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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_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.)

Purpose: Among metastatic breast cancer (MBC) patients, those with a triple-negative breast cancer phenotype (mTNBC) have the worst prognosis, but the benefit of chemotherapy beyond second line on outcome remains uncertain. The purpose of this study was to identify predictive factors of outcome after third- or fourth-line chemotherapy., Methods: The ESME-MBC database is a French prospective real-life cohort with homogeneous data collection, including patients who initiated first-line treatment for MBC (2008-2016) in 18 cancer centers. After selection of mTNBC cases, we searched for independent predictive factors (Cox proportional-hazards regression models) for overall survival (OS) on third- and fourth-line chemotherapy (OS3, OS4). We built prognostic nomograms based on the main prognostic factors identified., Results: Of the 22,266 MBC cases in the ESME cohort, 2903 were mTNBC, 1074 (37%) and 598 (20%) of which had received at least 3 or 4 lines of chemotherapy. PFS after first- and second-line chemotherapy (PFS1, PFS2) and number of metastatic sites ≥3 at baseline were identified by multivariate analysis as prognostic factors for both OS3 (HR = 0.76 95%CI[0.66-0.88], HR = 0.55 95%CI[0.46-0.65], HR = 1.36 95%CI[1.14-1.62], respectively), and OS4 (HR = 0.76 95%CI[0.63-0.91], HR = 0.56 95%CI[0.45-0.7], HR = 1.37 95%CI[1.07-1.74]), respectively. In addition, metastasis-free interval was identified as a prognostic factor for OS3 (p = 0.01), while PFS3 influenced OS4 (HR = 0.75 95%CI[0.57-0.98]). Nomograms predicting OS3 and OS4 achieved a C-index of 0.62 and 0.61, respectively., Conclusion: The duration of each previous PFS is a major prognostic factor for OS in mTNBC patients receiving third- or fourth-line chemotherapy. The clinical utility of nomograms including this information was not demonstrated., Competing Interests: Declaration of competing interest Dr. De La Motte Rouge reports personal fees and non-financial support from ASTRAZENECA, grants, personal fees and non-financial support from PFIZER, grants from NOVARTIS, personal fees and non-financial support from EISAI, personal fees and non-financial support from ROCHE, grants and non-financial support from MSD, outside the submitted work. Dr. Robain reports ESME Platform was supported by Roche, Astra Zeneca, BMS, Pfizer, Daiichi Sankyo, Eisai. Prof. Campone reports grants from Pfizer, grants from AstraZeneca, grants from Sanofi, grants from Pierre Fabre, grants from Takeda, personal fees from Novartis, personal fees from Lilly, outside the submitted work. Dr. MOURET-REYNIER reports grants from Novartis, Lilly, Pfizer, Roche, Pierre Fabre, MSD, outside the submitted work. All other authors declare no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Medical treatment of ovarian cancer is based on chemotherapy. Most patients, regardless of the initial stage of their disease, will need to be treated (grade A). Standard treatment relies on a carboplatin and paclitaxel combination (grade A). For advanced diseases (stage I-IIA1 or IIIB à IV), the addition of an antiangiogenic treatment with bevacizumab to the chemotherapy, followed by a maintenance for 15 months should be proposed as it allows better disease control (grade A). For patients with somatic or germline BRCA mutations and disease stage III or IV, olaparib is recommended as maintenance treatment for 24 months (grade B, but olaparib had not the French approval as first-line treatment at the time of the present recommendation editing). No other targeted therapy or immunotherapy has yet been proven effective at the initial phase of ovarian cancer treatment. The treatment of rare tumors with a special histology must be discussed in a specialized multidisciplinary meeting of the network of rare malignant tumors of the ovary (TMRO) labeled by the INCa., (Copyright © 2019. Published by Elsevier Masson SAS.)

Background: Cabazitaxel, abiraterone acetate (AA), and enzalutamide have been approved for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) following docetaxel chemotherapy. Whether taxanes and next-generation androgen receptor (AR) axis inhibitors are cross-resistant or not is a subject of debate., Objective: To evaluate the antitumour activity of cabazitaxel in mCRPC pretreated with abiraterone or enzalutamide., Design, Setting, and Participants: The antitumour activity of cabazitaxel was assessed in patients with mCRPC and progressive disease after treatment with docetaxel and AA. In parallel, cabazitaxel antitumour activity was studied in enzalutamide-resistant models., Outcome Measurements and Statistical Analysis: Changes in prostate-specific antigen (PSA) levels and progression-free survival were used to determine the activity of cabazitaxel treatment. Cell proliferation, immunofluorescence, and AR transactivation assay were used in enzalutamide-resistant models., Results and Limitations: A total of 79 patients who had progressive mCRPC after docetaxel (median: 8 cycles; range: 4-12 mo), and AA (median: 4.8 mo; range:1-55 mo) received cabazitaxel 25mg/m(2) every 3 weeks (median: 6 cycles; range:1-15 cycles). A PSA decline ≥30% was achieved in 48 patients (62%; 95% confidence interval [CI], 51-73), and a decline ≥50% was achieved in 28 patients (35%; 95% CI, 25-47). The median progression-free survival and overall survival were 4.4 and 10.9 mo, respectively. In vitro, cabazitaxel decreased cell viability in both enzalutamide-sensitive and enzalutamide-resistant prostate cancer cells within the same range of concentrations. PC3, an AR-negative cell line, exhibited similar sensitivity to cabazitaxel., Conclusions: Cabazitaxel and AR-pathway inhibitors are not cross-resistant. Preclinical data suggest that cabazitaxel activity does not act mainly through AR axis inhibition., Patient Summary: The antitumour activity of cabazitaxel, a chemotherapy agent, was studied in prostate cancer resistant to conventional hormonal therapy and to more recent endocrine therapies (abiraterone or enzalutamide). Cabazitaxel retained anticancer activity in more than half of the cases., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Treatment options for radioiodine resistant metastatic thyroid cancer patients are limited, and chemotherapy is considered an outdated therapeutic method for differentiated thyroid carcinoma. In this study, we evaluated the activity and safety of gemcitabine and oxaliplatin combination which is considered an out of label therapeutic method in patients with differentiated metastatic thyroid cancer refractory to 131-I treatment. Fourteen refractory patients (8 papillary, 6 follicular), six men/eight women with median age of 63 years and performance status (0-3) were included. Patients received gemcitabine (1,000 mg/m(2)) plus oxaliplatin (100 mg/m(2)) every 2 weeks until 12-cycles and each cycle correspond to 2 weeks treatment. This protocol was approved by the local Institutional Review Boards. Response rate was assessed every four cycles. Progression-free and overall survivals were calculated. Median treatment was 9.5 cycles (range 2-17) with 22 weeks duration. Overall response rate was 57%, with 7% achieving a complete response (1/14), 50% a partial response (7/14), and 28% with a stable disease. All patients with follicular subtype showed objective responses. Eleven patients progressed at a median time of 10.1 months; 10 of 14 patients still alive and the median survival was not reached (median follow-up of 19.8 months). The combination was generally well tolerated. No deaths occurred due to therapy and no grade IV toxicity was recorded. The most common treatment-related adverse events grade 1/3 includes asthenia, peripheral neuropathy, diarrhea, anemia, thrombocytopenia, and neutropenia. In conclusion, the GEMOX regimen is well tolerated and effective in advanced differentiated thyroid cancer. However, this retrospective data on a small sample size are considered preliminary and needs to be evaluated prospectively in a higher number of patients in a clinical trial.

Background: Ovarian yolk sac tumor (YST) is a very rare malignancy arising in young women. Chemotherapy has dramatically improved the prognosis. Current treatment consists of surgery followed by bleomycin, etoposide, and cisplatin (BEP) chemotherapy. However, given the rarity of this tumor, ovarian YST-specific survival and outcome after such treatment are not precisely known., Patients and Methods: This report concerns prospectively recorded cases that were either treated at Institut Gustave Roussy (Villejuif, France) or referred there for advice about therapy. From 1990 to 2006, 52 patients underwent surgery followed by BEP chemotherapy. Data on patient characteristics, treatment, survival, and fertility outcome were analyzed to assess treatment efficacy and gonadal toxicity after achieving a complete remission., Results: Thirty-five patients had stage I/II tumors while 17 patients presented with stage III/IV disease. With a median follow-up of 68 months, the overall 5-year survival and disease-free survival rates were 94% and 90%, respectively. Forty-one women underwent fertility-sparing surgery. Pregnancy was achieved in 12 of 16 (75%) women who attempted conception. Overall, 19 pregnancies have been recorded., Conclusions: BEP chemotherapy following fertility-sparing surgery is a very effective treatment of ovarian YSTs. Most of the patients who attempt conception after complete remission will have children.