighted regression). The surrogate threshold effect (Burzykowski T, Buyse M. Pharm Stat. 2006;5:173-186) was 0.82 for DFS/OS HR. Scenario analysis (n = 9 RCTs), which excluded chemotherapy trials, and patient-level analysis using FACE trial data were consistent with the base-case analysis., Conclusions: These analyses support DFS as a reliable surrogate endpoint for OS in adjuvant HR+/HER2- EBC trials. Using DFS as a surrogate measure will permit timelier access to novel treatments for patients with HR+/HER2- EBC., Competing Interests: Declaration of Competing Interest Representatives of the sponsor were responsible for trial design, data compilation, and confirming the accuracy of the analyses. All authors had access to the data and vouch for the completeness and accuracy of the data as well as the fidelity of the trial to the protocol. All authors participated in the writing and review of all manuscript drafts and contributed to the interpretation of the data. Medical writing support and editorial support were paid for by Novartis., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Ribociclib has been shown to have a significant overall survival benefit in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Whether this benefit in advanced breast cancer extends to early breast cancer is unclear., Methods: In this international, open-label, randomized, phase 3 trial, we randomly assigned patients with HR-positive, HER2-negative early breast cancer in a 1:1 ratio to receive ribociclib (at a dose of 400 mg per day for 3 weeks, followed by 1 week off, for 3 years) plus a nonsteroidal aromatase inhibitor (NSAI; letrozole at a dose of 2.5 mg per day or anastrozole at a dose of 1 mg per day for ≥5 years) or an NSAI alone. Premenopausal women and men also received goserelin every 28 days. Eligible patients had anatomical stage II or III breast cancer. Here we report the results of a prespecified interim analysis of invasive disease-free survival, the primary end point; other efficacy and safety results are also reported. Invasive disease-free survival was evaluated with the use of the Kaplan-Meier method. The statistical comparison was made with the use of a stratified log-rank test, with a protocol-specified stopping boundary of a one-sided P-value threshold of 0.0128 for superior efficacy., Results: As of the data-cutoff date for this prespecified interim analysis (January 11, 2023), a total of 426 patients had had invasive disease, recurrence, or death. A significant invasive disease-free survival benefit was seen with ribociclib plus an NSAI as compared with an NSAI alone. At 3 years, invasive disease-free survival was 90.4% with ribociclib plus an NSAI and 87.1% with an NSAI alone (hazard ratio for invasive disease, recurrence, or death, 0.75; 95% confidence interval, 0.62 to 0.91; P = 0.003). Secondary end points - distant disease-free survival and recurrence-free survival - also favored ribociclib plus an NSAI. The 3-year regimen of ribociclib at a 400-mg starting dose plus an NSAI was not associated with any new safety signals., Conclusions: Ribociclib plus an NSAI significantly improved invasive disease-free survival among patients with HR-positive, HER2-negative stage II or III early breast cancer. (Funded by Novartis; NATALEE ClinicalTrials.gov number, NCT03701334.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: In monarchE, abemaciclib demonstrated a sustained benefit in invasive disease-free survival and a tolerable safety profile at 42-months median follow-up. With no expected disease-related symptoms, therapies in the adjuvant setting should preserve quality of life (QoL). With all patients off abemaciclib, we report updated patient-reported outcomes (PROs) for the full 2-year treatment period and follow-up., Methods: Patients completed PROs including FACT-B, FACT-ES, and FACIT-Fatigue at baseline, 3, 6, 12, 18, and 24 months during treatment, and 1, 6, and 12 months after treatment discontinuation. Mixed effects repeated measures model estimated changes from baseline within and between arms for QoL scales and individual items. Meaningful changes were prespecified and no statistical testing was performed. Frequencies of responses to items associated with relevant adverse events and treatment bother were summarized., Results: At baseline, completion rates for PRO instruments were >96 %. Mean changes from baseline for all QoL scales were numerically similar within and between arms (ie, less than prespecified thresholds). The same was observed for all individual items, except diarrhea. Within abemaciclib arm, meaningful differences for diarrhea were observed at 3 and 6 months (mean increases of 1.19 and 1.03 points on 5-point scale, respectively). During treatment, most patients in both arms (69-78 %) reported being bothered "a little bit" or "not at all" by side effects. Overall, patterns for fatigue were similar between arms. During post-treatment follow-up, PROs in both arms were similar to baseline., Conclusion: PRO findings confirm a tolerable and reversible toxicity profile for abemaciclib. QoL was preserved with the addition of adjuvant abemaciclib to endocrine therapy, supporting its use in patients with HR+, HER2-, high-risk early breast cancer., Competing Interests: Declaration of Competing Interest SMT reports serving as a consulting or advisory role for Novartis, Pfizer, Merck, Eli Lilly and Company, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, Seattle Genetics, CytomX Therapeutics, Daiichi Sankyo, Gilead, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Infinity Therapeutics, Myovant (now Sumitovant Biopharma), Zetagen, Umoja Biopharma, Artios Pharma, Menarini/Stemline, Aadi Biopharma, Bayer, Incyte Corp, Jazz Pharmaceuticals, Natera; and research funding (to institute) from Genentech/Roche, Merck, Exelixis, Pfizer, Eli Lilly and Company, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, NanoString Technologies, Gilead, Seattle Genetics, OncoPep, Daiichi Sankyo, outside of the submitted work. VG reports personal fees for advisory board membership for AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly and Company, Exact Sciences, Gilead, Merck Serono, MSD, Novartis, Pfizer, Olema Oncology, Pierre Fabre; personal fees as an invited speaker for AstraZeneca, Daiichi Sankyo, Eli Lilly and Company, Exact Sciences, Gilead, GSK Novartis and Zentiva; personal fees for expert testimony for Eli Lilly and Company, outside of the submitted work. JHS reports no known competing financial interest or personal relationships that could have appeared to influence the submitted work. JC reports honoraria from Glaxo, AstraZeneca, Roche, Novartis, Pharmamar, Eisai, Eli Lilly and Company, Daichii Sankyo, Gilead, Seagen, MSD, Pierre Fabre, and Pfizer; serves as a consulting or advisory role for AstraZeneca, Roche, Novartis, Pharmamar, Eisai, Eli Lilly and Company, Glaxo, Daichii Sankyo, Gilead, Seagen, Deciphera, and Pfizer; and travel expenses from Novartis, Gilead, Pharmamar, and Daichii-Sankyo, outside of the submitted work. MHA reports no known competing financial interest or personal relationships that could have appeared to influence the submitted work. MT reports fees from Eli Lilly and Company for speaker’s bureau, outside of the submitted work. CB reports grants and research support to their institution from Nektar, Pfizer, Polyphor, Amgen, Daiichi Sankyo, Sanofi, Exelixis, Regeneron, Novartis, GSK, Janssen, OBI Pharma, Eli Lilly and Company, Seagen, Roche, Bristol-Myers Squibb, MSD, Merck Serono, AstraZeneca, Novocure, Aveo Oncology, Takeda, TRIO, PharmaMar, Celgene, PPD, Syneos Health, Labcorp, ICON, IQVIA, Parexel, Nuvisan, PSI, Worldwide, Gilead Sciences, Bayer, and Servier; ownership or stocks from Tummi and MEDSIR; and serves on the advisory boards and consulting with Boehringer-Ingelheim, GSK, Novartis, Pfizer, Roche/Genentech, Eisai, Bayer, MSD, AstraZeneca, Zodiac, Eli Lilly and Company, Sanofi, and Daiichi, outside of the submitted work. KM reports no known competing financial interest or personal relationships that could have appeared to influence the submitted work. RW, MMunoz, BSA, AML are employees and/or stock shareholders of Eli Lilly and Company. MMartin reports research grants from Roche, PUMA and Novartis; consulting/advisory fees from AstraZeneca, Amgen, Taiho Oncology, Roche/Genentech, Novartis, PharmaMar, Eli Lilly and Company, PUMA, Taiho Oncology, Daiichi Sankyo, Menarini/Stemline, and Pfizer; speakers’ honoraria from AstraZeneca, Lilly, Amgen, Roche/Genentech, Novartis, and Pfizer, outside of the submitted work. SRDJ reports grants or contracts from Pfizer, Puma Biotechnology, Eli Lilly and Company, AstraZeneca, Novartis, and Roche–Genentech for research funding to institute for laboratory studies and clinical trials; consulting fees from Eli Lilly and Company, AstraZeneca, Puma Biotechnology, Pfizer, Novartis, and Sanofi Genzyme for consulting or an advisory role; and payment or honoraria from Pfizer, Eisai, AstraZeneca, and Roche–Genentech for speaker's bureau, outside of the submitted work. PKL reports no known competing financial interest or personal relationships that could have appeared to influence the submitted work. NH reports honoraria for lectures and/or consulting froom Amgen, AstraZeneca, Daiichi-Sankyo, EPG Communication, Gilead, Eli Lilly and Company, MEDSCAPE, MSD, Novartis, Pierre-Fabre, Pfizer, Roche, Sandoz, Sanofi, Seagen, Springer, Viatris, and Zuelligpharma; ownership interest in Minority ownership as Co-Director West German Study Group (WSG), outside of the submitted work., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors palbociclib, ribociclib, and abemaciclib are standard-of-care therapy for hormone receptor-positive advanced or metastatic breast cancer, based on randomized trials showing improved progression-free survival for all 3 drugs and overall survival for ribociclib and abemaciclib. Results in early breast cancer are discordant, with sustained improvement in invasive disease-free survival demonstrated for abemaciclib but not other CDK4/6 inhibitors to date. We review nonclinical studies exploring mechanistic differences between the drugs, the impact of continuous dosing on treatment effect, and translational research into potential resistance mechanisms and prognostic and predictive markers. We focus particularly on how emerging findings may help us understand similarities and differences between the available CDK4/6 inhibitors. Even at late-stage clinical development, there remains much to learn about how agents in this class exert their varying effects., (© The Author(s) 2023. Published by Oxford University Press.)

Purpose: Predictive biomarkers for capecitabine benefit in triple-negative breast cancer (TNBC) have been recently proposed using samples from phase III clinical trials, including non-basal phenotype and biomarkers related to angiogenesis, stroma, and capecitabine activation genes. We aimed to validate these findings on the larger phase III GEICAM/CIBOMA clinical trial., Experimental Design: Tumor tissues from patients with TNBC randomized to standard (neo)adjuvant chemotherapy followed by capecitabine versus observation were analyzed using a 164-gene NanoString custom nCounter codeset measuring mRNA expression. A prespecified statistical plan sought to verify the predictive capacity of PAM50 non-basal molecular subtype and tested the hypotheses that breast tumors with increased expression of (meta)genes for cytotoxic cells, mast cells, endothelial cells, PDL2, and 38 individual genes benefit from adjuvant capecitabine for distant recurrence-free survival (DRFS; primary endpoint) and overall survival., Results: Of the 876 women enrolled in the GEICAM/CIBOMA trial, 658 (75%) were evaluable for analysis (337 with capecitabine and 321 without). Of these cases, 553 (84%) were profiled as PAM50 basal-like whereas 105 (16%) were PAM50 non-basal. Non-basal subtype was the most significant predictor for capecitabine benefit [HRcapecitabine, 0.19; 95% confidence interval (CI), 0.07-0.54; P < 0.001] when compared with PAM50 basal-like (HRcapecitabine, 0.9; 95% CI, 0.63-1.28; P = 0.55; Pinteraction<0.001, adjusted P value = 0.01). Analysis of biological processes related to PAM50 non-basal subtype revealed its enrichment for mast cells, extracellular matrix, angiogenesis, and features of mesenchymal stem-like TNBC subtype., Conclusions: In this prespecified correlative analysis of the GEICAM/CIBOMA trial, PAM50 non-basal status identified patients with early-stage TNBC most likely to benefit from capecitabine., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: KAMILLA is a single-arm safety study of trastuzumab emtansine (T-DM1) in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (BC; NCT01702571). We report the final analysis of cohort 2 (Asia) within the context of published cohort 1 (Global) findings., Methods: Patients had HER2-positive, locally advanced, or metastatic BC progressing after chemotherapy and anti-HER2 therapy or ≤6 months after adjuvant therapy. The primary objective was to further evaluate T-DM1 (3.6 mg/kg, administered intravenously every 3 weeks) safety/tolerability, including the following adverse events of primary interest (AEPIs): grade ≥3 AEPIs (hepatic events, allergic reactions, thrombocytopenia, hemorrhage events), all grade ≥3 treatment-related AEs, and all-grade pneumonitis., Results: KAMILLA enrolled 2185 patients (cohort 1, n = 2003; cohort 2, n = 182) as of 31 July 2019. Of these, 2002 and 181 per cohort were treated and included in the safety population. Approximately 70% of patients had two or more previous treatment lines in the metastatic setting. Median T-DM1 exposure was 5.6 and 5.0 months per cohort; median follow-up was 20.6 and 15.1 months. The overall AEPI rate was higher in cohort 2 (93/181; 51.4%) versus cohort 1 (462/2002; 23.1%), mostly driven by a higher grade ≥3 thrombocytopenia rate in cohort 2. In cohort 2, grade ≥3 thrombocytopenia was not associated with grade ≥3 hemorrhagic events and most (128/138) fully resolved. Grade ≥3 treatment-related AEPI rates were 18.4% (cohort 1) and 48.6% (cohort 2), the latter mainly due to thrombocytopenia. Any-grade pneumonitis rates were 1.0% and 2.2%. No new safety signals were identified. Median (95% confidence interval) progression-free survival was 6.8 months (5.8-7.6 months) and 5.7 months (5.5-7.0 months) in cohorts 1 and 2, respectively; median overall survival was 27.2 months (25.5-28.7 months) and 29.5 months (21.1 months to non-estimable). In both cohorts, median progression-free survival and overall survival decreased with increasing prior therapy lines., Conclusions: Cohort 2 results aligned with previous findings in Asian patients, supporting the manageable safety profile and use of T-DM1 in advanced BC., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: We aimed to improve efficacy and reduce toxicity of high-risk human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC) treatment by replacing taxanes and trastuzumab with trastuzumab emtansine (T-DM1)., Methods: The phase III KAITLIN study (NCT01966471) included adults with excised HER2-positive EBC (node-positive or node-negative, hormone receptor-negative, and tumor > 2.0 cm). Postsurgery, patients were randomly assigned 1:1 to anthracycline-based chemotherapy (three-four cycles) and then 18 cycles of T-DM1 plus pertuzumab (AC-KP) or taxane (three-four cycles) plus trastuzumab plus pertuzumab (AC-THP). Adjuvant radiotherapy/endocrine therapy was permitted. Coprimary end points were invasive disease-free survival (IDFS) in the intention-to-treat node-positive and overall populations with hierarchical testing., Results: The median follow-up was 57.1 months (interquartile range, 52.1-60.1 months) for AC-THP (n = 918) and 57.0 months (interquartile range, 52.1-59.8 months) for AC-KP (n = 928). There was no significant IDFS difference between arms in the node-positive (n = 1,658; stratified hazard ratio [HR], 0.97; 95% CI, 0.71 to 1.32) or overall population (n = 1846; stratified HR, 0.98; 95% CI, 0.72 to 1.32). In the overall population, the three-year IDFS was 94.2% (95% CI, 92.7 to 95.8) for AC-THP and 93.1% (95% CI, 91.4 to 94.7) for AC-KP. Treatment completion rates (ie, 18 cycles) were 88.4% for AC-THP and 65.0% for AC-KP (difference driven by T-DM1 discontinuation because of laboratory abnormalities [12.5%]). Similar rates of grade ≥ 3 (55.4% v 51.8%) and serious adverse events (23.3% v 21.4%) occurred with AC-THP and AC-KP, respectively. KP decreased clinically meaningful deterioration in global health status versus THP (stratified HR, 0.71; 95% CI, 0.62 to 0.80)., Conclusion: The primary end point was not met. Both arms achieved favorable IDFS. Trastuzumab plus pertuzumab plus chemotherapy remains the standard of care for high-risk HER2-positive EBC., Competing Interests: Ian E. KropEmployment: Freeline Therapeutics (I), PureTech (I)Leadership: AMAG Pharmaceuticals (I), Freeline Therapeutics (I), PureTech (I)Stock and Other Ownership Interests: AMAG Pharmaceuticals (I), Freeline Therapeutics (I), PureTech (I)Honoraria: Genentech/Roche, AstraZeneca¸ CelltrionConsulting or Advisory Role: Genentech/Roche, Seattle Genetics, Daiichi Sankyo, MacroGenics, Novartis, Merck, Bristol Myers Squibb, AstraZenecaResearch Funding: Genentech (Inst), Pfizer (Inst) Seock-Ah ImConsulting or Advisory Role: AstraZeneca, Novartis, Roche/Genentech, Eisai, Pfizer, Amgen, Hanmi, Lilly, GlaxoSmithKline, MSD, Daiichi SankyoResearch Funding: AstraZeneca (Inst), Pfizer (Inst), Roche/Genentech (Inst), Daewoong Pharmaceutical (Inst), Eisai (Inst)Other Relationship: Roche Carlos BarriosStock and Other Ownership Interests: Biomarker, MedSIR, TummiHonoraria: Novartis, Roche/Genentech, Pfizer, GlaxoSmithKline, Sanofi, Boehringer Ingelheim, Eisai¸ MSD, Bayer, Lilly, AstraZeneca, Zodiac PharmaConsulting or Advisory Role: Boehringer Ingelheim, Roche/Genentech, Novartis, GlaxoSmithKline, Eisai, Pfizer, AstraZeneca, Libbs, MSD Oncology, United Medical, LillyResearch Funding: Pfizer (Inst), Novartis (Inst), Amgen (Inst), AstraZeneca (Inst), Boehringer Ingelheim (Inst), GlaxoSmithKline (Inst), Roche/Genentech (Inst), Lilly (Inst), Sanofi (Inst), Taiho Pharmaceutical (Inst), Mylan (Inst), Merrimack (Inst), Merck (Inst), AbbVie (Inst), Astellas Pharma (Inst), BioMarin (Inst), Bristol Myers Squibb (Inst), Daiichi Sankyo (Inst), Abraxis BioScience (Inst), AB Science (Inst), Asana Biosciences (Inst), Medivation (Inst), Exelixis (Inst), ImClone Systems (Inst), LEO Pharma (Inst), Millennium (Inst), Janssen (Inst), Clinica Atlantis (Inst), INC Research (Inst), Halozyme (Inst), Covance (Inst), Celgene (Inst), inVentiv Health (Inst), Merck KGaA (Inst), Shanghai Henlius Biotech (Inst), Polyphor (Inst), PharmaMar (Inst)Travel, Accommodations, Expenses: Roche/Genentech, Novartis, Pfizer, BMS Brazil, AstraZeneca, MSD Oncology, Lilly Hervé BonnefoiTravel, Accommodations, Expenses: Roche, Pfizer Julie GralowConsulting or Advisory Role: Genentech, AstraZeneca, Hexal, Puma Biotechnology, Roche, Novartis, Seattle Genetics, Genomic Health Masakazu ToiHonoraria: Novartis, Takeda, Eisai, AstraZeneca, Chugai Pharma, Taiho Pharmaceutical, Yakult Pharmaceutical, Shimadzu, Pfizer, Lilly, Kyowa Kirin, Devicor Medical Products, Exact Sciences, Nippon KayakuConsulting or Advisory Role: Daiichi Sankyo, Kyowa Kirin, Bertis, Athenex, BMS, Kansai Medical, Terumo, Lux Biosciences, AstraZeneca¸ LillySpeakers' Bureau: Pfizer, AstraZeneca, Lilly, Daiichi SankyoResearch Funding: Taiho Pharmaceutical, Chugai Pharma, Shimadzu, Astellas Pharma, AFI technology, Japan Breast Cancer Research Group, Pfizer, Eisai, Daiichi Sankyo, AstraZeneca, Nippon Kayaku, Kyoto Breast Cancer Research Network, Shionogi, Lilly, Yakult Pharmaceutical, Lux Biosciences (Inst), GL Science (Inst)Patents, Royalties, Other Intellectual Property: JP 2017-143763 WO2017/131162A1, PCT/JP2016/004374Travel, Accommodations, Expenses: EisaiOther Relationship: Japan Breast Cancer Research Group, Kyoto Breast Cancer Research Network, Organization for Oncology and Translational Research, Breast Cancer research and Treatment, Frontier in Women's Cancer, Scientific Reports, International Journal of Clinical Oncology, Cancer Science, Asian Journal of Surgery, Asian Journal of Breast Surgery, British Journal of Cancer Luca GianniConsulting or Advisory Role: Roche, Pfizer, AstraZeneca, Genomic Health, Merck Sharp & Dohme, Synaffix, Celgene, Lilly, ADC Therapeutics, Odonate Therapeutics, Oncolytics, Genenta Science, Sandoz, METIS Precision Medicine, Novartis, Revolution Medicines, Zymeworks, G1 Therapeutics, Genentech, Onkaido Therapeutics, Taiho Pharmaceutical, Seattle Genetics, Synthon, Forty Seven, Sanofi, Amgen, Menarini, BioMedical Insights, Artemida Pharma LtdSpeakers' Bureau: Roche Product, Zymeworks, Revolution MedicinesPatents, Royalties, Other Intellectual Property: RocheTravel, Accommodations, Expenses: Celgene, Roche, Chugai Pharma, Pfizer Sandra M. SwainConsulting or Advisory Role: Inivata, Genentech/Roche, Daiichi Sankyo, Molecular Templates, Athenex, Silverback Therapeutics, AstraZeneca, Exact Sciences, Natera, Beijing Medical Award Foundation, Lilly, MerckResearch Funding: Genentech (Inst), Kailos Genetics (Inst)Travel, Accommodations, Expenses: Caris Life Sciences, Daiichi Sankyo, Genentech/RocheOther Relationship: AstraZeneca, RocheOpen Payments Link: https://openpaymentsdata.cms.gov/physician/801195/associated-research-funding Michelino De LaurentiisHonoraria: Roche, Novartis, Pfizer, Lilly, Amgen, Pierre Fabre, AstraZeneca, MSD, Seattle Genetics, Gilead Sciences, Takeda, IpsenConsulting or Advisory Role: Roche, Novartis, Pfizer, Lilly, Amgen, AstraZeneca, MSD, Pierre Fabre, Seattle Genetics, Gilead Sciences, Ipsen, TakedaSpeakers' Bureau: NovartisResearch Funding: Novartis, Roche, Lilly, Puma Biotechnology, Pfizer, Daiichi Sankyo, MSD, MacroGenics, Bristol Myers Squibb Zbigniew NoweckiTravel, Accommodations, Expenses: Roche/Genentech Chiun-Sheng HuangHonoraria: Roche, Novartis, Pfizer, AstraZenecaConsulting or Advisory Role: Amgen, Pfizer, Roche, Lilly, AstraZeneca, NovartisSpeakers' Bureau: Amgen, Pfizer, Roche, Novartis, AstraZenecaResearch Funding: AstraZeneca (Inst), Lilly (Inst), MSD (Inst), Novartis (Inst)¸ Pfizer (Inst), Roche (Inst), OBI Pharma (Inst), EirGenix (Inst), Daiichi Sankyo (Inst)Travel, Accommodations, Expenses: Pfizer, Roche, AstraZeneca Yoshinori ItoResearch Funding: Daiichi Sankyo (Inst), Chugai Pharma (Inst), Novartis (Inst), Parexel (Inst), EPS Associates Co, Ltd (Inst), MSD (Inst), AstraZeneca (Inst), Lilly (Inst) Jigna ShahEmployment: GenentechStock and Other Ownership Interests: GenentechTravel, Accommodations, Expenses: GenentechOther Relationship: Genentech Thomas BouletEmployment: Roche/Genentech Haiying LiuEmployment: GenentechStock and Other Ownership Interests: Roche/GenentechTravel, Accommodations, Expenses: Roche/Genentech Harrison MachariaEmployment: Roche/Genentech Peter TraskEmployment: Roche/GenentechStock and Other Ownership Interests: Genentech, Pfizer Chunyan SongEmployment: Roche/GenentechStock and Other Ownership Interests: Roche/Genentech Eric P. WinerHonoraria: Genentech/Roche, Genomic HealthConsulting or Advisory Role: Leap Therapeutics, Seattle Genetics, Jounce Therapeutics, GlaxoSmithKline, Carrick Therapeutics, Lilly, G1 Therapeutics, Syros Pharmaceuticals, Genentech/Roche, Gilead Sciences, Zymeworks, AthenexResearch Funding: Genentech (Inst)Other Relationship: InfiniteMD Nadia HarbeckStock and Other Ownership Interests: West German Study GroupHonoraria: Roche, Novartis, Amgen, Pfizer, AstraZeneca¸ Pierre Fabre, Daiichi-Sankyo, Exact Sciences, MSD, Seattle GeneticsConsulting or Advisory Role: Roche/Genentech, Novartis, Pfizer, Lilly, Sandoz, Daiichi Sankyo, AstraZeneca, West German Study Group (Inst), Pierre Fabre, Seattle Genetics, MSDResearch Funding: Roche/Genentech, Lilly, MSD¸ AstraZenecaNo other potential conflicts of interest were reported.

Purpose: PI3K/AKT pathway alterations are frequent in hormone receptor-positive (HR+) breast cancers. IPATunity130 Cohort B investigated ipatasertib-paclitaxel in PI3K pathway-mutant HR+ unresectable locally advanced/metastatic breast cancer (aBC)., Methods: Cohort B of the randomized, double-blind, placebo-controlled, phase 3 IPATunity130 trial enrolled patients with HR+ HER2-negative PIK3CA/AKT1/PTEN-altered measurable aBC who were considered inappropriate for endocrine-based therapy (demonstrated insensitivity to endocrine therapy or visceral crisis) and were candidates for taxane monotherapy. Patients with prior chemotherapy for aBC or relapse < 1 year since (neo)adjuvant chemotherapy were ineligible. Patients were randomized 2:1 to ipatasertib (400 mg, days 1-21) or placebo, plus paclitaxel (80 mg/m 2 , days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS)., Results: Overall, 146 patients were randomized to ipatasertib-paclitaxel and 76 to placebo-paclitaxel. In both arms, median investigator-assessed PFS was 9.3 months (hazard ratio, 1.00, 95% CI 0.71-1.40) and the objective response rate was 47%. Median paclitaxel duration was 6.9 versus 8.8 months in the ipatasertib-paclitaxel versus placebo-paclitaxel arms, respectively; median ipatasertib/placebo duration was 8.0 versus 9.1 months, respectively. The most common grade ≥ 3 adverse events were diarrhea (12% with ipatasertib-paclitaxel vs 1% with placebo-paclitaxel), neutrophil count decreased (9% vs 7%), neutropenia (8% vs 9%), peripheral neuropathy (7% vs 3%), peripheral sensory neuropathy (3% vs 5%) and hypertension (1% vs 5%)., Conclusion: Adding ipatasertib to paclitaxel did not improve efficacy in PIK3CA/AKT1/PTEN-altered HR+ HER2-negative aBC. The ipatasertib-paclitaxel safety profile was consistent with each agent's known adverse effects. Trial registration NCT03337724., (© 2021. The Author(s).)

Competing Interests: Disclosure FA reports receipt of research funding and has served as speaker/advisor (compensated to the hospital) for Roche, AstraZeneca, Daiichi Sankyo, Pfizer, Novartis and Eli Lilly. CHB reports grants/research support (to the institution) from Pfizer, Novartis, Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline (GSK), Roche/Genentech, Eli Lilly, Sanofi, Taiho Pharmaceutical, Mylan, Merrimack, Merck, AbbVie, Astellas Pharma, BioMarin, Bristol-Myers Squibb (BMS), Daiichi Sankyo, Abraxis Biosciences, AB Science, Asana Biosciences, Medivation, Exelixis, ImClone Systems, LEO Pharma, Millennium, Merck KGaA, Shanghai Henlius Biotech, Polyphor and PharmaMar; ownership or stocks in Biomarker, Tummi and MEDSir; and advisory boards and consulting for Boehringer Ingelheim, GSK, Novartis, Pfizer, Roche/Genentech, Eisai, Bayer, Merck Sharp & Dohme (MSD), AstraZeneca, Zodiac, Eli Lilly and Sanofi. JC has served as a consultant/advisor for Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Eli Lilly, MSD, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab and Gilead; received honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Eli Lilly, MSD and Daiichi Sankyo; received research funding to the institution from Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GmbH/Servier Affaires, Bayer Healthcare, Eisai, Roche, Guardanth Health, MSD, Pfizer, Piqur Therapeutics, Puma C and Queen Mary University of London; owns stock, patents and intellectual property for MedSIR; and received travel, accommodation and expenses from Roche, Novartis, Eisai, Pfizer and Daiichi Sankyo. GC has served as consultant or advisor for Roche, Eli Lilly and BMS; served on a speaker’s bureau for Roche, Pfizer and Eli Lilly; received travel funding from Pfizer and Roche; and received honoraria from Roche, Pfizer, Eli Lilly, Novartis, AstraZeneca and SeaGen, all outside the submitted work. EdA reports honoraria and/or advisory boards for Roche/Genentech, Novartis, Seattle Genetics, Zodiacs, Libbs and Pierre Fabre and Eli Lilly; travel grants from Roche/Genentech and GSK/Novartis; and research grants for his institute from Roche/Genentech, AstraZeneca, Novartis and Servier. AD reports research funding to institute from Genentech, Novartis, Pfizer and Calithera. RD reports research funding from AstraZeneca; and honoraria for consultancy/advisory board participation from AstraZeneca, Eisai, Eli Lilly, Novartis, Pfizer and Roche. DF reports honoraria for participation in symposia from Roche. AG reports honoraria for advisory boards from AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Novartis, Pfizer and Roche; honoraria for lectures from Eisai and Eli Lilly; and honoraria for expert testimony from Gentili. JG has served as a consultant/advisor for AstraZeneca, Daiichi Sankyo, Eisai, Exact Science, Eli Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Roche/Genentech and Seattle Genetics; received honoraria from AGM communication, Amgen, AstraZeneca, Daiichi Sankyo, Decision Santé, Edimark, Eisai, Exact Science, Kephren, Eli Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Roche/Genentech and Seattle Genetics; received research funding to the institution from Eisai, Exact Science and Roche/Genentech; is an ABC Global Alliance member; has a leadership role in AROMe and Nice St Paul de Vence Cours; and is involved in educational programmes for ESO. NH reports honoraria for lectures, advisory boards and/or personal fees from Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Sandoz and SeaGen; and minority ownership interest in the West German Study Group. SAH reports contracted research paid to institution from Ambrx, Amgen, AstraZeneca, Arvinas, Bayer, Cytomx, Daiichi Sankyo, Dignitana, Genentech/Roche, Gilead, GSK, Immunomedics, Eli Eli Lilly, Macrogenics, Novartis, Pfizer, OBI Pharma, Pieris, PUMA Biotechnologies, Radius, Sanofi, Seattle Genetics/SeaGen, Zymeworks, Phoenix Molecular Designs, Ltd. and Samumed; unpaid steering committee member for Novartis, Eli Lilly, Daiichi Sankyo/AstraZeneca, Genentech/Roche and Sanofi; travel expenses from Eli Lilly (2019); and uncompensated consulting/advisory boards for 4DPharma, Ambrx, Amgen, Artios, Arvinas, Daiichi Sankyo, Dantari, Genentech/Roche, Immunomedics, Macrogenics, Eli Eli Lilly, Novartis, NK Max, Pieris, Pyxis, SeaGen, Biotheranostics and Loxo. SAI reports advisory board participation (uncompensated) for Amgen, AstraZeneca, Daiichi Sankyo, Eisai, GSK, Hanmi, Eli Lilly, MSD, Novartis, Pfizer and Roche; and receipt of research funding/clinical trial budget from AstraZeneca, Dae Woong, Daiichi Sankyo, Eisai, Hanmi, Pfizer and Roche. DK reports honoraria from the European School of Oncology and MSD; non-renumerated membership of American Society for Clinical Oncology, American Society for Radiation Oncology, Arbeitsgemeinschaft Gynäkologische Onkologie, Arbeitsgemeinschaft Radiologische Onkologie, Deutsche Gesellschaft für Radioonkologie, Deutsche Gesellschaft für Senologie, European Society for Radiotherapy and Oncology and The Radiosurgery Society. WGK reports institutional research funding by the German Research Foundation and the medical faculty of LMU Munich; and serves as a non-compensated committee member of the European Organisation for Research and Treatment of Cancer and the European Society of Oncologic Imaging. SLoi reports research funding to her institution from Novartis, BMS, Merck, PUMA Biotechnologies, Eli Eli Lilly, Nektar Therapeutics, AstraZeneca, Roche-Genentech and Seattle Genetics; consultancy (not compensated) to Seattle Genetics, Novartis, BMS, Merck, AstraZeneca and Roche/Genentech; consultancy (paid to institution) to Aduro Biotech, Novartis, GSK, Roche/Genentech, AstraZeneca, Silverback Therapeutics, G1 Therapeutics, PUMA Biotechnologies, Pfizer, Gilead Therapeutics, Seattle Genetics and BMS; and Scientific Advisory Board Member of Akamara Therapeutics. SLoibl reports honoraria for advisory boards (to institute) from Bayer, BMS, Eirgenix, GSK, Eli Lilly and Merck; honoraria for lecture (to institute) from Samsung; honoraria for advisory boards and lectures (to institute) from Pierre Fabre and Prime/Medscape; grants and honoraria for advisory boards (to institute) from AbbVie and Celgene; grants and honoraria for advisory boards and lectures (to institute) from AstraZeneca; grants, non-financial support and honoraria for advisory boards, lectures and medical writing (to institute) from Daiichi Sankyo, Novartis, Pfizer and Roche; grants, non-financial support and honoraria for advisory boards and medical writing (to institute) from Immunomedics/Gilead, non-financial support and honoraria for advisory boards and medical writing (to institute) from PUMA Biotechnologies and SeaGen; and non-financial support and honoraria for advisory boards (to institute) from Amgen, all outside the submitted work. In addition, SLoibl has patents EP14153692.0, EP21152186.9, EP19808852.8 and Digital Ki67 Evaluator pending and patent EP15702464.7 issued, with royalties paid. SP-S reports honoraria and/or advisory board and/or speaker’s bureau and/or travel funding from Roche, Pfizer, Eli Eli Lilly, Novartis, AstraZeneca, MSD, Exact Sciences and Nanostring. Institutional research funding from Sharing Progress in Cancer Care and Pfizer. FP-L has received honoraria and/or advisory board and/or speaker’s bureau and/or travel funding from Roche, Pfizer, Eli Lilly, Novartis, AstraZeneca, MSD, SeaGen, Illumina, Exact Sciences, Myriad and Nanostring; and institutional research funding from AstraZeneca, Roche, MSD and Illumina. JR reports honoraria or research grants (to the institution) from Terumo, Sirtex Medical, Boston Scientific, Roche and AstraZeneca. MR reports honoraria from Research to Practice, Intellisphere and Physicians’ Education Resource; consultant or advisor for Artios Pharma (uncompensated), AstraZeneca (uncompensated), Change Healthcare, Daiichi Sankyo (uncompensated), Epic Sciences (uncompensated), Merck (uncompensated), Pfizer (uncompensated) and Zenith Pharmaceuticals (uncompensated); research funding to institute from AstraZeneca, Merck and Pfizer; and editorial services for AstraZeneca and Pfizer. HSR reports research support for clinical trials through the University of California from Pfizer, Merck, Novartis, Eli Lilly, Roche, Daiichi Sankyo, Seattle Genetics, Macrogenics, Sermonix, Boehringer Ingelheim, Polyphor, AstraZeneca, Ayala and Gilead; and honoraria from PUMA Biotechnologies (grant reviews for the US National Comprehensive Cancer Network 2021, steering committee 2020), Mylan (educational talk 2019), Samsung (educational talk and consultant 2019) and Napo Pharmaceuticals, Inc (consultant). CFS reports institutional research funding from Amgen, AstraZeneca, Daiichi Sanyko and the US Department of Defence; and travel funding and speaker honoraria from Novartis, AstraZeneca, Roche and Amgen. PS reports honoraria for participation in advisory boards and satellite symposia from AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, PUMA Biotechnologies, Roche, Eisai and Celgene; research funding to institute from Astellas, AstraZeneca, Genentech, Novartis, Oncogenex, Roche and Medivation. CS has served as consultant, participated in advisory boards or received travel grants from AstraZeneca, Byondis B.V., Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, Roche, MediTech, MSD, Novartis, Pfizer, Philips, Pierre Fabre, PintPharma, PUMA Biotechnologies, Sanofi-Aventis, SeaGen and Zymeworks. TS reports receipt of honoraria for advisory board participation for Roche and Pfizer. SMT reports receipt of institutional research funding from AstraZeneca, Eli Lilly, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Immunomedics/Gilead, Exelixis, BMS, Eisai, Nanostring, Cyclacel, Odonate and Seattle Genetics; and has served as an advisor/consultant (compensated) for AstraZeneca, Eli Lilly, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Immunomedics/Gilead, BMS, Eisai, Nanostring, PUMA Biotechnologies, Sanofi, Silverback Therapeutics, G1 Therapeutics, Athenex, OncoPep, Kyowa Kirin Pharmaceuticals, Daiichi Sankyo, Ellipsis, Infinity, 4D Pharma, Samsung Bioepsis Inc., Chugai Pharmaceuticals, BeyondSpring Pharmaceuticals, OncXerna, OncoSec Medical Incorporated, Certara, Mersana Therapeutics, CytomX and Seattle Genetics. NCT reports receipt of advisory board honoraria from AstraZeneca, BMS, Eli Lilly, MSD, Novartis, Pfizer, Roche/Genentech, GSK, Zentalis Pharmaceuticals, Repare Therapeutics and Arvinas; and research funding from AstraZeneca, BioRad, Pfizer, Roche/Genentech, MSD, Guardant Health, Invitae, Inivata, Personalis and Natera.

Purpose: The objective of this review is to address the barriers limiting access to treatment of advanced metastatic breast cancer (mBC) in Brazil, specifically for patients in the public health care system, arguably those with the least access to innovation., Materials and Methods: A selected panel of Brazilian experts in BC were provided with a series of relevant questions to address in a multiday conference. During the conference, responses were discussed and edited by the entire group through numerous drafts and rounds of discussion until a consensus was achieved., Results: The authors propose specific and realistic recommendations for implementing access to new drugs in cancer care in Brazil. Moreover, in creating these recommendations and framework, the authors strive to address the most important barriers and impediments for technology incorporation. A feasible and specific multidisciplinary process is proposed, which is based on the collective participation of all involved stakeholders., Conclusion: Given the current benefits and likely future developments, there is a great need to expand treatments for mBC not only in Brazil but also in most other countries in the world where access issues remain an unresolved demand. Adapting the current framework is essential for accomplishing this goal. The recommendations in this review can serve as a framework for adoption of new technologies in countries with limited resources., Competing Interests: Carlos BarriosStock and Other Ownership Interests: Biomarker, MedSIR, TummiHonoraria: Novartis, Roche/Genentech, Pfizer, GlaxoSmithKline, Sanofi, Boehringer Ingelheim, Eisai, Merck Sharp & Dohme, Lilly, Bayer, AstraZeneca, Zodiac PharmaConsulting or Advisory Role: Boehringer Ingelheim, Roche/Genentech, Novartis, GlaxoSmithKline, Eisai, Pfizer, AstraZeneca, Libbs, MSD Oncology, United Medical, LillyResearch Funding: Pfizer, Novartis, Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Roche/Genentech, Lilly, Sanofi, Taiho Pharmaceutical, Mylan, Merrimack, Merck, AbbVie, Astellas Pharma, Biomarin, Bristol-Myers Squibb, Daiichi Sankyo, Abraxis BioScience, AB Science, Asana Biosciences, Medivation, Exelixis, ImClone Systems, LEO Pharma, Millennium, Janssen, Clinica Atlantis, INC Research, Halozyme, Covance, Celgene, inVentiv Health, Merck KGaA, Shanghai Henlius Biotech, Polyphor, PharmaMarTravel, Accommodations, Expenses: Roche/Genentech, Novartis, Pfizer, BMS Brazil, AstraZeneca, MSD Oncology, Lilly Ruffo Freitas-JuniorHonoraria: Roche, Libbs, PfizerConsulting or Advisory Role: Roche, Novartis BrazilResearch Funding: Roche, Merck Sharp & Dohme, Novartis Biociencias, SanofiTravel, Accommodations, Expenses: Roche, Libbs Sandro MartinsConsulting or Advisory Role: Novartis, Pfizer Jose BinesHonoraria: Roche, Lilly, Novartis, Merck Sharp & Dohme, PfizerConsulting or Advisory Role: Roche, Lilly, Merck Sharp & DohmeTravel, Accommodations, Expenses: RocheNo other potential conflicts of interest were reported.

Competing Interests: Disclosure MSA reports receipt of consultation fees from Amgen, BMS, Celgene, Clinigen, Eisai, Genomic Health, GSK, Helsinn, Hospira, JnJ, Novartis, Merck, Merck Serono, Mundipharma, Pfizer, Pierre Fabre, Roche, Sandoz, Tesaro, Tevam Vifor, G1 Therapeutics and Lilly; receipt of honoraria for symposia lectures from Amgen, Bayer, Schering, Cephalon, Chugai, Eisai, Genomic Health, GSK, Helsinn, Hospira, Ipsen, JnJ Ortho Biotech, Kyowa Hakko Kirin, Merck, Merck Serono, Mundipharma, Novartis, Pfizer, Pierre Fabre, Roche, Sandoz, Sanofi, Tesaro, Taiho, Tevam Vifor, G1 Therapeutics and Lilly. CHB reports receipt of honoraria or consultation fees from Boehringer Ingelheim, GSK, Novartis, Pfizer, Roche/Genentech, Eisai, MSD, AstraZeneca and Bayer; receipt of grants/research support to the institution from AbbVie, Amgen, Astellas Pharma, AstraZeneca, BMS, Celgene, Covance, Lilly, Medivation, Merck Serono, MSD, Novartis, Pfizer, PharmaMar and Roche/Genentech. JB reports receipt of grants/research support grants to Karolinska Institute and University Hospital from Amgen, AstraZeneca, Bayer, Merck, Pfizer, Roche, Sanofi-Aventis; no personal payments; payment from UpToDate to Asklepios Medicine HB for a chapter on breast cancer prediction. LB reports receipt of grants/research support from Celgene, Genomic Health and Novartis; receipt of honoraria or consultation fees from AstraZeneca, Celgene, Daiichi Sankyo, Eisai, Genomic Health, Ipsen, Lilly, Novartis, Pfizer, Pierre Fabre and Roche. FC reports receipt of honoraria or consultation fees from Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, GSK, MacroGenics, Medscape, MSD, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre Fabre, prIME Oncology, Roche, Sanofi, Seattle Genetics and Teva. JC reports acting as a consultant/advisor for Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Servier, MSD, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim and Kyowa Kirin; received honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, MSD and Daiichi Sankyo; received research funding to the institution from Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer Healthcare, Eisai, F. Hoffmann-La Roche, Guardant Health, MSD, Pfizer, PIQUR Therapeutics, Puma C and Queen Mary University of London; holds stock, patents and intellectual property for MEDSIR; received travel, accommodation and expenses from Roche, Novartis, Eisai, Pfizer and Daiichi Sankyo. GC reports receipt of honoraria or consultation fees from Roche, Pfizer, Lilly, Novartis and SeaGen; participation in a sponsored speakers' bureau for SeaGen, Pfizer, Lilly and Novartis. NSES reports receipt of grants/research support to institution from Novartis; receipt of honoraria or consultation fees from Novartis, Roche, Pfizer, Lilly and AstraZeneca. ME reports acting in an advisory role for Novartis and Roche. AE reports receipt of grants/research support from AstraZeneca, Roche, Celltrion, Pfizer and Novartis. LF reports receipt of grants/research support from BMS, GSK, Myriad and Novartis; receipt of honoraria or consultation fees from BMS, AstraZeneca, Teva, Novartis, Eisai, Takeda, Pfizer, Lilly, Genomic Health and Myriad. PAF reports receipt of honoraria or consultation fees from AstraZeneca and Novartis; travel for lecture for Pfizer and Ipsen. KG reports receipt of grants/research support from AstraZeneca, Pfizer and BMS; receipt of honoraria or consultation fees from Pfizer, AstraZeneca, Novartis, Nanostring, Merck, Mylan, Genomic Health, Roche and BMS. JG reports receipt of grants/research support from Amgen, Eisai, Genomic Health, Novartis, Pfizer and Roche/Genentech; receipt of honoraria or consultation fees from Daiichi, Eisai, Genomic Health, Ipsen, MacroGenics, MSD, Mylan, Novartis, Onxeo, Pfizer and Roche/Genentech; participation in a sponsored speakers' bureau for Eisai, Genomic Health, Ipsen, Novartis, Pfizer and Roche/Genentech. NH reports receipt of honoraria or consultation fees from Amgen, AstraZeneca, Celgene, Daiichi Sakyo, Lilly, MSD, Novartis, Odonate, Pfizer, Roche, Sandoz/Hexal and Seattle Genetics. RK reports receipt of grants/research support from Pfizer Malaysia. BEK reports receipt of grants/research support to institution from Roche; receipt of honoraria for advisory boards and educational presentations as well as travel and meeting expenses from Roche; receipt of honoraria for advisory boards and educational presentations from Novartis. SBK reports receipt of grants/research support to institution from Novartis, Sanofi-Aventis, Kyowa Kirin Inc. and DongKook Pharm Co.; receipt of consultancy fees from Novartis, AstraZeneca, Lilly, Enzychem, Daehwa Pharmaceutical Co. Ltd, ISU ABXIS and Daiichi Sankyo. NUL reports receipt of grants/research support from Genentech and Seattle Genetics; receipt of honoraria or consultation fees from Seattle Genetics, Daiichi Sankyo and Puma. SAM reports receipt of honoraria from Pfizer and Lilly; SN reports receipt of grants/research support from Roche, Pfizer, BMS and Novartis; participation in a sponsored speakers' bureau for Roche, Pfizer, BMS, Merck and Novartis. LN reports receipt of honoraria from Sermonix Oncology Ad Board, Prime Oncology, Sarah Lawrence Lecture, Context advisory board, Oncology Pioneers Science Lecture Series, BCRF programmatic review meeting and CSHL external advisory board meeting. SO reports receipt of grants/research support from Chugai, Eisai, Taiho, Daiichi Sankyo; participation in a sponsored speakers' bureau for Chugai, AstraZeneca, Eisai, Taiho, Pfizer and Lilly. OP reports participation in a sponsored speakers' bureau for Takeda, Roche, Pfizer, Novartis and Lilly. SPS has participated in a speakers' bureau and received honoraria from Roche, AstraZeneca, Novartis, Pfizer, Nanostring and Teva; reports consultancy for Roche, AstraZeneca, Novartis and Pfizer. FPL reports receipt of grants/research support from Roche; receipt of honoraria or consultation fees from Roche, Puma, Pierre Fabre and AstraZeneca. AP reports personal financial interests and lecture fees for Roche, Pfizer, Novartis, Amgen, BMS and Daiichi Sankyo; participation in an advisory role/consultancy for Roche, Pfizer, Novartis, Amgen, BMS, Puma and Oncolytics Biotech; institutional financial interests include contracted research for Novartis, Nanostring, Roche and Boehringer; lecture fees from Nanostring technologies; clinical trials for Novartis, Roche, Boehringer, Daiichi Sankyo, Pfizer, Lilly and Amgen. HSR reports receipt of grants/research support from Pfizer, Merck, Novartis, Lilly, Genentech, OBI, Odonate, Daiichi Sankyo, Eisai, Seattle Genetics, MacroGenics and Immunomedics. ES reports receipt of honoraria or consultation fees from Amgen, AstraZeneca, Clinigen, Egis, Eli Lilly, Genomic Health, Novartis, Pfizer, Pierre Fabre, Roche, Sandoz and TLC Biopharmaceuticals; travel support from Amgen, AstraZeneca, Egis, Novartis, Pfizer and Roche; contracted research for Amgen, AstraZeneca, Boehringer, Eli Lilly, Merck, Novartis, Pfizer, Roche and Samsung; holds stock in Eli Lilly. EPW reports receipt of grants/research support from Merck and Genentech/Roche; receipt of honoraria or consultation fees from Carrick Therapeutics, Genentech/Roche, Genomic Health, GSK, Jounce, Leap, Lilly, Merck and Seattle Genetics; research fees to institute from Genentech/Roche and Merck; participation in a scientific advisory board for Leap. BX reports receipt of advisory fees from Novartis and Roche; fees for serving on a speakers' bureau from AstraZeneca, Pfizer, Roche and Eisai. FA, FB, BK, FEL, GWS, CT and TW have not reported any potential conflict of interest. GSB, MJC, LAC, AC, RH, XH, BVO and DAV have declared no significant conflict of interest.

Prior pooled analysis of eribulin studies (301 and 305) indicated eribulin prolonged overall survival (OS) in patients with locally advanced/metastatic breast cancer (MBC) regardless of visceral or nonvisceral disease. This hypothesis-generating post hoc analysis examined the efficacy of eribulin according to the location of metastatic sites at baseline in 1864 pretreated patients with locally advanced/MBC from studies 301 and 305. Analyses included OS, progression-free survival (PFS), and objective response rate; OS and PFS were also analyzed according to estrogen-receptor status. Eribulin appeared efficacious in patients with locally advanced/MBC, irrespective of the location of metastases at baseline. A nominally significant difference in OS in favor of patients randomized to eribulin compared with control in patients with bone, lymph node, and chest wall/breast/skin metastases at baseline was observed. Additionally, a difference in OS was also seen in patients with liver metastases randomized to eribulin versus control (median: 13.4 versus 11.3 months, respectively; hazard ratio, 0.84 [95% CI: 0.72, 0.97]). Results of this exploratory analysis suggest that eribulin may be efficacious for the treatment of locally advanced/MBC for patients with bone, liver, lung, lymph node, and chest wall/breast/skin metastases.

Background: Denosumab is a fully human monoclonal antibody that binds to, and inhibits, the receptor activator of RANKL (TNFSF11) and might affect breast cancer biology, as shown by preclinical evidence. We aimed to assess whether denosumab combined with standard-of-care adjuvant or neoadjuvant systemic therapy and locoregional treatments would increase bone metastasis-free survival in women with breast cancer., Method: In this international, double-blind, randomised, placebo-controlled, phase 3 study (D-CARE), patients were recruited from 389 centres in 39 countries. We enrolled women (aged ≥ 18 years) with histologically confirmed stage II or III breast cancer and an Eastern Cooperative Oncology Group performance status of 0 or 1. On eligibility confirmation, investigators at each site telephoned an interactive voice response system to centrally randomly assign patients (1:1) based on a fixed stratified permuted block randomisation list (block size 4) to receive either denosumab (120 mg) or matching placebo subcutaneously every 3-4 weeks, starting with neoadjuvant or adjuvant chemotherapy, for about 6 months and then every 12 weeks for a total duration of 5 years. Stratification factors were breast cancer therapy, lymph node status, hormone receptor and HER2 status, age, and geographical region. The primary endpoint was the composite endpoint of bone metastasis-free survival. This trial is registered with ClinicalTrials.gov, NCT01077154., Findings: Between June 2, 2010, and Aug 24, 2012, 4509 women were randomly assigned to receive denosumab (n=2256) or placebo (n=2253) and included in the intention-to-treat analysis. The primary analysis of the study was done when all patients had the opportunity to complete 5 years of follow-up with an analysis data cutoff date of Aug 31, 2017. The primary endpoint of bone metastasis-free survival was not significantly different between the groups (median not reached in either group; hazard ratio 0·97, 95% CI 0·82-1·14; p=0·70). The most common grade 3 or worse treatment-emergent adverse events, reported in patients who had at least one dose of the investigational product (2241 patients with denosumab vs 2218 patients with placebo), were neutropenia (340 [15%] vs 328 [15%]), febrile neutropenia (112 [5%] vs 142 [6%]), and leucopenia (62 [3%] vs 61 [3%]). Positively adjudicated osteonecrosis of the jaw occurred in 122 (5%) of 2241 patients treated with denosumab versus four (<1%) of 2218 patients treated with placebo; treatment-emergent hypocalcaemia occurred in 152 (7%) versus 82 (4%). Two treatment-related deaths occurred in the placebo group due to acute myeloid leukaemia and depressed level of consciousness., Interpretation: Despite preclinical evidence suggesting RANKL inhibition might delay bone metastasis or disease recurrence in patients with early-stage breast cancer, in this study, denosumab did not improve disease-related outcomes for women with high-risk early breast cancer., Funding: Amgen., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: In the phase 3 MARIANNE trial, trastuzumab emtansine (T-DM1) with or without pertuzumab showed noninferior progression-free survival and better tolerability than trastuzumab plus a taxane (HT) for the first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer. This article reports the final descriptive overall survival (OS) analysis, updated safety data, and additional patient-reported outcomes and biomarker analyses., Methods: OS was assessed in 1095 patients with HER2-positive breast cancer and no prior therapy for advanced disease who had been randomized to HT, T-DM1 plus a placebo (hereafter T-DM1), or T-DM1 plus pertuzumab (T-DM1+pertuzumab). A post hoc exploratory landmark analysis of OS, baseline patient and disease characteristics, and tumor biomarkers in patients with and without an objective tumor response (OR) according to the Response Evaluation Criteria in Solid Tumors within 6.5 months of randomization was conducted., Results: The median OS was similar across groups (50.9, 53.7, and 51.8 months for the HT, T-DM1, and T-DM1+pertuzumab groups, respectively). Among patients with an OR, the median OS was longer with T-DM1 (64.4 months) and T-DM1+pertuzumab (not reached) versus HT (56.3 months). No baseline characteristics or biomarkers were strongly associated with OR. The incidence of grade 3 or higher adverse events was greater with HT (55.8%) than T-DM1 (47.1%) or T-DM1+pertuzumab (48.6%). The median time to clinically meaningful deterioration (a 3-point or greater change) in neurotoxicity symptoms was shorter with HT (2.1 months) and T-DM1+pertuzumab (4.2 months) than T-DM1 (6.2 months). Fewer patients reported alopecia and diarrhea and were bothered by treatment side effects in the T-DM1 arm., Conclusions: These results support T-DM1 as a first-line treatment for patients with HER2-positive metastatic breast cancer who are deemed unsuitable for taxane-based therapy., (© 2019 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Purpose: Breast cancer (BC) in young women is uncommon and tends to present with more aggressive characteristics. To better understand and characterize this scenario in Brazil through real-world data, we performed a subanalysis of AMAZONA III study (ClinicalTrials.gov identifier: NCT02663973)., Methods: The AMAZONA III study (GBECAM 0115) is a prospective registry that included 2,950 women newly diagnosed with invasive BC in Brazil from January 2016 until March 2018 at 22 sites. Valid data were obtained from 2,888 patients regarding age at diagnosis and complete baseline information. To compare epidemiologic and clinicopathological features at the time of diagnosis, patients with BC were divided into two groups according to age: ≤ 40 years and > 40 years. Quantitative variables were described as means, and categorical variables were described as frequencies and percentages and compared using the Pearson's χ 2 test., Results: Of 2,888 women diagnosed with BC, 486 (17%) were ≤ 40 years old. Young women had higher educational level, most were employed and a significant number were married ( P < . 001 for all associations). Younger patients were more symptomatic at BC diagnosis ( P < . 001), and they also presented more frequently with stage III, T3/T4, grade 3 tumors, HER-2-positive, luminal B, and triple-negative subtypes., Conclusion: Brazilian women younger than age 40 years have unfavorable clinicopathological features of BC at diagnosis, with more aggressive subtypes and advanced stage when compared with older women. These differences are not explained by socioeconomic or ethnic imbalances. The causes of a higher prevalence of BC among young women in Brazil deserve additional investigation.

Background: We report longitudinal health-related quality-of-life (HRQoL) data from the international, randomized, double-blind, placebo-controlled phase III ExteNET study, which demonstrated an invasive disease-free survival benefit of extended adjuvant therapy with neratinib over placebo in human epidermal growth factor receptor-2-positive early-stage breast cancer., Patients and Methods: Women (N  = 2840) with early-stage HER2-positive breast cancer who had completed trastuzumab-based adjuvant therapy were randomly assigned to neratinib 240  mg/day or placebo for 12  months. HRQoL was an exploratory end point. Patients completed the Functional Assessment of Cancer Therapy-Breast (FACT-B) and EuroQol 5-Dimensions (EQ-5D) questionnaires at baseline and months 1, 3, 6, 9, and 12. Changes from baseline were compared using analysis of covariance with no imputation for missing values. Sensitivity analyses used alternative methods. Changes in HRQoL scores were regarded as clinically meaningful if they exceeded previously reported important differences (IDs)., Results: Of the 2840 patients (intention-to-treat population), 2407 patients were evaluable for FACT-B (neratinib, N  = 1171; placebo, N  = 1236) and 2427 patients for EQ-5D (neratinib, N  = 1186; placebo, N  = 1241). Questionnaire completion rates exceeded 85%. Neratinib was associated with a decrease in global HRQoL scores at month 1 compared with placebo (adjusted mean differences: FACT-B total, -2.9 points; EQ-5D index, -0.02), after which between-group differences diminished at later time-points. Except for the FACT-B physical well-being (PWB) subscale at month 1; all between-group differences were less than reported IDs. The FACT-B breast cancer-specific subscale showed small improvements with neratinib at months 3-9, but all were less than IDs. Sensitivity analyses exploring missing data did not change the results., Conclusions: Extended adjuvant neratinib was associated with a transient, reversible decrease in HRQoL during the first month of treatment, possibly linked to treatment-related diarrhea. With the exception of the PWB subscale at month 1, all neratinib-related HRQoL changes did not reach clinically meaningful thresholds. ClinicalTrials.gov: NCT00878709., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry., Methods: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP)., Results: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10 -8 . For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10 -7 , hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10 -7 , HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster., Conclusions: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Over the last 20 years, aromatase inhibitors (AI) have been tested in clinical trials as first-line therapy for hormone receptor-positive (HR-positive) advanced breast cancer (ABC), firstly as experimental arms, when they proved to be effective, and recently as control arms. This analysis aims to evaluate trends in progression-free survival (PFS) and time to progression (TTP) over time., Patients and Methods: A literature review was conducted using the MEDLINE database to identify randomized controlled phase II or III trials which reported PFS or TTP of at least one arm using first-line AI HR-positive ABC patients. A linear correlation was used to access the association between the year of the first patient enrolled and the observed PFS/TTP., Results: The search retrieved 19 trials, accounting for 4552 postmenopausal patients divided into 21 separate AI treatment arms. The PFS/TTP increased from 6 to 9 months in the earlier trials to 13-16 months in the current era, representing an absolute gain of approximately 7 months, without the addition of any other drug. Our analysis showed a positive correlation between the year of the first patient enrolled in these trials and median PFS/TTP reported (R 2  = 0.34; p < 0.01). No correlation was found between the year of the first patient included in these trials and other potential prognostic factors such as visceral metastasis at baseline (R 2  = 0.26; p = 0.20) or exposure to adjuvant therapy (R 2  = 0.05; p = 0.18)., Conclusion: Patients treated with first-line AIs in the more recently conducted trials have longer PFS/TTP when compared to their counterparts treated with the same drugs in older studies. These findings have important implications for the estimation of sample size and follow-up periods for the planning of future trials as well as in the translation of the results into clinical practice decisions.

We sought to uncover genetic drivers of hormone receptor-positive (HR + ) breast cancer, using a targeted next-generation sequencing approach for detecting expressed gene rearrangements without prior knowledge of the fusion partners. We identified intergenic fusions involving driver genes, including PIK3CA, AKT3, RAF1 , and ESR1 , in 14% (24/173) of unselected patients with advanced HR + breast cancer. FISH confirmed the corresponding chromosomal rearrangements in both primary and metastatic tumors. Expression of novel kinase fusions in nontransformed cells deregulates phosphoprotein signaling, cell proliferation, and survival in three-dimensional culture, whereas expression in HR + breast cancer models modulates estrogen-dependent growth and confers hormonal therapy resistance in vitro and in vivo Strikingly, shorter overall survival was observed in patients with rearrangement-positive versus rearrangement-negative tumors. Correspondingly, fusions were uncommon (<5%) among 300 patients presenting with primary HR + breast cancer. Collectively, our findings identify expressed gene fusions as frequent and potentially actionable drivers in HR + breast cancer. Significance: By using a powerful clinical molecular diagnostic assay, we identified expressed intergenic fusions as frequent contributors to treatment resistance and poor survival in advanced HR + breast cancer. The prevalence and biological and prognostic significance of these alterations suggests that their detection may alter clinical management and bring to light new therapeutic opportunities. Cancer Discov; 8(3); 336-53. ©2017 AACR. See related commentary by Natrajan et al., p. 272 See related article by Liu et al., p. 354 This article is highlighted in the In This Issue feature, p. 253 ., (©2017 American Association for Cancer Research.)

Objective: To evaluate whether a country's Human Development Index (HDI) can help explain the differences in the country's breast cancer and gynecological cancer incidence and mortality rates in the Pan-American region., Study Design: Ecological analysis., Methods: Pan-American region countries with publicly available data both in GLOBOCAN 2012 and the United Nations Development Report 2012 were included (n = 28). Incidence and mortality rates age-standardized per 100,000 were natural log-transformed for breast cancer, ovarian cancer, corpus uteri cancer, and cervical cancer. The mortality-to-incidence ratio (MIR) was calculated for each site. Pearson's correlation test and a simple linear regression were performed., Results: The HDI showed a positive correlation with breast cancer and ovarian cancer incidence and mortality rates, respectively, and a negative correlation with cervical cancer incidence and mortality rates. The HDI and corpus uteri cancer showed no association. MIR and the HDI showed a negative correlation for all tumor types except ovarian cancer. An increment in 1 HDI unit leads to changes in cancer rates: in breast cancer incidence β = 4.03 (95% confidence interval [CI] 2.61; 5.45) P < 0.001, breast cancer mortality β = 1.76 (95% CI 0.32; 3.21) P = 0.019, and breast cancer-MIR β = -0.705 (95% CI 0.704; 0.706) P < 0.001; in cervical cancer incidence β = -3.28 (95% CI -4.78; -1.78) P < 0.001, cervical cancer mortality β = -4.63 (95% CI -6.10; -3.17) P < 0.001, and cervical cancer-MIR β = -1.35 (95% CI -1.83; -0.87) P < 0.001; in ovarian cancer incidence β = 3.26 (95% CI 1.78; 4.75) P < 0.001, ovarian cancer mortality β = 1.82 (95% CI 0.44; 3.20) P = 0.012, and ovarian cancer-MIR β = 5.10 (95% CI 3.22; 6.97) P < 0.001; in corpus uteri cancer incidence β = 2.37 (95% CI -0.33; 5.06) P = 0.83, corpus uteri cancer mortality β = 0.68 (95% CI -2.68; 2.82) P = 0.96, and corpus uteri cancer-MIR β = -2.30 (95% CI -3.19; -1.40) P < 0.001., Conclusions: A country's HDI should be considered to understand disparities in breast cancer and gynecological cancer in the Pan-American region., (Copyright © 2017 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

New research questions emerge as medical needs continue to evolve and as we improve our understanding of cancer biology and treatment of malignancies. Although significant advances have been made in some areas of breast cancer research resulting in improvements in therapies and outcomes over the last few decades, other areas have not benefited to the same degree and we continue to have many gaps in our knowledge. This article summarizes the 12 short and medium-term clinical research needs in breast cancer deemed as priorities in 2016 by a panel of experts, in an attempt to focus and accelerate future research in the most needed areas: (i) de-escalate breast cancer therapies in early breast cancer without sacrificing outcomes; (ii) explore optimal adjuvant treatment durations; (iii) develop better tools and strategies to identify patients with genetic predisposition; (iv) improve care in young patients with breast cancer; (v) develop tools to speed up drug development in biomarker-defined populations; (vi) identify and validate targets that mediate resistance to chemotherapy, endocrine therapy and anti-HER2 therapies; (vii) evaluate the efficacy of local-regional treatments for metastatic disease; (viii) better define the optimal sequence of treatments in the metastatic setting; (ix) evaluate the clinical impact of intra-patient heterogeneity (intra-tumor, inter-tumor and inter-lesion heterogeneity); (x) better understand the biology and identify new targets in triple-negative breast cancer; (xi) better understand immune surveillance in breast cancer and further develop immunotherapies; and (xii) increase survivorship research efforts including supportive care and quality of life., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose Trastuzumab and pertuzumab are human epidermal growth factor receptor 2 (HER2) -targeted monoclonal antibodies, and trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that combines the properties of trastuzumab with the cytotoxic activity of DM1. T-DM1 demonstrated encouraging efficacy and safety in a phase II study of patients with previously untreated HER2-positive metastatic breast cancer. Combination T-DM1 and pertuzumab showed synergistic activity in cell culture models and had an acceptable safety profile in a phase Ib and II study. Methods In the MARIANNE study, 1,095 patients with centrally assessed, HER2-positive, advanced breast cancer and no prior therapy for advanced disease were randomly assigned 1:1:1 to control (trastuzumab plus taxane), T-DM1 plus placebo, hereafter T-DM1, or T-DM1 plus pertuzumab at standard doses. Primary end point was progression-free survival (PFS), as assessed by independent review. Results T-DM1 and T-DM1 plus pertuzumab showed noninferior PFS compared with trastuzumab plus taxane (median PFS: 13.7 months with trastuzumab plus taxane, 14.1 months with T-DM1, and 15.2 months with T-DM1 plus pertuzumab). Neither experimental arm showed PFS superiority to trastuzumab plus taxane. Response rate was 67.9% in patients who were treated with trastuzumab plus taxane, 59.7% with T-DM1, and 64.2% with T-DM1 plus pertuzumab; median response duration was 12.5 months, 20.7 months, and 21.2 months, respectively. The incidence of grade ≥ 3 adverse events was numerically higher in the control arm (54.1%) versus the T-DM1 arm (45.4%) and T-DM1 plus pertuzumab arm (46.2%). Numerically fewer patients discontinued treatment because of adverse events in the T-DM1 arms, and health-related quality of life was maintained for longer in the T-DM1 arms. Conclusion T-DM1 showed noninferior, but not superior, efficacy and better tolerability than did taxane plus trastuzumab for first-line treatment of HER2-positive, advanced breast cancer.

Disease progression despite existing endocrine therapies remains a major challenge to the effective management of hormone-receptor-positive (HR(+)), human epidermal growth factor receptor-2-negative (HER2(-)), advanced breast cancer. Recent advances in elucidating the molecular mechanisms of disease progression have identified the existence of adaptive "cross-talk" between the estrogen receptor (ER) and various growth factor receptor and intracellular signaling pathways, allowing breast cancer cells to escape the inhibitory effects of endocrine therapy. These findings provide the clinical rationale for enhancing or extending endocrine sensitivity by combining endocrine therapy with a targeted agent against a compensatory pathway. In BOLERO-2, adding the mTOR inhibitor everolimus to endocrine therapy significantly improved progression-free survival (PFS) in patients with HR(+) advanced breast cancer previously treated with nonsteroidal aromatase inhibitor therapy. Notably, PFS benefits were comparable in subgroup analyses of first- and later-line settings. These results contrast with those of the large first-line HORIZON study, wherein adding the mTOR inhibitor temsirolimus to endocrine therapy did not improve PFS. Therefore, it is unclear whether a targeted agent should only be combined with endocrine therapy to restore endocrine sensitivity or whether it may also prevent or delay resistance in hormone-sensitive advanced breast cancer. Numerous additional targeted agents are currently being evaluated in combination with endocrine therapies, including PI3K, cyclin-dependent kinase 4/6, SRC, and histone deacetylase inhibitors. Appropriate patient selection based on prior treatment history will become increasingly important in maximizing the incremental benefit derived from these new agents combined with existing endocrine therapies in HR(+) advanced breast cancer., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Aromatase inhibitors are the preferred adjuvant endocrine therapy for the majority of postmenopausal women with hormone-responsive early breast cancer. Although generally more effective than tamoxifen, aromatase inhibitor therapy is associated with increased bone loss and fracture risk., Patients and Methods: Postmenopausal women receiving adjuvant letrozole (2.5 mg/day for 5 years; N = 1065) were randomly assigned to immediate zoledronic acid (zoledronate) 4 mg every 6 months for 5 years, or delayed zoledronate (initiated for fracture or on-study bone mineral density [BMD] decrease). The primary end point was the change in lumbar spine BMD at 12 months. Lumbar spine and total hip BMD at subsequent follow-up, disease-free survival (DFS), and overall survival were assessed as secondary end points., Results: At 60 months (final analysis), the mean change in lumbar spine BMD was +4.3% with immediate zoledronate and -5.4% with delayed intervention (P < 0.0001). Immediate zoledronate reduced the risk of DFS events by 34% (hazard ratio [HR] = 0.66; P = 0.0375) with fewer local (0.9% versus 2.3%) and distant (5.5% versus 7.7%) recurrences versus delayed zoledronate. In the delayed group, delayed initiation of zoledronate substantially improved DFS versus no zoledronate (HR = 0.46; P = 0.0334)., Conclusions: Immediate zoledronate in postmenopausal women receiving letrozole preserved BMD and is associated with improved DFS compared with letrozole alone. Clinical Trials Registration No NCT00171340.

Unlabelled: Breast cancer (BC) is the leading cause of malignancy-related deaths among women aged ≤45 years. There are unexplored and uncertain issues for BC in this particular group in Latin America. The aim of this study is to evaluate BC incidence and mortality among young women and related clinicopathological and survivorship aspects in this region., Materials and Methods: Data were obtained from Globocan 2008 and the International Agency for Research on Cancer's Cancer Incidence in Five Continents series plus databases. We requested collaboration from the 12 different national cancer institutes in Latin America through SLACOM, the Latin American and Caribbean Society of Medical Oncology, and conducted a systematic literature review to obtain local data regarding the prevalence of BC among young women and their characteristics, outcomes, and survivorship-related issues., Results: BC incidence and mortality proportions for Latin American women aged <44 years were higher when compared with those of developed countries (20% vs. 12% and 14% vs. 7%, respectively). We found only a few Latin American series addressing this topic, and prevalence varied between 8% and 14%. Stage II and III disease, high histological grade, and triple-negative and HER2 BC were features frequently observed among young Latin American BC patients., Conclusion: The rising incidence and mortality of BC in young Latin American women is a call to action in the region. It is necessary to monitor the epidemiological and clinical data through reliable cancer registries and to consider the implementation of protocols for education of patients and health professionals. This unmet, growing burden must be considered as a top priority of the national programs in the fight against BC, and models of specialized units should be implemented for this particular group of patients to provide better care for this emergent challenge.

Background: Hormone receptor-positive advanced breast cancer is an increasing health burden. Although endocrine therapies are recognised as the most beneficial treatments for patients with hormone receptor-positive advanced breast cancer, the optimal sequence of these agents is currently undetermined., Methods: We reviewed the available data on randomised controlled trials (RCTs) of endocrine therapies in this treatment setting with particular focus on RCTs reported over the last 15 years that were designed based on power calculations on primary end points., Results: In this paper, data are reviewed in postmenopausal patients for the use of tamoxifen, aromatase inhibitors and fulvestrant. We also consider the available data on endocrine crossover studies and endocrine therapy in combination with chemotherapy or growth factor therapies. Treatment options for premenopausal patients and those with estrogen receptor-/human epidermal growth factor receptor 2-positive tumours are also evaluated., Conclusion: We present the level of evidence available for each endocrine agent based on its efficacy in advanced breast cancer and a diagram of possible treatment pathways.

Most breast tumors depend on female sex hormones for development and growth, thus being amenable to endocrine therapies. In the management of estrogen receptor (ER)-positive, advanced breast cancer, conventional wisdom dictates the use of endocrine therapy for patients with good prognostic features, whereas chemotherapy is recommended for the treatment of visceral crisis. There is, however, considerable uncertainty regarding the best initial strategy for patients with poor prognostic features other than visceral crisis, such as small-volume visceral involvement and a short disease-free interval after adjuvant therapy. In this article, we examine the role of chemotherapy in ER-positive, advanced breast cancer. Our review of the literature suggests that, in the absence of visceral crisis, endocrine agents should always be considered a major option for the initial treatment of ER-positive, metastatic breast cancer due to their proven efficacy and favorable toxicity profile. Although certain chemotherapy agents can induce higher response rates and more rapid responses, which are desirable effects in particular situations, the up-front use of chemotherapy does not seem to influence the overall outcome of the disease. In the subset of patients with epidermal growth factor type 2-positive disease, on the other hand, current data still do not support the use of endocrine agents alone.