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Background: Circadian rhythms regulate cellular physiology and could influence the efficacy of endocrine therapy (ET) in breast cancer (BC). We prospectively tested this hypothesis within the UNIRAD adjuvant phase III trial (NCT01805271)., Methods: 1278 patients with high-risk hormonal receptor positive (HR+)/HER2 negative (HER2-) primary BC were randomly assigned to adjuvant ET with placebo or everolimus. Patients prospectively reported in a diary the daily timing of ET intake among four 6-h slots (06:00-11:59 (morning), 12:00-17:59 (afternoon), 18:00-23:59 (evening), or 24:00-05:59 (nighttime). The association between ET timing and disease-free survival (DFS) was a prespecified secondary endpoint of the trial and the results of this observational study are reported here., Findings: ET timing was recorded by 855 patients (67.2%). Patients declaring morning (n = 465, 54.4%) or afternoon (n = 45, 5.4%) ET intake were older than those declaring evening (n = 339, 39.6%) or nighttime (n = 5, 0.6%) intake. With a median follow-up of 46.7 months, 118 patients had a local (n = 30) or metastasis relapse (n = 84), and 41 patients died. ET intake timing was not associated with DFS in the whole population (HR = 0.77, 95% CI [0.53-1.12]). The association between ET intake timing and DFS according to the stratification factors revealed interactions with ET agent (tamoxifen versus Aromatase inhibitors (AI) with an increased DFS in the group of evening/nighttime versus morning/afternoon tamoxifen intake (HR = 0.43, 95% CI [0.22-0.85]), while no association was found for AI intake (HR = 1.07, 95% CI [0.68-1.69]). The interaction between ET intake timing and ET agent remained in multivariable analysis (HR = 0.38 [0.16-0.91])., Interpretation: Tamoxifen intake in the evening/nighttime could be recommended in patients with high-risk HR+/HER2- BC while awaiting for results from further ET timing studies., Funding: UNIRAD was Supported by a grant from the French Ministry of Health PHRC 2012 and received funding from La Ligue contre le Cancer, Cancer Research-UK, Myriad Genetics, and Novartis., Competing Interests: Declaration of interests The authors declared no competing interest with this study. Dr Giacchetti declared travel expenses from MSD and Novartis to SABCS 2022 meeting and ASCO 2023 meeting where these data were presented (SABCS 2022 Abstract 1,305,036; ASCO 2023 Abstract 412,092)., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The purpose of this study was to evaluate the prognostic value of the multigene EndoPredict test in prospectively collected data of patients screened for the randomized, double-blind, phase III UNIRAD trial, which evaluated the addition of everolimus to adjuvant endocrine therapy in high-risk, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer., Patients and Methods: Patients were classified into low or high risk according to the EPclin score, consisting of a 12-gene molecular score combined with tumor size and nodal status. Association of the EPclin score with disease-free survival (DFS) and distant metastasis-free survival (DMFS) was evaluated using Kaplan-Meier estimates. The independent prognostic added value of EPclin score was tested in a multivariate Cox model after adjusting on tumor characteristics., Results: EndoPredict test results were available for 768 patients: 663 patients classified as EPclin high risk (EPCH) and 105 patients as EPclin low risk (EPCL). Median follow-up was 70 months (range 1-172 months). For the 429 EPCH randomized patients, there was no significant difference in DFS between treatment arms. The 60-month relapse rate for patients in the EPCL and EPCH groups was 0% and 7%, respectively. Hazard ratio (HR) supposing continuous EPclin score was 1.87 [95% confidence interval (CI) 1.4-2.5, P < 0.0001]. This prognostic effect remained significant when assessed in a Cox model adjusting on tumor size, number of positive nodes and tumor grade (HR 1.52, 95% CI 1.09-2.13, P = 0.0141). The 60-month DMFS for patients in the EPCL and EPCH groups was 100% and 94%, respectively (adjusted HR 8.10, 95% CI 1.1-59.1, P < 0.0001)., Conclusions: The results confirm the value of EPclin score as an independent prognostic parameter in node-positive, hormone receptor-positive, HER2-negative early breast cancer patients receiving standard adjuvant treatment. EPclin score can be used to identify patients at higher risk of recurrence who may warrant additional systemic treatments., Competing Interests: Disclosure FPL: advisor for AstraZeneca, Daiichi Sankyo, Genomic Health, GILEAD, GSK, Lilly, Menarini/Stemline, MSD, Myriad, Nanostring, Novartis, Pfizer, Pierre-Fabre, Roche; funding: MSD, Myriad, AstraZeneca, Daiichi Sankyo; travel/expenses: AstraZeneca, BMS, Daiichi Sankyo, MSD, Novartis, Pfizer. FD: advisor for Daichi, Seagen, Novartis, Gilead, Lilly, MSD; travel/expenses: Daichi, Novartis, Pfizer. PC: advisor for Pfizer, Lilly; travel/expenses: Roche, Pfizer, Lilly, Novartis, Sanofi, BMS. JG: advisor for Daiichi Sankyo, Gilead, Pfizer; travel/expenses: Eisai Europe. MC: advisor for Novartis, Sandoz, Accord, Sanofi, Lilly, AstraZeneca, AbbVie, Seattle Genetics, Daiichi Sankyo; consulting fees: Pierre Fabre, Sanofi, Novartis, Servier, Daiichi Sankyo; travel//expenses: Novartis, AstraZeneca, Pfizer, Roche. ACHB: advisor for Novartis, AstraZeneca, Pfizer, Novartis, Clovis Onco, Seattle Genetics, Eisai, Daiichi Sankyo/Astra Zeneca, MSD. SG: advisor for Eisai, Lilly; funding: Merck, AstraZeneca; travel/expenses: Lilly. PB: advisor for Ipsen, BMS, MSD, Pfizer, Merck KGaA, Astellas, Novartis, Gilead, Bayer; travel/expenses: BMS, Pfizer, Janssen-Cilag, Astellas, MSD, Ipsen, Merck. AM: advisor for Pfizer; travel/expenses: AstraZeneca, Pierre Fabre, Lilly. MS: travel/expenses: Eisai Europe. MLT: consulting fees: Myriad Genetics. JB: funding: AstraZeneca, Merck Sharp & Dohme, Puma Biotech, Pfizer, Roche, Lilly, Janssen-Cilag, Clovis Onco; travel/expenses: Pfizer. FA: stock and other ownership interests: PEGASCY; funding: AstraZeneca, Novartis, Pfizer, Lilly, Roche, Daiichi; travel/expenses: Novartis, Roche, GlaxoSmithKline, AstraZeneca. TB: advisor for Roche, Novartis, AstraZeneca, Pfizer, Seattle Genetics, MSD; funding: Roche, Novartis, AstraZeneca, Seattle Genetics, Pfizer; travel/expenses: Roche, Pfizer, AstraZeneca. All other authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: In the PAOLA-1/ENGOT-ov25 trial (NCT02477644), adding maintenance olaparib to bevacizumab provided a substantial progression-free survival benefit in patients with newly diagnosed advanced ovarian cancer and homologous recombination deficiency (HRD)-positive tumors, irrespective of clinical risk. Subsequently, a clinically meaningful improvement in overall survival was reported with olaparib plus bevacizumab in the HRD-positive subgroup. We report updated progression-free survival and overall survival by clinical risk and HRD status., Methods: Patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab received maintenance olaparib (up to 24 months) plus bevacizumab (up to 15 months in total) or placebo plus bevacizumab. This post hoc analysis evaluated 5-year progression-free survival and mature overall survival in patients classified by clinical risk and HRD status., Results: Of 806 randomized patients, 74% were higher-risk and 26% were lower-risk. In higher-risk HRD-positive patients, the hazard ratio (HR) for progression-free survival was 0.46 (95% confidence interval (95% CI) 0.34 to 0.61), with 5-year progression-free survival of 35% with olaparib plus bevacizumab versus 15% with bevacizumab alone; and the HR for overall survival was 0.70 (95% CI 0.50 to 1.00), with 5-year overall survival of 55% versus 42%, respectively. In lower-risk HRD-positive patients, the HR for progression-free survival was 0.26 (95% CI 0.15 to 0.45), with 5-year progression-free survival of 72% with olaparib plus bevacizumab versus 28% with bevacizumab alone; and the HR for overall survival was 0.31 (95% CI 0.14 to 0.66), with 5-year overall survival of 88% versus 61%, respectively. No benefit was seen in HRD-negative patients regardless of clinical risk., Conclusion: This post hoc analysis indicates that in patients with newly diagnosed advanced HRD-positive ovarian cancer, maintenance olaparib plus bevacizumab should not be limited to those considered at higher risk of disease progression. Five-year progression-free survival rates support long-term remission and suggest an increased potential for cure with particular benefit suggested in lower-risk HRD-positive patients., Competing Interests: Competing interests: Domenica Lorusso reports consultancy fees (personal) from Amgen, AstraZeneca, Clovis Oncology, Genmab, GSK, Immunogen, MSD, PharmaMar, and Seagen; membership on an advisory board (personal) for AstraZeneca, Clovis Oncology, Corcept, Genmab, GSK, Immunogen, Merck Serono, MSD, Oncoinvest, PharmaMar, Seagen, and Sutro; and research funding (institutional) from AstraZeneca, Clovis Oncology, Genmab, GSK, Immunogen, Incyte, MSD, Novartis, PharmaMar, Roche, and Seagen; and travel support from Roche, PharmaMar, AstraZeneca, Clovis Oncology, and GSK. Marie-Ange Mouret-Reynier reports board membership (personal and institution) for Pfizer, Lilly, Novartis, MSD, and AstraZeneca; and research funding (personal and institution) from Pfizer, Lilly, Novartis, MSD, and AstraZeneca. Philipp Harter reports honoraria from Amgen, AstraZeneca, GSK, Roche, Sotio, Stryker, Zai Lab, MSD, Clovis, Eisai, Mersana, and Exscientia; membership on an advisory board for AstraZeneca, Roche, GSK, Clovis, Immunogen, MSD, Miltenyi, Novartis, and Eisai; and research funding (institutional) from AstraZeneca, Roche, GSK, Genmab, Immunogen, Seagen, Clovis, and Novartis. Claire Cropet reports no conflicts of interest. Cristina Caballero reports no conflicts of interest. Pia Wolfrum-Ristau reports no conflicts of interest.Toyomi Satoh reports no conflicts of interest. Ignace Vergote reports consulting fees (personal) from Agenus, Akesobio, AstraZeneca, BMS, Deciphera Pharmaceuticals, Eisai, Elevar Therapeutics, Exelixis, Roche, Genmab, GSK, Immunogen, Jazz Pharmaceuticals, Karyopharm, Mersana, Molecular Partners, MSD, Novocure, Novartis, Oncoinvent, OncXerna, Regeneron, Sanofi, Seagen, Sotio, Verastem Oncology, and Zentalis; contracted research (via KULeuven; institution) for Oncoinvent AS; corporate sponsored research (institution) from Amgen and Roche; and travel support (personal) from Karyopharm, Genmab, and Novocure.Gabriella Parma reports no conflicts of interest. Trine Jakobi Nøttrup reports no conflicts of interest. Coriolan Lebreton reports honoraria (personal) from Eisai, Clovis Oncology, MSD, and GSK. Peter A Fasching reports membership on an advisory board (personal) for Agendia, AstraZeneca, Daiichi-Sankyo, Eisai, Hexal, Lilly, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi Aventis, and Seagen; invited speaker fees (personal) from AstraZeneca, Daiichi-Sankyo, Eisai, Gilead, Lilly, MSD, Novartis, and Seagen; and medical writing support (personal) from Roche. Carmela Pisano reports membership on an advisory board (personal) for AstraZeneca, MSD and GSK; and honoraria (personal) from Clovis Oncology. Luis Manso reports no conflicts of interest. Hugues Bourgeois reports no conflicts of interest. Ingo Runnebaum reports no conflicts of interest. Claudio Zamagni reports reports grants or contract to self from Amgen, Celgene, Daiichi, Eisai, Eli Lilly, GSK, MSD, and PharmaMar; grants or contract to self and institution from AstraZeneca, Instituto Gentili, Novartis, Pfizer, Pierre Fabre, Roche, Seagen, Tesaro, and Teva; support for attending meetings and/or travel from Celgene, Instituto Gentili, Novartis, Pfizer, PharmaMar, Pierre Fabre, Roche, and Tesaro; participation on a data safety monitoring board or advisory board for Amgen, AstraZeneca, Celgene, Daiichi, Eisai, Eli Lilly, GSK, MSD, Novartis, Pfizer, PharmaMar, QuintilesIMS, Roche, and Tesaro; and other financial or non-interests for Amgen, AstraZeneca, Daiichi, GSK, MSD, Novartis, Pfizer, PharmaMar, QuintilesIMS, Roche, and Tesaro. Anne-Claire Hardy-Bessard reports membership on an advisory board (personal) for MSD, AstraZeneca, GSK, Pfizer, and Novartis. Andreas Schnelzer reports no conflicts of interest. Michel Fabbro reports honoraria from GSK. Barbara Schmalfeldt reports honoraria from Roche, AstraZeneca, Tesaro, Clovis, GSK, and MSD; consultancy or advisory roles from Roche, AstraZeneca, Tesaro, Clovis, GSK, and MSD; membership of a speaker’s bureau for Roche, AstraZeneca, Tesaro, Clovis, GSK, and MSD; research funding from Roche, AstraZeneca, Tesaro, Clovis, GSK, and MSD; and funding for travel or accommodation expenses from Roche, AstraZeneca, and Tesaro. Dominique Berton reports no conflicts of interest. Antje Belau reports honoraria from Roche, AstraZeneca, Clovis, MSD, Daiichi Sankyo Company, Lilly, and Seagen; advisory roles for Pfizer, Roche, AstraZeneca, MSD, Lilly, Daiichi Sankyo Company, and Seagen; and funding for travel or accommodation expenses from Roche, AstraZeneca, and Daiichi Sankyo Company. Jean-Pierre Lotz reports no conflicts of interest. Martina Gropp-Meier reports no conflicts of interest. Laurence Gladieff reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Clovis, Eisai, GSK, and MSD; and participation on an advisory board for AstraZeneca, GSK, and MSD. Hans-Joachim Lück reports participation on advisory boards for AstraZeneca, GSK, Seagen, Gilead, Novartis, and Lilly and speaker roles for AstraZeneca, Lilly, Gilead, Pfizer, and Novartis. Sophie Abadie-Lacourtoisie reports no conflicts of interest. Eric Pujade-Lauraine reports membership on an advisory board (personal) for Roche, GSK, and AstraZeneca; Independent Data Monitoring Committee board membership (personal) for Agenus and Incyte; and employment (personal) at ARCAGY Research. Isabelle Ray-Coquard reports honoraria (personal) from Abbvie, Agenus, Advaxis, BMS, PharmaMar, Genmab, Pfizer, AstraZeneca, Roche, GSK, MSD, Deciphera, Mersena, Merck Sereno, Novartis, Amgen, Tesaro, and Clovis Oncology; honoraria (institution) from GSK, MSD, Roche, and BMS; advisory/consulting fees from Abbvie, Agenus, Advaxis, BMS, PharmaMar, Genmab, Pfizer, AstraZeneca, Roche/Genentech, GSK, MSD, Deciphera, Mersena, Merck Sereno, Novartis, Amgen, Tesaro, and Clovis Oncology; research grant/funding (personal) from MSD, Roche, and BMS; research grant/funding (institution) from MSD, Roche, BMS, Novartis, AstraZeneca, and Merck Sereno; and travel support from Roche, AstraZeneca, and GSK., (© IGCS and ESGO 2024. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Background: Initial TRITON2 (NCT02952534) results demonstrated the efficacy of rucaparib 600 mg BID in patients with metastatic castration-resistant prostate cancer (mCRPC) associated with a BRCA1 or BRCA2 (BRCA) or other DNA damage repair (DDR) gene alteration., Objective: To present the final data from TRITON2., Design, Setting, and Participants: TRITON2 enrolled patients with mCRPC who had progressed on one or two lines of next-generation androgen receptor-directed therapy and one taxane-based chemotherapy., Outcome Measurements and Statistical Analysis: The primary endpoint was objective response rate (ORR; as per the modified Response Evaluation Criteria in Solid Tumor Version 1.1/Prostate Cancer Clinical Trials Working Group 3 criteria in patients with measurable disease by independent radiology review [IRR]); prostate-specific antigen (PSA) response rate (≥50% decrease from baseline [PSA50]) was a key secondary endpoint., Results and Limitations: As of July 27, 2021 (study closure), TRITON2 had enrolled 277 patients, grouped by mutated gene: BRCA (n = 172), ATM (n = 59), CDK12 (n = 15), CHEK2 (n = 7), PALB2 (n = 11), or other DDR gene (Other; n = 13). ORR by IRR was 46% (37/81) in the BRCA subgroup (95% confidence interval [CI], 35-57%), 100% (4/4) in the PALB2 subgroup (95% CI, 40-100%), and 25% (3/12) in the Other subgroup (95% CI, 5.5-57%). No patients within the ATM, CDK12, or CHEK2 subgroups had an objective response by IRR. PSA50 response rates (95% CI) in the BRCA, PALB2, ATM, CDK12, CHEK2, and Other subgroups were 53% (46-61%), 55% (23-83%), 3.4% (0.4-12), 6.7% (0.2-32%), 14% (0.4-58%), and 23% (5.0-54%), respectively., Conclusions: The final TRITON2 results confirm the clinical benefit and manageable safety profile of rucaparib in patients with mCRPC, including those with an alteration in BRCA or select non-BRCA DDR gene., Patient Summary: Almost half of TRITON2 patients with BRCA-mutated metastatic castration-resistant prostate cancer had a complete or partial tumor size reduction with rucaparib; clinical benefits were also observed with other DNA damage repair gene alterations., (Crown Copyright © 2023. Published by Elsevier B.V. All rights reserved.)

Recommendations for clinical practice, Nice/Saint-Paul-de-Vence 2022-2023: Management of localized endometrial cancer Endometrial cancer is the most frequent gynecological cancers in industrialized countries and its incidence increases. The newmolecularclassification allows determination of the risk of recurrence and helps orienting therapeutic management. Surgery remains the cornerstone of treatment. Minimally invasive approach must be preferred for stages I and II. Surgery includes hysterectomy with bilateral adnexectomy, sentinel lymph node biopsy even in high risk diseases and omentectomy for non-endometrioid tumors (except in case of clear cells tumors). Fertility preservation can be proposed in low grade, stage I tumors without myometrial involvement. In stage III/IV disease, lymph node debulking without totallymphadenectomy is indicated. In case of peritoneal carcinomatosis, first-line cytoreductive surgery is recommended if complete resection can be achieved. Adjuvant therapy is not recommended in low risk tumors. In intermediate risk tumors, curietherapy is indicated. In tumors with high-intermediate risk, curietherapy and external radiotherapy are indicated according to prognostic factors (stage II, lymphovascular invasion); adjuvant chemotherapy can be considered on a case-by-case basis. In high risk tumors, chemotherapy and external radiotherapy are recommended using a concomitant or sequential approach., (Copyright © 2023 Elsevier Masson SAS. Tous droits réservés. All rights reserved.)

Background: Current standards for toxicity reporting do not fully capture the impact of adverse events (AEs) on patients' quality of life (QoL). This study aimed to evaluate the association between toxicity and QoL by using toxicity scores that take into account CTCAE grade grouping and AE duration and cumulation., Methods: Analyses were performed on the AURELIA trial dataset, including 361 patients with platinum-resistant ovarian cancer treated with chemotherapy alone or with bevacizumab. Global and physical functioning QoL were issued from the EORTC QoL Questionnaire-Core 30 (QLQ-C30), collected at baseline and 8/9 and 16/18 weeks after treatment initiation. Four toxicity scores were computed: the total number of AEs, multiplied by their grade and not, and the cumulative duration of AEs, weighted by their grade and not. Each score included all AEs or only grade 3/4 nonlaboratory or treatment-related AEs. The relationship between toxicity scores and QoL was assessed through linear mixed regression., Results: We found that 171 (47.5%) and 43 (11.9%) patients experienced at least one grade 3 or 4 AE, respectively, whereas 113 (31.4%) experienced grade 2 AEs only. Physical QoL was negatively associated with all toxicity scores when computed with all grades of AEs (all P<.01), with a weaker association when treatment-related AEs were considered. Global QoL was negatively associated with toxicity scores computed with nonlaboratory all-grade AEs only (β, -3.42 to -3.13; all P<.01). Degrees of association were lower when considering the AE duration., Conclusions: In this analysis of patients with platinum-resistant ovarian cancer, toxicity scores based on the cumulative number of AEs, modulated or not by grade, were more effective at predicting QoL changes than those based on AE duration. Toxicity impact on QoL was better reflected when grade 2 AEs were taken into account together with grade 3/4 AEs, whatever their treatment imputability, and when laboratory AEs were excluded.

Background: The objective of the CHEOPS trial was to assess the benefit of adding aromatase inhibitor (AI) to metronomic chemotherapy, oral vinorelbine, 50 mg, three times a week for pre-treated, HR + /HER2- metastatic breast cancer patients., Methods: In this multicentric phase II study, patients had to have progressed on AI and one or two lines of chemotherapy. They were randomized between oral vinorelbine (Arm A) and oral vinorelbine with non-steroidal AI (Arm B)., Results: 121 patients were included, 61 patients in Arm A and 60 patients in Arm B. The median age was 68 years. 109 patients had visceral metastases. They all had previously received an AI. The study had been prematurely stopped following the third death due to febrile neutropenia. Median PFS trend was found to be different with 2.3 months and 3.7 months in Arm A and Arm B, respectively (HR 0.73, 95%CI 0.50-1.06, p value = 0.0929). No statistical difference was shown in OS and better tumor response. 56 serious adverse events corresponding to 25 patients (21%) were reported (respectively, 12 (20%) versus 13 (22%) for arms A and B) (NS)., Conclusion: The addition of AI to oral vinorelbine over oral vinorelbine alone in aromatase inhibitor-resistant metastatic breast cancer was associated with a non-significant improvement of PFS. Several unexpected serious adverse events were reported. Metronomic oral vinorelbine schedule, at 50 mg three times a week, requires close biological monitoring. The question of hormonal treatment and chemotherapy combination remains open., (© 2023. The Author(s).)

Purpose: Everolimus, an oral inhibitor of the mammalian target of rapamycin, improves progression-free survival in combination with endocrine therapy (ET) in postmenopausal women with aromatase inhibitor-resistant metastatic breast cancer. However, the benefit of adding everolimus to ET in the adjuvant setting in early breast cancer is unknown., Patients and Methods: In this randomized double-blind phase III study, women with high-risk, hormone receptor-positive, human epidermal growth factor receptor 2-negative primary breast cancer were randomly assigned to everolimus or placebo for 2 years combined with standard ET. Stratification factors included ET agent, receipt of neoadjuvant versus adjuvant chemotherapy, progesterone receptor status, duration of ET before random assignment, and lymph node involvement. The primary end point was disease-free survival (DFS). The trial is registered with ClinicalTrials.gov (identifier: NCT01805271)., Results: Between June 2013 and March 2020, 1,278 patients were randomly allocated to receive everolimus or placebo. At the first interim analysis, the trial was stopped for futility and a full analysis undertaken once data snapshot complete. One hundred forty-seven patients have had a DFS event reported and at 3 years, DFS did not differ between patients who received ET plus everolimus (88% [95% CI, 85 to 91]) or ET plus placebo (89% [95% CI, 86 to 91; hazard ratio, 0.95; 95% CI, 0.69 to 1.32; P = .77]). Grade ≥ 3 adverse events were reported in 22.9% of patients (29.9% with everolimus v 15.9% with placebo, P < .001). 53.4% everolimus-treated patients permanently discontinued experimental treatment early compared with placebo-treated 22.3%., Conclusion: Among high-risk patients, everolimus added to adjuvant ET did not improve DFS. Tolerability was a concern, with more than half of patients stopping everolimus before study completion. Everolimus cannot be recommended in the adjuvant setting.

Background: In advanced oestrogen receptor-positive, HER2-negative breast cancer, acquired resistance to aromatase inhibitors frequently stems from ESR1-mutated subclones, which might be sensitive to fulvestrant. The PADA-1 trial aimed to show the efficacy of an early change in therapy on the basis of a rising ESR1 mutation in blood (bESR1 mut ), while assessing the global safety of combination fulvestrant and palbociclib., Methods: We did a randomised, open-label, phase 3 trial in 83 hospitals in France. Women aged at least 18 years with oestrogen receptor-positive, HER2-negative advanced breast cancer and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited and monitored for rising bESR1 mut during first-line aromatase inhibitor (2·5 mg letrozole, 1 mg anastrozole, or 25 mg exemestane, orally once per day, taken continuously) and palbociclib (125 mg orally once per day on days 1-21 of a 28-day cycle) therapy. Patients with newly present or increased bESR1 mut in circulating tumour DNA and no synchronous disease progression were randomly assigned (1:1) to continue with the same therapy or to switch to fulvestrant (500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1) and palbociclib (dosing unchanged). The randomisation sequence was generated within an interactive web response system using a minimisation method (with an 80% random factor); patients were stratified according to visceral involvement (present or absent) and the time from inclusion to bESR1 mut detection (<12 months or ≥12 months). The co-primary endpoints were investigator-assessed progression-free survival from random assignment, analysed in the intention-to-treat population (ie, all randomly assigned patients), and grade 3 or worse haematological adverse events in all patients. The trial is registered with Clinicaltrials.gov (NCT03079011), and is now complete., Findings: From March 22, 2017, to Jan 31, 2019, 1017 patients were included, of whom 279 (27%) developed a rising bESR1 mut and 172 (17%) were randomly assigned to treatment: 88 to switching to fulvestrant and palbociclib and 84 patients to continuing aromatase inhibitor and palbociclib. At database lock on July 31, 2021, randomly assigned patients had a median follow-up of 35·3 months (IQR 29·2-41·4) from inclusion and 26·0 months (13·8-34·3) from random assignment. Median progression-free survival from random assignment was 11·9 months (95% CI 9·1-13·6) in the fulvestrant and palbociclib group versus 5·7 months (3·9-7·5) in the aromatase inhibitor and palbociclib group (stratified HR 0·61, 0·43-0·86; p=0·0040). The most frequent grade 3 or worse haematological adverse events were neutropenia (715 [70·3%] of 1017 patients), lymphopenia (66 [6·5%]), and thrombocytopenia (20 [2·0%]). The most common grade 3 or worse adverse events in step 2 were neutropenia (35 [41·7%] of 84 patients in the aromatase inhibitor and palbociclib group vs 39 [44·3%] of 88 patients in the fulvestrant and palbociclib group) and lymphopenia (three [3·6%] vs four [4·5%]). 31 (3·1%) patients had grade 3 or worse serious adverse events related to treatment in the overall population. Three (1·7%) of 172 patients randomly assigned had one serious adverse event in step 2: one (1·2%) grade 4 neutropenia and one (1·2%) grade 3 fatigue among 84 patients in the aromatase inhibitor and palbociclib group, and one (1·1%) grade 4 neutropenia among 88 patients in the fulvestrant and palbociclib group. One death by pulmonary embolism in step 1 was declared as being treatment related., Interpretation: PADA-1 is the first prospective randomised trial showing that the early therapeutic targeting of bESR1 mut results in significant clinical benefit. Additionally, the original design explored in PADA-1 might help with tackling acquired resistance with new drugs in future trials., Funding: Pfizer., Competing Interests: Declaration of interests F-CB reports, outside the submitted work, grants or contracts from Novartis, Lilly, Amgen, Sanofi, Radius, Seagen, AstraZeneca, General Electric, Menarini/Stemline, Menarini Silicon Biosystems, Merck, Pfizer, Prolynx, Rain Therapeutics, and Roche; consulting fees from AstraZeneca, Exact Sciences, General Electric, GlaxoSmithKline, Lilly, Menarini/Stemline, Novartis, Pfizer, Rain Therapeutics, and Sanofi; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Lilly, Menarini/Stemline, Pfizer, Rain Therapeutics, and Sanofi; support for attending meetings or travel from AstraZeneca, Pfizer, Novartis, and Roche; and applied for an international patent (application number PCT/EP2019/056445), filed on March 14, 2019, named: method for identifying one or more mutations in a hotspot mutation sequence. A-CH-B reports, outside the submitted work, consulting fees from AstraZeneca and Merck Sharpe & Dohme; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from MSD, AstraZeneca, Daiichi, GSK, Seagen, and Gilead; support for attending meetings or travel from Novartis, Pfizer, and Daiichi; and participation on a data safety monitoring board or advisory board for MSD, AstraZeneca, Daiichi, Pfizer, Novartis, GSK, Seagen, Gilead, and Eisai. TB reports, outside the submitted work, grants or contracts from Roche, AstraZeneca, Pfizer, and SeaGen; and consulting fees from AstraZeneca, Daiichi, Lilly, SeaGen, Roche, Novartis, and Pfizer. J-YP reports, outside the submitted work, grants or contracts from Servier and Menarini; consulting fees from Pfizer, Daiichi Sankyo, AstraZeneca, and MSD; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Daiichi Sankyo, Gilead, MSD, Seagen, Novartis, Lilly, Pierre Fabre, and Amgen; support for attending meetings or travel from Roche and AstraZeneca; and participation on a data safety monitoring board or advisory board for Sanofi and Novartis. TdlMR reports, outside the submitted work, grants or contracts from Novartis, Pfizer, AstraZeneca, MSD, Roche, Pfizer, and Seagen; consulting fees from AstraZeneca, Clovis Oncology, Eisai, MSD, Novartis, Pfizer, Roche, Sanofi, Tesaro, GSK, and Seagen; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from GSK. RS reports, outside the submitted work, grants or contracts from AstraZeneca; consulting fees from GSK; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Novartis, GSK, Clovis, and AstraZeneca; and support for attending meetings or travel from Pfizer, Roche, GSK, and Bristol Myers Squibb. J-SF reports, outside the submitted work, consulting fees from Pfizer, Lilly, Novartis, AstraZeneca, Clovis Oncology, GSK, Gilead, Daiichi Sankyo, and Seagen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Lilly, Novartis, AstraZeneca, Gilead, Daiichi Sankyo, and Seagen; and support for attending meetings or travel from Pfizer, Lilly, Novartis, AstraZeneca, Clovis Oncology, GSK, Gilead, Daiichi Sankyo, and Seagen. SL reports, outside the submitted work, grants or contracts from Novartis, Eisai, and BMS; consulting fees from Pfizer, Novartis, Lilly, AstraZeneca, Sanofi, Astellas, Janssen, Ipsen, Roche, BMS, Daiichi, Seagen, and Pierre Fabre; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer, Novartis, Lilly, AstraZeneca, Sanofi, Astellas, Janssen, Ipsen, Roche, BMS, Daiichi, Seagen, and Pierre Fabre; payment for expert testimony from Pfizer, Novartis, Lilly, AstraZeneca, Sanofi, Astellas, Janssen, Ipsen, Roche, BMS, Daiichi, and Seagen; support for attending meetings or travel from Pfizer, Novartis, AstraZeneca, Janssen, BMS, Daiichi, and Seagen; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from BMS. CL reports, outside the submitted work, consulting fees from MSD, Daiichi, Roche, and AstraZeneca; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Lilly; support for attending meetings or travel from Roche, Pfizer, Sandoz, Lilly, and AstraZeneca; and participation on a data safety monitoring board or advisory board for Roche, AstraZeneca, and Lilly. AL reports, outside the submitted work, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, MSD, and Clovis; participation on a data safety monitoring board or advisory board for AstraZeneca, MSD, and Clovis; and leadership or fiduciary role in other board for GINECO group. JG reports, outside the submitted work, support for attending meetings or travel from Lilly and Daiichi; and participation on a data safety monitoring board or advisory board for Daiichi and Pfizer. HV reports, outside the submitted work, grants or contracts from Eisai, Novartis, AstraZeneca, Daiichi, and Pfizer; and support for attending meetings or travel from Eisai, GSK, MSD, and Novartis. CG-T reports, outside the submitted work, grants or contracts from Pfizer; consulting fees from Pfizer; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Astrazeneca, Pfizer and Novartis; and support for attending meetings or travel from MSD, Mylan, and Pfizer. BP reports, outside the submitted work, consulting fees from AstraZeneca, Myriad, Pierre Fabre, and Pfizer; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Daiichi Sankyo, Novartis, and Puma; support for attending meetings or travel from AstraZeneca, Pierre Fabre, and MSD; and participation on a data safety monitoring board or advisory board for Novartis, AstraZeneca, and Daiichi Sankyo. FA reports, outside the submitted work, reports grants or contracts from Roche, AstraZeneca, Daiichi Sankyo, Pfizer, Novartis, and Lilly; and consulting fees from Gilead, Guardant Health, MedImmune, and Relay Therapeutics. LA reports, outside the submitted work, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Roche, MSD, AstraZeneca, and BMS; and support for attending meetings or travel from Roche. JL reports a Pfizer grant to his institution for carrying out this study. SD reports, outside the submitted work, grants or contracts from AstraZeneca, Pfizer, Novartis, Roche Genentech, Lilly, Puma, Myriad, Orion, Amgen, Sanofi, MSD, BMS, Seagen, and Taiho; consulting fees from Isis/Servier, Cellectis, Pierre Fabre, and General Electric; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Seagen, AstraZeneca, Pfizer, Exact Sciences, Daiichi, and Lilly; support for attending meetings or travel from Pfizer, AstraZeneca, and Roche Genentech; and participation on a data safety monitoring board or advisory board for AstraZeneca, Sanofi, Orion, and Rappta. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Anti-angiogenic rechallenge with bevacizumab plus chemotherapy is effective in recurrent ovarian cancer (rOC); however, data are limited on tyrosine kinase inhibitors after progression on maintenance bevacizumab., Methods: In the randomized phase II TAPAZ trial, patients with rOC during the first year of bevacizumab maintenance therapy were assigned 2:1 to either weekly paclitaxel 65 mg/m 2 plus pazopanib 600-800 mg daily or standard weekly paclitaxel 80 mg/m 2 . The primary endpoint was 4-month progression-free survival (PFS) rate., Results: Overall, 116 patients were randomized and treated: 79 with combination therapy and 37 with single-agent paclitaxel. Median follow-up was 13.1 months. There was no difference between treatment arms in 4-month PFS rate (61% [95% CI, 51-73%] with the combination versus 68% [95% CI, 54-85%] with paclitaxel alone), median PFS (4.9 [95% CI, 4.1-6.1] versus 5.8 [95% CI, 4.8-7.4] months, respectively) or median overall survival (13.6 versus 12.9 months, respectively). The combination was associated with more grade 3/4 toxicities (87% versus 70%, respectively) and toxicity-related paclitaxel discontinuations (22% versus 11%). Pazopanib was discontinued for toxicity in 44% of patients, most commonly for gastrointestinal and vascular events. There were two treatment-related deaths, both in the combination arm (pulmonary embolism and gastrointestinal perforation). At month 4, patient-reported outcomes deteriorated from baseline in the combination arm, particularly for abdominal/gastrointestinal symptoms, which showed a clinically important difference versus paclitaxel alone., Conclusions: In rOC progressing during maintenance bevacizumab, adding pazopanib to paclitaxel did not improve efficacy, increased toxicity, and compromised chemotherapy delivery., Clinicaltrials: govregistration:NCT02383251., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The clinical actionability of circulating tumor DNA requires sensitive detection methods with a short turnaround time. In the PADA-1 phase 3 trial (NCT03079011), metastatic breast cancer patients treated with an aromatase inhibitor and palbociclib were screened every 2 months for activating ESR1 mutations in blood ( bESR1 mut ). We report the feasibility of the droplet digital polymerase chain reaction (ddPCR) and cross-validation with next-generation sequencing (NGS). bESR1 mut testing was centralized in two platforms using the same ddPCR assay. Results were reported as copies/mL of plasma and mutant allele frequency (MAF). We analyzed 200 positive ddPCR samples with an NGS assay (0.5-1% sensitivity). Overall, 12,552 blood samples were collected from 1017 patients from 83 centers. Among the 12,525 available samples with ddPCR results, 11,533 (92%) were bESR1 mut -negative. A total of 267 patients newly displayed bESR1 mut (26% patients/2% samples) with a median copy number of 14/mL (range: 4-1225) and a median MAF of 0.83% (0.11-35), 648 samples (20% patients/5% samples) displayed persistent bESR1 mut , and 77 (<1%) samples encountered a technical failure. The median turnaround time from blood drawing to result notification was 13 days (Q1:9; Q3:21 days). Among 200 ddPCR-positive samples tested, NGS detected bESR1 mut in 168 (84%); 25 of the 32 cases missed by NGS had low MAF and/or low coverage. In these 200 samples, bESR1 mut MAF by both techniques had an excellent intraclass correlation coefficient (ICC = 0.93; 95% CI [0.85; 0.97]). These results from a large-scale trial support the feasibility and accuracy of real-time bESR1 mut tracking by ddPCR, opening new opportunities for therapeutic interventions.

Introduction: The combination of a CDK4/6 inhibitor with an aromatase inhibitor (AI) has recently become the gold standard for AI-sensitive first line treatment of oestrogen receptor-positive (ER+) HER2-negative (HER2-) advanced breast cancer. However, most patients receiving this combination will ultimately progress and require further therapies.Several studies have demonstrated that the onset of a ESR1 gene mutation lead to AIs resistance in the advanced setting. ESR1 mutations can be detected in circulating tumour DNA (ctDNA) using a digital PCR assay. Our study aims to prove the clinical efficacy of periodic monitoring for emerging or rise of ESR1 mutations in ctDNA to trigger an early change from AI plus palbociclib to fulvestrant plus palbociclib treatment while assessing global safety., Methods: PADA-1 is a randomised, open-label, multicentric, phase III trial conducted in patients receiving AI and palbociclib as first line therapy for metastatic ER +HER2- breast cancer. 1000 patients will be included and treated with palbociclib in combination with an AI. Patients will be screened for circulating blood ESR1 mutation detection at regular intervals. Patients for whom a rising circulating ESR1 mutation is detected without tumour progression (up to N=200) will be randomised (1:1) between (1) Arm A: no modification of therapy; and (2) Arm B: palbociclib in combination with fulvestrant, a selective ER down-regulator. At tumour progression, an optional crossover will be offered to patients randomised in arm A. The coprimary endpoints are (1) Grade ≥3 haematological toxicities and their associations with baseline characteristics and (2) progression-free survival in randomised patients., Ethics and Dissemination: The study has been approved by the French medicines agency (ANSM) and by an ethics committee (ref 01/17&#95;1 CPP Ouest-IV Nantes) in January 2017. The trial results will be published in academic conference presentations and international peer-reviewed journals., Trial Registration Numbers: EudraCT: 2016-004360-18; NCT03079011., Competing Interests: Competing interests: SD: reports grants and non-financial support from Pfizer, grants from Novartis, grants and non-financial support from AstraZeneca, grants and non-financial support from Roche Genentech, grants from Lilly, grants from Puma, grants from Myriad, grants from Orion, grants from Amgen, grants from Sanofi, grants from Genomic Health, grants from GE, grants from Servier, grants from MSD, grants from BMS, grants from Pierre Fabre, outside the submitted work. A-CH-B: reports personal fees from AstraZeneca, personal fees from Daiichi, personal fees from Clovis, personal fees from GSK, personal fees from MSD, personal fees from Novartis, personal fees from Pfizer, personal fees from Roche outside the submitted work. TB: reports personal fees and non-financial support from Roche, grants, personal fees and non-financial support from Novartis, grants, personal fees and non-financial support from AstraZeneca, grants, personal fees and non-financial support from Pfizer, personal fees from Seagen, outside the submitted work. TDLMR: reports grants, personal fees and non-financial support from Pfizer, grants and non-financial support from Novartis, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Roche Genentech, grants and non-financial support from MSD, personal fees and non-financial support from TESARO-GSK, personal fees from CLOVIS ONCOLOGY, personal fees from MYLAN, outside the submitted work. FA: reports grants from Roche, grants from AstraZeneca, grants from Daiichi Sankyo, grants from Pfizer, grants from Novartis, grants from Lilly, outside the submitted work. LA: report personal fees from Roche, personal fees from MSD, personal fees from AstraZeneca, personal fees fromBMS, outside the submitted work. FC: reports grants from AstraZeneca, grants, personal fees and non-financial support from Roche, personal fees from Lilly, personal fees and non-financial support from Merck Serono, personal fees and non-financial support from BMS, outside the submitted work. F-CB: reports grants from PFIZER, during the conduct of the study; grants, personal fees and non-financial support from PFIZER, grants, personal fees and non-financial support from NOVARTIS, personal fees from LILLY, personal fees and non-financial support from ROCHE, personal fees and non-financial support from AstraZeneca, personal fees from AMGEN, personal fees from SANOFI, personal fees from Radius, grants and personal fees from Seagen, granst from Prolynx outside the submitted work; In addition, F-CB has a patent ctDNA detection by ddPCR pending., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Adding maintenance olaparib to bevacizumab provided a significant progression-free survival (PFS) benefit in patients with newly diagnosed, advanced ovarian cancer in the randomized, double-blind PAOLA-1/ENGOT-ov25 trial (NCT02477644). We analyzed PFS by clinical risk and biomarker status., Methods: Patients received olaparib 300 mg twice daily for up to 24 months plus bevacizumab 15 mg/kg every 3 weeks for up to 15 months in total, or placebo plus bevacizumab. This post hoc exploratory analysis evaluated PFS in patients classified as higher risk (stage III with upfront surgery and residual disease or neoadjuvant chemotherapy; stage IV) or lower risk (stage III with upfront surgery and no residual disease), and by biomarker status., Results: Of 806 randomized patients, 74% were higher risk and 26% were lower risk. After a median 22.9 months of follow-up, PFS favored olaparib plus bevacizumab versus placebo plus bevacizumab in higher-risk patients (hazard ratio [HR] 0.60; 95% confidence interval [CI] 0.49-0.74) and lower-risk patients (0.46; 0.30-0.72). Olaparib plus bevacizumab provided a substantial PFS benefit versus bevacizumab alone in the homologous recombination deficiency (HRD)-positive subgroup (higher risk: HR 0.39; 95% CI 0.28-0.54 and lower risk: 0.15; 0.07-0.30), with 24-month PFS rates in lower-risk patients of 90% versus 43%, respectively (Kaplan-Meier estimates)., Conclusions: In PAOLA-1, maintenance olaparib plus bevacizumab provided a substantial PFS benefit in HRD-positive patients with a reduction of risk of progression or death of 61% in the higher-risk group and of 85% in the lower-risk group compared with bevacizumab alone., Competing Interests: Declaration of Competing Interest Philipp Harter reports grant support from AstraZeneca, Roche, GlaxoSmithKline, Boehringer Ingelheim, Medac, and Genmab; and consulting fees from Amgen, AstraZeneca, Roche, Tesaro, GlaxoSmithKline, Sotio, Zai Lab, Merck Sharp & Dohme, Clovis Oncology, and Immunogen. Marie Ange Mouret-Reynier has nothing to disclose. Sandro Pignata reports honoraria from AstraZeneca, Roche, Merck Sharp & Dohme, Pfizer, Tesaro, Clovis Oncology and PharmaMar. Claire Cropet has nothing to disclose. Antonio González-Martín reports grants from Roche and GSK (funding for ENGOT ov-41 trial and ANITA); consulting fees from Alkermes, Amgen, AstraZeneca, Clovis Oncology, GSK, Genmab, Mersana, Roche, Immunogen, MSD, Oncoinvent, PharmaMar, Sotio, and Takeda; honoraria from AstraZeneca, Clovis Oncology, GSK, Roche, and MSD; support for attending meetings and/or travel from AstraZeneca, GSK, Roche, MSD and PharmaMar; and being the Chairman of GEICO and Chairman of ENGOT (2018–2020). Gerhard Bogner reports advisory board fees from AstraZeneca and Roche. Keiichi Fujiwara reports consulting fees and grant support from Pfizer, Eisai, Merck Sharp & Dohme, Taiho, Zeria, Chugai Pharmaceutical, Genmab and Takeda Pharmaceutical Company, receiving grant support from Immunogen, Oncotherapy and Regeneron, and receiving consulting fees from Novartis, Kyowa Hakko Kirin, Daiichi Sankyo, Mochida Pharmaceutical and NanoCarrier. Ignace Vergote reports grant support from Amgen and Roche; research support from Oncoinvent AS and Genmab; consulting fees from Aksebio, Amgen (Europe) GmbH, AstraZeneca, Bristol Myers Squibb, Carrick Therapeutics, Clovis Oncology, Deciphera Pharmaceuticals, Eisai, Elevar Therapeutics, F. Hoffman-La Roche Ltd., Genmab, GSK, Immunogen Inc., Jazz Pharma, Karyopharm, Mersana, Millennium Pharmaceuticals, MSD, Novocure, Novartis, Octimet Oncology NV, Oncoinvent AZ, Seagen, Sotio a.s., Verastem Oncology, Zentalis; and support for attending meetings and travel from Amgen, AstraZeneca, MSD, Roche, Tesaro. Nicoletta Colombo reports research grants from AstraZeneca, PharmaMar and Roche; honoraria for lectures from AstraZeneca, Tesaro, Novartis, Clovis Oncology, Merck Sharp and Dohme, GlaxoSmithKline and Eisai; honoraria for advisory boards from Roche, PharmaMar, AstraZeneca, Clovis Oncology, Merck Sharp and Dohme, GlaxoSmithKline, Tesaro, Pfizer, BioCad, Immunogen, Mersana, Eisai and Oncxema; and is a Steering Committee member on ESMO clinical guidelines and a Scientific Committee Chair for Acto Onlus. Trine Jakobi Nøttrup has nothing to disclose. Anne Floquet reports support for attending meetings and travel from AstraZeneca, GSK and PharmaMar. Ahmed El-Balat reports an advisory role for Roche, Clovis Oncology and Tesaro; lecture honoraria from Roche, Astra Zeneca and Olympus; travel support from AstraZeneca, PharmaMar and Teva. Giovanni Scambia reports grants/research support from MSD Italia S.r.l.; consulting fees from Johnson & Johnson, and TESARO Bio Italy S.r.l; and speaker's bureau fees from Clovis Oncology Italy Srl and MSD Italia Srl. Eva Maria Guerra Alia reports consulting fees from Roche, Clovis Oncology, GSK-Tesaro, PharmaMar, AstraZeneca and MSD; travel support from Roche, Baxter and GSK-Tesaro; participation on a data safety monitoring board or advisory board for Roche, Clovis Oncology, GSK-Tesaro, PharmaMar, AstraZeneca and MSD. Michel Fabbro reports honoraria from Astra Zeneca and GSK. Barbara Schmalfeldt reports consulting fees from AstraZeneca, Roche and MSD; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Roche, Tesaro, GSK, MSD, and Clovis Oncology; travel support from AstraZeneca and Roche; participation on a data safety monitoring board or advisory board for AstraZeneca, Roche, GSK, MSD; and leadership or fiduciary role for Deutsche Gesellschaft für Gynäkologie und Geburtshilfe. Anne-Claire Hardy-Bessard reports consulting and advisory board fees from AstraZeneca, Clovis Oncology, GSK, Novartis, Pfizer, Roche and Seagen. Ingo Runnebaum reports lecture and advisory board fees from AstraZeneca, Tesaro, Clovis Oncology, and GlaxoSmithKline. Eric Pujade-Lauraine reports lecture fees and speaker's bureau fees from AstraZeneca, GSK, Tesaro, and Roche; lecture fees from Clovis and Pfizer; expert testimony fees from AstraZeneca; travel support from AstraZeneca and GSK; participation on a data safety monitoring board or advisory board from AstraZeneca, Roche and Incyte; and is employed by ARCAGY Research. Isabelle Ray-Coquard reports honoraria (self) from Abbvie, Agenus, Advaxis, BMS, PharmaMar, Genmab, Pfizer, AstraZeneca, Roche, GSK, MSD, Deciphera, Mersena, Merck Sereno, Novartis, Amgen, Tesaro and Clovis; honoraria (institution) from GSK, MSD, Roche and BMS; advisory/consulting fees from Abbvie, Agenus, Advaxis, BMS, PharmaMar, Genmab, Pfizer, AstraZeneca, Roche/Genentech, GSK, MSD, Deciphera, Mersana, Merck Sereno, Novartis, Amgen, Tesaro and Clovis; research grant/funding (self) from MSD, Roche and BMS; research grant/funding (institution) from MSD, Roche, BMS, Novartis, Astra Zeneca and Merck Sereno; and travel support from Roche and AstraZeneca and GSK., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the efficacy and safety of regorafenib versus tamoxifen in platinum-sensitive ovarian cancer biological recurrence, defined by CA-125 increase without radiological (RECIST criteria) or symptomatic evidence of progression., Patients and Methods: 116 patients with platinum-sensitive ovarian cancer presenting an isolated increase of CA-125 were planned to be randomized. Regorafenib was administered orally at 160 or 120 mg daily, 3 weeks on/1 week off or tamoxifen at 40 mg daily, until disease progression or development of unacceptable toxicity. The primary endpoint was Progression-Free Survival, assessed by progression according to RECIST 1.1 or death (by any cause). Secondary endpoints included Overall Survival, Best Response and CA-125 response rate., Results: 68 patients were randomized. Median age was 67 years (range: 30-87). Primary site of cancer was ovarian for most patients (92.6%). Tumors were predominantly serous / (89.7%), high grade (83.6%) and initial FIGO staging was III for 69.6% of the patients. Most (79.4%) patients were included after the first line of platinum-based treatment. After a median follow-up of 32 months, there was no difference of progression-free survival (PFS) between regorafenib and tamoxifen groups (p = 0.72), with median PFS of 5.6 months (CI 90%: 3.84-7.52) for the tamoxifen arm and 4.6 months (CI 90%: 3.65-7.33) for the regorafenib arm. There was also no difference in term of overall survival, best response or CA-125 response, delay to next therapy. Regorafenib presented a less favorable safety profile than tamoxifen, with grade 3/4 events occurring for 90.9% of the patients compared to 54.3% for tamoxifen. The most frequent were cutaneous, digestive, and biological events. Notably, hand-foot syndrome occurred in 36.4% of these patients., Conclusion: Regorafenib presented an unfavorable toxicity profile compared to tamoxifen, with no superior efficacy in this population of patients., Competing Interests: Declaration of Competing Interest Dr. Trédan reports supports from the present manuscripts to ARCAGY GINECO from Bayer HealthCare, grants or contracts from Roche, BMS and MSD-Merck (payments to his institution), consulting fees from Roche, Pfizer, Astra-Zeneca, Lilly, Novartis-Sandoz, Daiichi-Sankyo, Seagen Pierre Fabre, MSD-Merck, Eisai (payments to him), payments/honoraria from Roche, Pfizer, Astra-Zeneca, Lilly, Novartis-Sandoz, Daiichi-Sankyo, Seagen, Pierre Fabre, MSD-Merck, Eisai, support for attending meeting and/or travel from Roche, Astra-Zeneca, Pfizer (payments to him). Dr. Hardy-Bessard reports payment/honoraria from MSD, Astra-Zeneca, GSK and participation on data safety monitoring board/advisory board with Clovis, MSD, Astra-Zeneca, GSK, Novartis, Pfizer. Dr. Lortholary reports payment/honoraria from Astra-Zeneca, Roche, MSD, Clovis, Novartis, support for attending meetings/travel from Roche and Astra-Zeneca and participation in a Data Safety Monitoring Board/Advisory board with Astra-Zeneca, Roche, MSD, Clovis and Novartis. Dr. Frenel reports payments/honoraria from Astra Zeneca, Lilly, Daiichi, Pfizer, Amgen, support for attending meetings/travel from Pfizer and Astra Zeneca, and participation on a Data Safety Monitoring Board/advisory board from Pfizer, Lilly, Novartis, GSK, Astra-Zeneca, MSD, Roche and Clovis. Dr. Louvet reports payments/honoraria from Merck, Roche, Servier and Amgen and support for attending meetings/travels from Roche and Merck. Dr. You reports consulting fees from MSD, Astra-Zeneca, GSK, Bayer, Roche, ECS Progastrine, Novartis, LEK, Amgen, Clovis, Merck Serono, BMS, Seagen. Amélie Anota reports consulting fees from Roche, Astra-Zeneca, Sandoz, Pfizer/Hospira, payment or honoraria for lectures from Astra-Zeneca and BMS and support for attending meetings/travels from Roche, Astra-Zeneca and Novartis. Pr Ray-Coquard reports consulting fees from Amgen, Astra-Zeneca, Clovis Oncology, Genmab, GSK, ImmunoGen, Merck Sharp & Dohme, Pfizer/Merck-Sereno, PharmaMar, and Roche, grants/contracts with Roche, BMS, MSD, GSK Company and support for attending meetings/travels from Astra-Zeneca, Roche, GSK and Clovis. The remaining authors declare no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The panel of therapeutic options available for medical treatment of relapsed ovarian cancer increased over the last years. In late, platinum-sensitive relapse, standard treatment remains platinum-based polychemotherapy. The choice between bevacizumab added to chemotherapy followed by maintenance and inhibitors of poly-(ADP-riboses) polymerases (PARPi) after response to platinum-based therapy should be discussed, taking into account prior treatment, contraindications, and disease characteristics (biology, symptoms…). The addition of bevacizumab at first platinum-sensitive relapse can be considered if it has not been administered in first line, and it is optional (rechallenge) if previously administered (but without Marketing Authorization in this setting). PARPi are indicated for maintenance therapy after response to platinum-based chemotherapy (whatever the treatment line), regardless of BRCA mutational status, in case of no prior administration. Early relapses are associated with poor prognosis and therapeutic options are more limited. They are treated by monochemotherapy without platinum agents, associated with bevacizumab if not administered previously. Beyond first early relapse, there is no standard and inclusion in a clinical trial should be proposed if possible. Several clinical studies assessing associations of immunotherapy and chemotherapy and/or antiangiogenic drugs and/or targeted therapies (such as PARPi) are ongoing in early or late relapse., (Copyright © 2021 Société FranÇaise du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés.)

Objective: This phase II clinical trial evaluated the safety and antitumor activity of balstilimab, an anti-PD-1 antibody, in patients with previously-treated, recurrent/metastatic cervical cancer., Methods: Eligible patients were 18 years or older with recurrent and/or metastatic cervical cancer and who had relapsed after a prior platinum-based treatment regimen for advanced disease. Balstilimab was administered intravenously at 3 mg/kg once every two weeks, for up to 24 months. The primary endpoint was objective response rate (ORR, RECIST v1.1) as assessed by an independent review committee., Results: At data cutoff, 161 women (median age, 53 years [range 25-81]) were enrolled and treated with balstilimab. Of these, 140 had measurable disease at baseline and one prior line of platinum-based therapy in the metastatic, persistent, or recurrent setting; these patients were included in the efficacy analyses. The ORR was 15% (95% CI, 10.0%-21.8%) and included 5 patients with a complete response and 16 with a partial response. The median duration of response was 15.4 months. In patients with PD-L1-positive tumors the ORR was 20%, however patients with PD-L1-negative tumors also responded to balstilimab (ORR, 7.9%). Responses were not restricted to tumors of squamous cell histology, and an ORR of 12.5% was seen in the subset of patients with cervical adenocarcinoma. The disease control rate was 49.3% (95% CI, 41.1%-57.5%). Immune-mediated enterocolitis (3.1%) and diarrhea (1.9%) were the most common grade 3 or higher treatment-related adverse events., Conclusion: Balstilimab demonstrated meaningful and durable clinical activity, with manageable safety, in patients with previously-treated, recurrent/metastatic cervical cancer., Competing Interests: Declaration of Competing Interest DMO reports personal fees and institutional grants from AstraZeneca, GSK/Tesaro, ImmunoGen, Janssen/Johnson & Johnson, Abbvie, Regeneron, Amgen, Clovis Oncology, Novocure, Genentech/Roche, Iovance, Eisai, Agenus, Merck, SeaGen, Novartis, Mersana; personal fees from Ambry, GOG Foundation, Myriad Genetics, Tarveda, Rubis, and Elevar; additional institutional funding from VentiRx Array Biopharma, EMD Serono, Ergomed, Ajinomoto Inc., Ludwig Cancer Research Stemcentrx, Inc., CERULEAN Pharma, Bristol-Myers Squibb, Serono, TRACON Pharmaceuticals, INC Research, Inc., inVentiv Health Clinical, PRA Intl and GenMab. AO reports personal fees from AstraZeneca, PharmaMar, Roche, Clinical Care Options, Clovis Oncology, Deciphera Pharmaceuticals, ImmunoGen, GenMab, Mersana, prIME Oncology, GlaxoSmithKline, and Tesaro; funding from AstraZeneca, Daiichi Sankyo, Eli Lilly and Company, Genentech, Immunomedics, Macrogenics, Merck Sharp & Dohme, Novartis, Pfizer, Piqur Therapeutics, Roche, Synthon, and Zenith Pharmaceuticals. BJM reports personal fees from Agenus, Akeso Bio, AstraZeneca, Genmab/Seattle Genetics, Iovance, Merck, Puma, Roche/Genentech, GOG Foundation, and GSK/Tesaro. FS reports personal fees and travel support from AstraZeneca, GSK/Tesaro, Merck Sharp & Dohme, Sandoz (Novartis), and Clovis Oncology, and Roche. CR reports personal fees from Merck, BMS, Roche, AstraZeneca, and Pfizer. LG reports personal fees from AstraZeneca, Clovis Oncology, GlaxoSmithKline, Merck Sharp & Dohme, and Roche; travel support from AstraZeneca and PharmaMar. AL reports personal fees from AstraZeneca, Tesaro, Clovis Oncology, Merck Sharp & Dohme, BIOCAD, AbilityPharma, Seattle Genetics, and Zentalis; institutional fees, grant and travel support from GlaxoSmithKline and Merck Serono. KNM reports personal fees from Aravive, AstraZeneca, Bristol Myers Squibb, Eisai, Elevar, GSK/Tesaro, Genentech/Roche, ImmunoGen, Merck, Mersana, Myriad, OncXerna, Sorrento, and VBL Therapeutics; funding from PTC Therapeutics, Lilly, and Merck. ACHB reports personal fees from AstraZeneca, Clovis Oncology, GlaxoSmithKline, Novartis, Pfizer, Roche, and Seagen. JA reports personal fees from AstraZeneca, GlaxoSmithKline, Roche, Merck Sharp & Dohme, PharmaMar; funding from Janssen and Merck Sharp & Dohme; travel support from Janssen, GlaxoSmithKline, and Novartis. CPO reports personal fees from Abbvie, AstraZeneca, Bristol Myers Squibb, Clovis Oncology, Genmab, GlaxoSmithKline, Tesaro, Mersana, PharmaMar; funding from Lilly, Roche, and Sanofi. CRdA reports personal fees from Merck Sharp & Dohme. LMR reports personal fees from AstraZeneca, Clovis Oncology, Eisai, EMD Serono, Genentech/Roche, GlaxoSmithKline, GOG Foundation, Mersana Therapeutics, Merck, Myriad Genetics, OnTarget, Rubius, BluPrint Oncology, Products in Knowledge; grant funding from Akeso Bio, Genentech, and Merck; travel support from GlaxoSmithKline. WOF reports employment by, and stock ownership in, Agenus Inc. MA reports employment by Agenus Inc. IRC reports personal fees from Abbvie, AstraZeneca, Bristol Myers Squibb, Clovis Oncology, Genmab, GlaxoSmithKline, Tesaro, Mersana, PharmaMar, and Roche; research funding from Bristol Myers Squibb, GlaxoSmithKline, and Merck Sharp & Dohme. All remaining authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The COVID-19 pandemic has a major impact at all stages of cancer treatment. Risk of death from COVID-19 in patients treated for a cancer is high. COVID-19 vaccines represent a major issue to decrease the rate of severe forms of the COVID-19 cases and to maintain a normal cancer care. It is difficult to define the target population for vaccination due to the limited data available and the lack of vaccine doses available. It appears theoretically important to vaccinate patients with active cancer treatment or treated since less than three years, as well as their family circle. In France, patients actually defined at "high risk" for priority access to vaccination are those with a cancer treated by chemotherapy. A panel of experts recently defined another "very high-priority" population, which includes patients with curative or palliative first or second-line chemotherapy, as well as patients requiring surgery or radiotherapy involving a large lung volume, lymph nodes and/or of hematopoietic tissue. Ideally, it is best to vaccinate before cancer treatment. Despite the lack of published data, COVID-19 vaccines can also be performed during chemotherapy by avoiding periods of bone marrow aplasia and if possible, to do it in cancer care centers. It is necessary to implement cohorts with immunological and clinical monitoring of vaccinated cancer patients. To conclude, considering the current state of knowledge, the benefit-risk ratio strongly favours COVID-19 vaccination of all cancer patients., (Copyright © 2021 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Purpose: Combining bevacizumab with paclitaxel significantly improves progression-free survival (PFS) versus paclitaxel alone in HER2-negative metastatic breast cancer (MBC). Eribulin is active and tolerable in pretreated MBC. To assess whether eribulin may offer a more tolerable yet effective combination partner for bevacizumab, we evaluated a bevacizumab/eribulin combination regimen as first-line therapy for MBC., Methods: In this single-arm phase II study, patients with histologically confirmed HER2-negative MBC and no prior chemotherapy for MBC received eribulin 1.23 mg/m 2 on days 1 and 8 every 3 weeks for ≥6 cycles plus bevacizumab 15 mg/kg on day 1 every 3 weeks until disease progression. The primary endpoint was non-progression rate at 1 year. Secondary endpoints included objective response rate (ORR), PFS, and safety., Results: The median age of the 61 treated female patients was 59 years, 16% had triple-negative MBC, 30% had ≥3 metastatic sites, and 71% had received prior (neo)adjuvant chemotherapy. Patients received a median of six eribulin and nine bevacizumab cycles. The non-progression rate at 1 year was 32% (95% confidence interval [CI]: 20-43%), ORR was 47% (95% CI: 34-60%), and median PFS was 8.3 months (95% CI: 7.0-9.6 months). The only grade ≥3 clinical adverse events in >5% of patients were hypertension (39%), neutropenia (26%), thrombosis (10%), and paresthesia/dysesthesia (7%)., Conclusion: First-line eribulin/bevacizumab combination therapy showed interesting activity in MBC with an acceptable safety profile, including a particularly low incidence of high-grade neuropathy., Competing Interests: Declaration of competing interest FC reports grants, personal fees, and non-financial support from AstraZeneca, grants from Roche Diagnostics, and personal fees and non-financial support from Roche and Lilly, outside the submitted work. BY reports consulting/advisory roles for AstraZeneca and advisory boards for Roche, GSK/Tesaro, Clovis, Novartis, MSD, BMS, Amgen, and ECS Progastrin, all outside the submitted work. GE reports personal fees and research support from Roche and Novartis, personal fees from Pfizer and Amgen, and research support from MSD, Odonate, Dompé Farmaceutici, AstraZeneca, and MacroGenics, outside the submitted work. A–CH–B, FB, AL, JG, JM-B, BL, JM, J-MF, A-MS, AMa, RD, and IM have nothing to disclose., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Cancer patients are thought to have an increased risk of developing severe Coronavirus Disease 2019 (COVID-19) infection and of dying from the disease. In this work, predictive factors for COVID-19 severity and mortality in cancer patients were investigated., Patients and Methods: In this large nationwide retro-prospective cohort study, we collected data on patients with solid tumours and COVID-19 diagnosed between March 1 and 11th June 2020. The primary end-point was all-cause mortality and COVID-19 severity, defined as admission to an intensive care unit (ICU) and/or mechanical ventilation and/or death, was one of the secondary end-points., Results: From April 4 to 11th June 2020, 1289 patients were analysed. The most frequent cancers were digestive and thoracic. Altogether, 424 (33%) patients had a severe form of COVID-19 and 370 (29%) patients died. In multivariate analysis, independent factors associated with death were male sex (odds ratio 1.73, 95%CI: 1.18-2.52), The Eastern Cooperative Oncology Group Performance Scale (ECOG PS) ≥ 2 (OR 3.23, 95%CI: 2.27-4.61), updated Charlson comorbidity index (OR 1.08, 95%CI: 1.01-1.16) and admission to ICU (OR 3.62, 95%CI 2.14-6.11). The same factors, age along with corticosteroids before COVID-19 diagnosis, and thoracic primary tumour site were independently associated with COVID-19 severity. None of the anticancer treatments administered within the previous 3 months had any effect on mortality or COVID-19 severity, except for cytotoxic chemotherapy in the subgroup of patients with detectable severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by reverse transcriptase polymerase chain reaction (RT-PCR), which was associated with a slight increase of the risk of death (OR 1.53; 95%CI: 1.00-2.34; p = 0.05). A total of 431 (39%) patients had their systemic anticancer treatment (such as chemotherapy, targeted or immune therapy) interrupted or stopped following diagnosis of COVID-19., Conclusions: Mortality and COVID-19 severity in cancer patients are high and are associated with general characteristics of patients. We found no deleterious effects of recent anticancer treatments, except for cytotoxic chemotherapy in the RT-PCR-confirmed subgroup of patients. In almost 40% of patients, the systemic anticancer therapy was interrupted or stopped after COVID-19 diagnosis., Competing Interests: Conflict of interest statement Pr Lièvre reports grants from BayerLilly, Merck and Novartis, personal fees from AAA, Amgen, Bayer, BMS,Celgene, HalioDx, Incyte, Ipsen, Lilly, Merck, Novartis, Pierre Fabre, Roche, Sandoz, Sanofi, Servier and non-financial support from AAA, Amgen, bayer, Incite, Ipsen, Merck, Novartis, Pierre Fabre, Pfizer, Roche, Sandoz, Servier and Integragen outside of the submitted work. Dr. Turpin reports personal fees from MYLAN, personal fees from MERCK SERONO, personal fees from AMGEN, non-financial support from MERCK-SERONO, non-financial support from SANOFI, non-financial support from PFIZER outside the submitted work. Dr. Ahle reports grants from Biogen, grants from Novartis, grants from Roche, grants from Sanofi, grants from Abbvie, outside the submitted work.Dr Bouché reports personal fees from Merck KGaA, Roche Genentech, Bayer, Astra-Zeneca, Grunenthal, MSD, Amgen, Servier, and Pierre Fabre outside the submitted work. Dr. Neuzillet reports personal fees from SERVIER, other from OSE Immunotherapeutic, grants from ROCHE, personal fees and other from AstraZeneca, personal fees and other from Bristol-Myers Squibb, personal fees from Amgen, personal fees from Merck, personal fees from MSD, personal fees from Novartis, personal fees from Incyte, personal fees from Mylan, personal fees from Baxter, personal fees from Nutricia, personal fees from Fresenius-Kabi, outside the submitted work . Pr Michel reports personal fees from Bayer, Servier, Amgen, Shire and Lilly and non-personal fees from Bayer, Merck, Amgen, Shire, Roche and Lilly outside the submitted work. Dr. Canellas reports personal fees from BMS, personal fees from Aztra Zeneca, non-financial support from Boerhinger Ingheleim, non-financial support from Roche, outside the submitted work . Dr. Wislez reports personal fees from Boeringher Ingelheim, personal fees and non-financial support from ROCHE, personal fees and non-financial support from MSD, personal fees from BMS, personal fees from Astra Zeneca, personal fees from Amgen, outside the submitted work. Dr. Mansi reports personal fees from Roche, personal fees from Eisai, personal fees from Exact Science, personal fees from Novartis, outside the submitted work . Dr Colomba received personnal fees from IPSEN, BMS, Pfizer, Sanofi, GSK outside the submitted work. Pr. Idbaih reports grants and other from Carthera (september 2019), grants from Transgene, grants from Sanofi, grants from Air Liquide, other from Leo Pharma, grants from Nutritheragene, outside the submitted work. Pr. Aparicio reports personal fees and non-financial support from Roche, personal fees from Ipsen, personal fees from Amgen, personal fees from Servier, personal fees from Sanofi, outside the submitted work. All other authors declare no competing interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Malignant ovarian germ cell tumors are rare tumors, affecting young women with a generally favorable prognosis. The French reference network for Rare Malignant Gynecological Tumors (TMRG) aims to improve their management. The purpose of this study is to report clinicopathological features and long-term outcomes, to explore prognostic parameters and to help in considering adjuvant strategy for stage I patients., Patients and Methods: Data from patients with MOGCT registered among 13 of the largest centers of the TMRG network were analyzed. We report clinicopathological features, estimated 5-year event-free survival (5y-EFS) and 5-year overall survival (5y-OS) of MOGCT patients., Results: We collected data from 147 patients including 101 (68.7%) FIGO stage I patients. Histology identifies 40 dysgerminomas, 52 immature teratomas, 32 yolk sac tumors, 2 choriocarcinomas and 21 mixed tumors. Surgery was performed in 140 (95.2%) patients and 106 (72.1%) received first line chemotherapy. Twenty-two stage I patients did not receive chemotherapy. Relapse occurred in 24 patients: 13 were exclusively treated with upfront surgery and 11 received surgery and chemotherapy. 5y-EFS was 82% and 5y-OS was 92.4%. Stage I patients who underwent surgery alone had an estimated 5y-EFS of 54.6% and patients receiving adjuvant chemotherapy 94.4% (P < .001). However, no impact on estimated 5y-OS was observed: 96.3% versus 97.8% respectively (P = .62). FIGO stage, complete primary surgery and post-operative alpha fetoprotein level significantly correlated with survival., Conclusion: Adjuvant chemotherapy does not seem to improve survival in stage I patients. Active surveillance can be proposed for selected patients with a complete surgical staging., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Trabectedin and pegylated liposomal doxorubicin (PLD) is an effective combination therapy for platinum-sensitive recurrent ovarian cancer (ROC), particularly for disease relapsing within 6-12 months of platinum therapy. The non-interventional PROSPECTYON study evaluated trabectedin/PLD in French clinical practice., Patients and Methods: Patients with ROC after at least one platinum-based regimen received 1.1 mg/m 2 trabectedin plus 30 mg/m 2 PLD every 3 weeks. Efficacy and safety were evaluated in subgroups according to platinum-free interval [6-12 versus ≥12 months (partially or fully platinum sensitive, respectively)]., Results: Recurrent disease was partially platinum-sensitive in 58 patients and fully sensitive in 33 patients treated between July 2014 and June 2016. Patients in both subgroups received a median of six cycles of trabectedin and PLD. The most common grade 3 or more toxicities were haematological. Median progression-free survival was 6 months for both subgroups., Conclusion: Trabectedin/PLD is a valuable treatment option for partially or fully platinum-sensitive ROC., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim of the Study: Our goal was to evaluate the impact of progression type (prostate-specific antigen [PSA] only, radiological or clinical) at initiation of first-, second- and third life-extending therapy (LET) on treatment outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients, by performing a post-hoc analysis using data from the CATS international registry., Methods: The 669 consecutive mCRPC patients of the CATS registry were classified according to their type of progression at initiation of each LET: PSA only (PSA-p), radiological (±PSA) (Radio-p); or clinical (±PSA, ±radiological) progression (Clin-p). Overall survival (OS), the primary endpoint, was calculated from initiation of the first-, second- and third-LET to death for each sequence., Results: Median OS was shorter in the Clin-p group compared with the PSA-p group (14-month difference in first line; around 7-month difference in second- and third line). Shorter progression-free survival (PFS) was also observed in Clin-p patients, whatever the treatment is. Clinical progression seemed to be associated with a shorter duration of therapy with androgen receptor-targeted therapy (ART) compared with taxanes., Conclusions: Clinical progression at initiation of a LET is associated with poor outcomes including shorter PFS and OS as well as clinical and biological features of aggressive disease. Stratifying patients in clinical trials according to disease progression type may prevent selection bias and data heterogeneity. In daily practice, first signs of clinical progression may prompt physicians to consider starting a new LET, independently of PSA levels., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: This study estimated time without symptoms or toxicity (TWiST) with niraparib compared with routine surveillance (RS) in the maintenance treatment of patients with recurrent ovarian cancer., Patients and Methods: Mean progression-free survival (PFS) was estimated for niraparib and RS by fitting parametric survival distributions to Kaplan-Meier data for 553 patients with recurrent ovarian cancer who were enrolled in the phase III ENGOT-OV16/NOVA trial. Patients were categorized according to the presence or absence of a germline BRCA mutation-g BRCA mut and non-g BRCA mut cohorts. Mean time with toxicity was estimated based on the area under the Kaplan-Meier curve for symptomatic grade 2 or greater fatigue, nausea, and vomiting adverse events (AEs). Time with toxicity was the number of days a patient experienced an AE post-random assignment and before disease progression. TWiST was estimated as the difference between mean PFS and time with toxicity. Uncertainty was explored using alternative PFS estimates and considering all symptomatic grade 2 or greater AEs., Results: In the g BRCA mut and non-g BRCA mut cohorts, niraparib treatment resulted in a mean PFS benefit of 3.23 years and 1.44 years, respectively, and a mean time with toxicity of 0.28 years and 0.10 years, respectively, compared with RS. Hence, niraparib treatment resulted in a mean TWiST benefit of 2.95 years and 1.34 years, respectively, compared with RS, which is equivalent to more than four-fold and two-fold increases in mean TWiST between niraparib and RS in the g BRCA mut and non-g BRCA mut cohorts, respectively. This TWiST benefit was consistent across all sensitivity analyses, including modeling PFS over 5-, 10-, and 15-year time horizons., Conclusion: Patients who were treated with niraparib compared with RS experienced increased mean TWiST. Thus, patients who were treated with niraparib in the ENGOT-OV16/NOVA trial experienced more time without symptoms or symptomatic toxicities compared with control.

Purpose: We conducted a double-randomised phase III trial to evaluate a concomitant taxane-anthracycline regimen in node-positive breast cancer and the efficacy of trastuzumab in the human epidermal growth factor receptor 2 (HER2)-positive subpopulation., Methods: A total of 3010 patients with node-positive breast cancer were randomly assigned to receive 6 cycles of 500 mg/m 2 of fluorouracil, 100 mg/m 2 of epirubicin and 500 mg/m 2 of cyclophosphamide (FEC) or 75 mg/m 2 of epirubicin and 75 mg/m 2 of docetaxel (ED). Patients with HER2-positive tumours were secondary randomly assigned to either trastuzumab or observation. The primary end-point was disease-free survival (DFS) in the two chemotherapy arms., Results: After a 115-month median follow-up, DFS was not significantly better in the ED arm (DFS: 70%, 95% confidence interval [CI]: 67-72) than in the FEC arm (DFS: 68%, 95% CI: 65-70; hazard ratio [HR] = 0.88, 95% CI: 0.77-1.01; p = 0.064). The OS was not different between FEC (OS: 80%, 95% CI: 78-83) and ED (OS: 81%, 95% CI: 79-83); HR = 0.97, 95% CI: 0.81-1.16; p = 0.729). ED appeared more toxic. In the 528 HER2-positive subset, there was trend for a higher DFS, in the intention-to-treat population, in the trastuzumab arm (DFS: 68%, 95% CI: 61-74) than in the observation arm (DFS: 60%, 95% CI: 54-66; HR = 0.77, 95% CI: 0.57-1.03; p = 0.079). In the per-protocol population, DFS was significantly higher in the trastuzumab arm (DFS: 70%, 95% CI: 63-76) than in the observation arm (DFS: 59%, 95% CI: 53-65; HR = 0.69, 95% CI: 0.51-0.94; p = 0.0156). The OS was not different between these 2 arms., Conclusion: This study did not show superiority of the concomitant anthracycline-taxane arm which was more toxic in high-risk node-positive breast cancer patients. Long-term results of the HER2-positive subpopulation are in line with those of the other adjuvant trastuzumab trials but quantitatively less pronounced mostly because of lack of power., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: Regarding cancer antigen 125 (CA-125) longitudinal kinetics during chemotherapy, the actual predictive value of the Gynecologic Cancer Intergroup (GCIG) CA-125 response criterion is questioned. The modeled CA-125 elimination rate constant KELIM exhibited higher prognostic value in patients with recurrent ovarian cancer enrolled in the CALYPSO trial. The objective was to validate the higher predictive and prognostic values of KELIM during first-line treatments., Experimental Design: Data from three large phase III trials were analyzed: AGO OVAR 9 [learning set: carboplatin-paclitaxel (CP) ± gemcitabine; n = 1,288]; AGO OVAR 7 (validation set: CP ± topotecan; n = 192); and ICON7 (validation set: CP ± bevacizumab; n = 1,388). The CA-125 profiles were fit with a nonlinear mixed-effect model during the first 100 days, and the individual KELIM were calculated. KELIM prognostic and predictive values for survival were assessed against GCIG criterion and other prognostic factors in univariate/multivariate analyses., Results: The GCIG CA-125 endpoint provided no meaningful predictive/prognostic information. C-index analyses confirmed the higher predictive value of KELIM compared with GCIG criterion for progression-free survival and overall survival (OS). KELIM provided reproducible prognostic information. Patients with favorable KELIM ≥ upper tercile (0.0711 per days) consistently experienced better OS, with HRs between 0.44 and 0.58 (e.g., median OS >65 months vs. <35 months)., Conclusions: Modeled KELIM provides higher predictive and prognostic information based on CA-125 longitudinal kinetics compared with GCIG response criteria during first-line chemotherapy. Integration of this endpoint in guidelines may be considered. Individual KELIM and survival simulations can be calculated at http://www.biomarker-kinetics.org/. Further assessment of the surrogate value of KELIM treatment-related variations in a GCIG meta-analysis is warranted. See related commentary by Maitland et al., p. 5182 ., (©2019 American Association for Cancer Research.)

Background: Platinum-resistant ovarian cancer (PROC) is associated with a variable prognosis and unpredictable survival times. We have developed and validated a prognostic nomogram with the objective of improving the prediction of overall survival (OS) in patients treated with chemotherapy., Methods: The nomogram was developed using data from a training cohort of patients from two trials, including the chemotherapy-only arm in AURELIA and all randomised patients in CARTAXHY. Multivariable proportional hazards models were generated based on pretreatment characteristics to develop a nomogram that classifies patients based on OS. We subsequently assessed the performance of the nomogram in terms of discrimination and calibration in independent validation patient cohorts: PENELOPE and the bevacizumab-chemotherapy arm of AURELIA., Results: The nomogram included six significant OS predictors, in order of importance: performance status, ascites, size of the largest tumour, CA-125, platinum-free interval and primary platinum resistance (C-statistic 0.69). In the training cohort, the median OS in the good, intermediate and poor prognosis groups was 25.3, 15.2 and 7.4 months, respectively. In the PENELOPE validation cohort (C-statistic 0.59), the median OS in the good, intermediate and poor prognosis groups was 18.5, 10.3 and 5.8 months, respectively. In the AURELIA bevacizumab-chemotherapy validation cohort (C-statistic 0.67), the median OS in good, intermediate and poor prognosis groups was 26.7, 13.8 and 10.0 months, respectively., Conclusions: This nomogram with six pretreatment characteristics allows prediction of OS in PROC and could be used for stratification of patients in clinical trials as well as for counselling patients about prognosis., (Copyright © 2019. Published by Elsevier Ltd.)

Purpose: Endocrine therapy (ET) used to reduce the risk of recurrence in hormone receptor-expressing disease (75% of breast cancers) is associated with worsening of climacteric symptoms with a negative impact on quality of life (QoL). Homeopathy might allow a better management of hot flushes (HF)., Methods: In this multicenter randomized double-blind placebo-controlled phase III study ( ClinicalTrials.gov NCT01246427), we enrolled ≥ 18 years old women with histologically proven non metastatic localized breast cancer, with Eastern Cooperative Oncology Group-Performance Status (ECOG-PS) ≤ 1, treated for at least 1 month with adjuvant ET, and complaining about moderate to severe HF. Patients should not be scheduled for chemotherapy or radiotherapy, and had no associated pathology known to induce HF. After a 2- to 4-week placebo administration, we randomly assigned (1:1) patients with HFS ≥ 10 using an interactive web-based centralized platform to BRN-01 homeopathic medicine complex (Actheane®) in arm A or Placebo (Arm P). Randomization was stratified by adjuvant ET (taxoxifen/aromatase inhibitor) and recruiting site. HF scores (HFS) were calculated as the mean of HF frequencies before randomization, at 4, and at 8 weeks post-randomization (pre-, 4w,- and 8w-) weighted by a 4-level intensity scale. Primary endpoint was assessed at 4-week post-randomization, as the variation between pre- and 4w-HFS. Secondary endpoints included HFS variation between pre- and 8w-HFS, compliance and tolerance assessed 8 weeks after randomization, and QoL and satisfaction assessed at 4- and 8-week post-randomization., Results: Two hundred ninety-nine patients were included, and 138 (46.2%) randomized (A, 65; P, 73). Median 4w-HFS absolute variation (A, - 2.9; P, - 2.5 points, p = 0.756) and relative decrease (A, - 17%; P, - 15%, p = 0.629) were not statistically different. However, 4w-HFS decreased for 46 (75%) in A vs 48 (68%) patients in P arm. 4w-QoL was stable or improved for respectively 43 (72%) vs 51 (74%) patients (p = 0.470)., Conclusions: The efficacy endpoint was not reached, and BRN-01 administration was not demonstrated as an efficient treatment to alleviate HF symptoms due to adjuvant ET in breast cancer patients. However, the study drug administration led to decreased HFS with a positive impact on QoL. Without any recommended treatment to treat or alleviate the HF-related disabling symptoms, Actheane® could be a promising option, providing an interesting support for better adherence to ET, thereby reducing the risk of recurrence with a good tolerance profile.

Importance: Androgen-deprivation therapy (ADT) plus docetaxel is the standard of care in hormone-naive metastatic prostate cancer but is of uncertain benefit in a nonmetastatic, high-risk prostate cancer setting., Objective: To assess the benefit of ADT plus docetaxel in patients presenting with rising prostate-specific antigen (PSA) levels after primary local therapy and high-risk factors but no evidence of metastatic disease., Design, Setting, and Participants: This open-label, phase 3, randomized superiority trial comparing ADT plus docetaxel vs ADT alone enrolled patients from 28 centers in France between June 4, 2003, and September 25, 2007; final follow-up was conducted April 12, 2017, and analysis was performed May 2 to July 31, 2017. Patients had undergone primary local therapy for prostate cancer, were experiencing rising PSA levels, and were considered to be at high risk of metastatic disease. Stratification was by prior local therapy and PSA-level doubling time (≤6 vs >6 months), and intention-to-treat analysis was used., Interventions: Patients were randomly assigned to receive ADT (1 year) plus docetaxel, 70 mg/m2 (every 3 weeks [6 cycles]), or ADT alone (1 year)., Main Outcomes and Measures: The primary outcome was PSA progression-free survival (PSA-PFS). Secondary end points were PSA response, radiologic PFS, overall survival, safety, and quality of life., Results: Overall, 254 patients were randomized (1:1) to the trial; median age, 64 years in the ADT plus docetaxel arm, 66 years in the ADT alone arm. At a median follow-up of 30.0 months, the median PSA-PFS was 20.3 (95% CI, 19.0-21.6) months in the ADT plus docetaxel arm vs 19.3 (95% CI, 18.2-20.8) months in the ADT alone arm (hazard ratio [HR], 0.85; 95% CI, 0.62-1.16; P = .31). At a median follow-up of 10.5 years, there was no significant between-arm difference in radiologic PFS (HR, 1.03; 95% CI, 0.74-1.43; P = .88). Overall survival data were not mature. The most common grade 3 or 4 hematologic toxic effects in the ADT plus docetaxel arm were neutropenia (60 of 125 patients [48.0%]), febrile neutropenia (10 [8.0%]), and thrombocytopenia (4 [3.0%]). There was no significant between-arm difference in overall quality of life., Conclusions and Relevance: Compared with ADT alone, combined ADT plus docetaxel therapy with curative intent did not significantly improve PSA-PFS in patients with high-risk prostate cancer and rising PSA levels and no evidence of metastatic disease., Trial Registration: French Health Products Safety Agency identifier: 030591; ClinicalTrials.gov identifier: NCT00764166.

Background: Carboplatin and pegylated liposomal doxorubicin combination is a standard regimen in platinum-sensitive recurrent ovarian cancer patients. The pegylated liposomal doxorubicin shortage from 2011 to 2013 urged assessment of the efficacy and tolerance of non-pegylated liposomal doxorubicin in combination with carboplatin., Methods: MYCA was a multicenter 2-step phase Ib-II single arm trial meant to assess the safety and efficacy of carboplatin AUC 5 mg/min.mL combined with non-pegylated liposomal (dose escalation from 40 to 50 mg/m 2 during phase Ib step; and 50 mg/m2 during phase II step), every 4 weeks in patients with platinum-sensitive relapse. The primary objective was disease control rate (DCR) at 12 months., Results: From 2012 to 2014, 87 patients were enrolled. They were treated as second (78%) or third line (22%) treatment. Total of 67 patients (78%) completed 6 cycles. G-CSF support was prescribed to 58% patients. The DCR at 12 months was 30.0% (95% CI, 20.3-39.7); the median PFS was 10.0 months (95% CI, 8.6-11.0). The median overall survival was 28.1 months (95% CI, 22.3-32.5); and the objective response rate was 58% (95% CI, 47-68). Grade 3-4 neutropenia, anemia and thrombocytopenia were observed in 17%, 13% and 1%, respectively; febrile neutropenia in 6%. One patient who did not receive GCSF support died from febrile neutropenia., Conclusion: Non-pegylated liposomal doxorubicin-carboplatin combination exhibits an acceptable safety profile, with GCSF prophylaxis. Acknowledging the lack of direct comparison, efficacy in terms of 12 month DCR was comparable with standard treatments., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The optimal sequence of life-extending therapies in metastatic castration-resistant prostate cancer (mCRPC) is unknown., Objective: To evaluate outcomes among mCRPC patients treated with docetaxel (DOC), cabazitaxel (CABA), and a novel androgen receptor-targeted agent (ART; abiraterone acetate or enzalutamide) according to three different sequences., Design, Setting, and Participants: Data from 669 consecutive mCRPC patients were retrospectively collected between November 2012 and October 2016., Outcome Measurements and Statistical Analysis: The primary endpoint was the prostate-specific antigen (PSA) response (decrease ≥50% from baseline) to each therapy. Secondary endpoints included best clinical benefit, time to PSA progression, radiological progression-free survival (rPFS), overall survival (OS), and toxicity., Results and Limitations: A total of 158 patients received DOC→CABA→ART (group 1), 456 received DOC→ART→CABA (group 2), and 55 received ART→DOC→CABA (group 3). At baseline, PSA progression only and Gleason <8 were more common in group 3. PSA response on DOC was lower in group 3 than in other groups (p=0.02) and PSA response on CABA was higher in the second than in the third line (p=0.001). In Group 3, rPFS on ART (6.6 mo) and DOC (9.2 mo) was also shorter than in the other groups. OS calculated from the first life-extending therapy reached 34.8, 35.8, and 28.9 mo in groups 1, 2 and 3, respectively (p=0.007). Toxicity was comparable between the arms. The main limitations of the trial are its retrospective design and the low number of patients in group 3., Conclusions: In this retrospective trial, sequencing of DOC, CABA, and one ART, was associated with median OS of up to 35.8 mo. CABA seemed to retain its activity regardless of treatment sequence. DOC activity after ART appeared to be reduced, but the data are insufficient to conclude that cross-resistance occurs., Patient Summary: The order of drugs administered to patients with metastatic castration-resistant prostate cancer could impact their efficacy, with cabazitaxel appearing to retain its activity whatever the therapeutic sequence., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Treatment option in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel (DOC), cabazitaxel (CABA) and new hormone therapy (NHT) is limited. Rechallenge with DOC is limited because of cumulative toxicities. This study investigated the activity and safety of CABA rechallenge in mCRPC., Patients and Methods: Clinical data were collected retrospectively in 17 centres in Europe. Eligible patients had undergone rechallenge with cabazitaxel after three previous lines of treatment (DOC, NHT and CABA, in any order). Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method. Data on toxicities were collected., Results: A total of 69 of 562 patients (Eastern Cooperative Oncology Group performance status 0-1 69%) were rechallenged with CABA (25 mg/m 2 q3w, 58%; 20 mg/m 2 q3w, 27.5%; other, 14.5%) for 1-10 (median 6) cycles; 76.8% received prophylactic granulocyte colony-stimulating factor. Median radiological or clinical PFS with CABA rechallenge was 7.8 months and 11.9 months with initial CABA therapy. OS was 13.7 months (95% confidence interval [CI]: 9.3-15.7) from the first CABA rechallenge cycle, 59.9 months (47.8-67.1) from the first life-extending therapy in mCRPC and 78.3 months (66.4-90.7) from mCRPC diagnosis. Best clinical benefit was improved (34.3%) or stable (47.8%). Lack of response to rechallenge occurred in 17.9% of patients (3.1% with initial CABA). The level of prostate-specific antigen decreased by ≥ 50% in 24% of patients at rechallenge (71% with initial CABA). There was no grade ≥III peripheral neuropathy or nail disorders., Conclusions: CABA rechallenge may be a treatment option without cumulative toxicity in heavily pretreated patients with mCRPC who are still fit and had a progression >3 months after the last CABA injections., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Expression IV survey evaluated the patients' expectations to a maintenance therapy., Methods: From January 2015 to March 2016, 401 French patients, in first line or recurrent disease, answered a 24-items anonymous questionnaire. The results were specifically analyzed according to the demographic characteristics and treatment lines., Results: Among the patients, 62% had already been informed about maintenance therapy. Thirty-seven percent of patients received a maintenance treatment: 111 patients during first line and 39 patients in relapse. Expectations of patients were: 1) the chance of cure (73%), 2) the tumor shrinkage (36%), 3) quality of life improvement (35%) and 4) tumor growth reduction (27%). Among the responders, 42% were willing to take the treatment for 6-24 months, 20% for 24-60 months and 38% until tumor progression. 64% of patients expected more than a 6 months progression-free survival. Patients older than 70 years were less informed than their younger counterparts (48% vs 66%) and had lesser hope for cure with maintenance treatment (60% vs 77%). Patients in relapse had more expectation than patients in remission (tumor shrinkage: 47% vs 22%, slowing of tumor growth: 37% vs 15%, improving the progression-free survival of more than 6 months: 71% vs 53%, respectively). Among patients, 48% in relapse consented to take a treatment until progression vs 24% of patients in remission., Conclusion: This sub-analysis in French patients demonstrate a gap between the efficacy of maintenance therapy and the patients' expectations in ovarian cancer, particularly in relapsing disease justifying better information and explanations., (Copyright © 2018 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Purpose Cabazitaxel 25 mg/m 2 (C25) significantly improved overall survival (OS) versus mitoxantrone ( P < .001) in postdocetaxel patients with metastatic castration-resistant prostate cancer (mCRPC) in the phase III TROPIC study. The phase III PROSELICA study ( ClinicalTrials.gov identifier: NCT01308580) assessed the noninferiority of cabazitaxel 20 mg/m 2 (C20) versus C25 in postdocetaxel patients with mCRPC. Methods Patients were stratified by Eastern Cooperative Oncology Group performance status, measurability of disease per Response Evaluation Criteria in Solid Tumors (RECIST), and region, and randomly assigned to receive C20 or C25. To claim noninferiority of C20 (maintenance of ≥ 50% of the OS benefit of C25 v mitoxantrone in TROPIC) with 95% confidence level, the upper boundary of the CI of the hazard ratio (HR) for C20 versus C25 could not exceed 1.214 under a one-sided 98.89% CI after interim analyses. Secondary end points included progression-free survival, prostate-specific antigen (PSA), tumor and pain responses and progression, health-related quality of life, and safety. Results Overall, 1,200 patients were randomly assigned (C20, n = 598; C25, n = 602). Baseline characteristics were similar in both arms. Median OS was 13.4 months for C20 and 14.5 months for C25 (HR, 1.024). The upper boundary of the HR CI was 1.184 (less than the 1.214 noninferiority margin). Significant differences were observed in favor of C25 for PSA response (C20, 29.5%; C25, 42.9%; nominal P < .001) and time to PSA progression (median: C20, 5.7 months; C25, 6.8 months; HR for C20 v C25, 1.195; 95% CI, 1.025 to 1.393). Health-related quality of life did not differ between cohorts. Rates of grade 3 or 4 treatment-emergent adverse events were 39.7% for C20 and 54.5% for C25. Conclusion The efficacy of cabazitaxel in postdocetaxel patients with mCRPC was confirmed. The noninferiority end point was met; C20 maintained ≥ 50% of the OS benefit of C25 versus mitoxantrone in TROPIC. Secondary efficacy end points favored C25. Fewer adverse events were observed with C20.

Background: In 2008, a study of the characteristics of hospitalised patients led to the development of a prognostic tool that distinguished three populations with significantly different 2-month survival rates. The goal of our study aimed at validating prospectively this prognostic tool in outpatients treated for cancer in terminal stage, based on four factors: performance status (ECOG) (PS), number of metastatic sites, serum albumin and lactate dehydrogenase., Patients and Methods: PRONOPALL is a multicentre study of current care. About 302 adult patients who met one or more of the following criteria: life expectancy under 6 months, performance status ≥ 2 and disease progression during the previous chemotherapy regimen were included across 16 institutions between October 2009 and October 2010. Afterwards, in order to validate the prognostic tool, the score was ciphered and correlated to patient survival., Results: Totally 262 patients (87%) were evaluable (27 patients excluded and 13 unknown score). Median age was 66 years [37-88], and women accounted for 59%. ECOG PS 0-1 (46%), PS 2 (37%) and PS 3-4 (17%). The primary tumours were: breast (29%), colorectal (28%), lung (13%), pancreas (12%), ovary (11%) and other (8%). About 32% of patients presented one metastatic site, 35% had two and 31% had more than two. The median lactate dehydrogenase level was 398 IU/l [118-4314]; median serum albumin was 35 g/l [13-54]. According to the PRONOPALL prognostic tool, the 2-month survival rate was 92% and the median survival rate was 301 days [209-348] for the 130 patients in population C, 66% and 79 days [71-114] for the 111 patients in population B, and 24% and 35 days for [14-56] the 21 patients in population A. These three populations survival were statistically different (P <0.0001)., Conclusion: PRONOPALL study confirms the three prognostic profiles defined by the combination of four factors. This PRONOPALL score is a useful decision-making tool in daily practice., (© The Author 2017. 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.)

Treatment for Platinum Sensitive Relapses of Ovarian Cancer: Despite large improvements in treatment efficacy, the cure rate of ovarian cancer has not radically changed. Relapses both remain frequent and are still synonymous with chronic disease. Most of them are platinum-sensitive, and can be successfully treated with successive lines of chemotherapy. Surgery may have a role to play but its real impact, population selection criteria, and adequate timing still have to be established. Regarding medical treatments, the availability of new targeted therapeutics, such as bevacizumab and olaparib, complicates decision making. Moreover, allergic drug reactions to platins worsen treatment management. In practice, treatment decision making integrates patient profiles and wishes, types and numbers of previous medical treatments along with BRCA status., (© 2017 Elsevier Masson SAS. Tous droits réservés.)

Background: We present a pooled analysis of predictive and prognostic values of circulating tumour cells (CTC) and circulating endothelial cells (CEC) in two prospective trials of patients with inflammatory breast cancer (IBC) treated with neoadjuvant chemotherapy combined with neoadjuvant and adjuvant bevacizumab., Patients and Methods: Nonmetastatic T4d patients were enrolled in two phase II multicentre trials, evaluating bevacizumab in combination with sequential neoadjuvant chemotherapy of four cycles of FEC followed by four cycles of docetaxel in HER2-negative tumour (BEVERLY-1) or docetaxel and trastuzumab in HER2-positive tumour (BEVERLY-2). CTC and CEC were detected in 7.5 and 4 ml of blood, respectively, with the CellSearch System., Results: From October 2008 to September 2010, 152 patients were included and 137 were evaluable for CTC and CEC. At baseline, 55 patients had detectable CTC (39%). After four cycles of chemotherapy, a dramatic drop in CTC to a rate of 9% was observed (P < 0.01). Pathological complete response (pCR) rate was 40%. No correlation was found between CTC or CEC levels and pCR rate. Median follow-up was 43 months. CTC detection (≥1 CTC/7.5 ml) at baseline was associated with shorter 3-year disease-free survival (39% versus 70% for patients without CTC, P < 0.01, HR 2.80) and shorter 3-year overall survival (OS) (P < 0.01). In multivariate analysis, independent prognostic parameters for shorter survival were absence of hormonal receptors, no pCR and CTC detection at baseline. CEC level at baseline or variations during treatment had no prognostic value., Conclusion: In this pooled analysis of two prospective trials in nonmetastatic IBC, detection rate of CTC was 39% with a strong and independent prognostic value for survival. Combination of pCR after neoadjuvant treatment with no CTC detection at baseline isolated a subgroup of IBC with excellent OS (94% 3-year OS), suggesting that CTC count could be part of IBC stratification in prospective trials., (© 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.)

Introduction: As most patients with ovarian cancer experience multiple remissions and relapses, oncologists must prepare ahead for long-term treatment. While platinum-based regimens are standard of care for platinum-sensitive recurrence, there are circumstances in which platinum rechallenge is not the best approach. These situations include patients with limited sensitivity to platinum; patients with residual toxicity from previous platinum therapy; and patients at risk of developing hypersensitivity reactions. An alternative regimen for these patients is the non-platinum combination of trabectedin + pegylated liposomal doxorubicin (PLD). Areas covered: In this review, case studies are presented to illustrate how careful strategic planning, in terms of therapeutic choices and optimal sequencing, can achieve good outcomes in difficult-to-treat patients. Expert commentary: Advantages with use of trabectedin + PLD in selected patients with platinum-sensitive recurrent ovarian cancer include additional time to recover from platinum-related toxicities, avoidance of hypersensitivity reactions, and the 'sequence effect' by which trabectedin may enhance response to next platinum and prolong survival.

Background: The current study was performed to determine the efficacy and safety of first-line combination therapy with bevacizumab, paclitaxel, and capecitabine for triple-negative, locally advanced/metastatic breast cancer (LA/MBC)., Methods: Patients with measurable triple-negative LA/MBC who had received no prior chemotherapy for their disease received 4-weekly cycles of paclitaxel (80 mg/m 2 on days 1, 8, and 15 for up to 6 cycles) combined with capecitabine (800 mg/m 2 twice daily on days 1-5, 8-12, and 15-19) and bevacizumab (10 mg/kg on days 1 and 14) repeated every 4 weeks until disease progression or unacceptable toxicity occurred. The primary endpoint was the objective response rate; secondary endpoints were progression-free survival, duration of response, overall survival, and safety., Results: Between April 2010 and March 2012, 62 eligible patients were enrolled. The median age of the patients was 57 years, 74% had received adjuvant chemotherapy, and 65% had visceral metastases. Patients received a median of 6 cycles (range, 1-45 cycles). The objective response rate was 77% (95% confidence interval [95% CI] 66%-88%), including complete response in 19% of patients. The median duration of response was 5.6 months (range, 1.3-27.6 months). The median progression-free survival was 7.6 months (95% CI, 6.3-9.0 months) and the median overall survival was 19.2 months (95% CI, 17.4-20.9 months). The most common grade ≥3 adverse events were hypertension (35% of patients) and neutropenia (23% of patients); 5% of patients experienced febrile neutropenia. Grade ≥2 hand-foot syndrome, alopecia, and nail toxicity each occurred in 40% of patients (adverse events were recorded before every cycle and graded according to Common Terminology Criteria for Adverse Events [version 4.0]). Treatment was interrupted because of toxicity in 22% of patients., Conclusions: A triplet regimen of paclitaxel, capecitabine, and bevacizumab followed by maintenance therapy with capecitabine and bevacizumab demonstrated high activity and manageable safety in this difficult-to-treat population. Cancer 2016;122:3119-26. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Breast cancer remains a potentially lethal disease, which requires aggressive treatments and is associated with long-term consequences. Its prognosis is linked to both tumor biology and burden at diagnosis. Although treatments have allowed important improvements in prognosis over the past 20 years, breast cancer screening remains necessary. Mammographic screening allows earlier stage diagnoses and a decrease of breast cancer specific mortality. However, breast cancer screening modalities should be revised with the objective to address demonstrated limitations of mammographic screening (limited benefit, imperfect sensitivity and specificity, overdiagnoses, radiation-induced morbidity). Furthermore, both objective and perceived performances of screening procedures should be improved. Numerous large international efforts are ongoing, leading to scientific progresses that should have rapid clinical implications in this area. Among them is improvement of imaging techniques performance, development of real time diagnosis, and development of new non radiological screening techniques such as the search for circulating tumor DNA, development of biomarkers able to allow precise risk evaluation and stratified screening. As well, overtreatment is currently addressed by biomarker-based de-escalation clinical trials. These advances need to be associated with strong societal support, as well as major paradigm changes regarding the way health and cancer prevention is perceived by individuals., (Copyright © 2016 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Background: Addition of bevacizumab to standard chemotherapy in the neoadjuvant setting in patients with HER2-negative metastatic breast cancer improves progression-free survival and the proportion of patients achieving pathological complete response. In the BEVERLY-1 (UCBG-0802) trial we aimed to assess the addition of bevacizumab to neoadjuvant and adjuvant chemotherapy in the treatment of patients with HER2-negative inflammatory breast cancer., Methods: We did this phase 2, single-arm trial at 20 hospitals in France. We enrolled women aged 18 years or older who had non-metastatic HER2-negative inflammatory breast cancer. Patients underwent 3-week treatment cycles, receiving neoadjuvant intravenous fluorouracil (500 mg/m(2)), epirubicin (100 mg/m(2)), cyclophosphamide (500 mg/m(2)), and bevacizumab (15 mg/kg) during cycles 1-4, then docetaxel (100 mg/m(2)) and bevacizumab during cycles 5-8. 2-4 weeks after surgery, patients received adjuvant radiotherapy, hormone therapy (if they had a hormone receptor-positive tumour), and adjuvant intravenous bevacizumab. The primary endpoint was pathological complete response in breast and axillary lymph nodes after neoadjuvant treatment, determined after centralised review in accordance with Sataloff classification and assessed in the intention-to-treat population. Our analysis of toxic effects included all patients who received at least one dose of bevacizumab. The trial is complete and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT00820547., Findings: Between Jan 16, 2009, and Sept 8, 2010, we enrolled 101 patients, one of whom withdrew consent before treatment, leaving 100 patients in the primary endpoint analysis. After neoadjuvant therapy, 19 (19% [95% CI 12-28]; p=0·16) of 100 patients achieved a pathological complete response according to centralised review. The most frequent grade 3-4 events during the neoadjuvant phase were neutropenia (89 [89%] of 100 patients), febrile neutropenia (37 [37%]), and mucositis (23 [23%]) and during the adjuvant phase the most frequent grade 3-4 adverse event was proteinuria (5 [7%] of 75 patients). One (1%) patient died of thrombotic microangiopathy after cycle 1, which was thought to be related to bevacizumab. Two patients (3%) developed transitory heart failure. 48 (48%) patients had serious adverse events, the most frequent of which was febrile neutropenia (28 [28%])., Interpretation: Our results suggest that the addition of bevacizumab to neoadjuvant and adjuvant chemotherapy does not provide clinical benefit to patients with non-metastatic HER2-negative inflammatory breast cancer. Longer follow-up and correlative studies to identify patients who might benefit from bevacizumab are needed., Funding: Roche, La Ligue Nationale contre le Cancer, UNICANCER, and Chugai Pharma., (Copyright © 2016 Elsevier Ltd. All rights reserved.)