Search

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.

Background: Cervical cancers are mainly caused by an oncogenic HPV. For locally advanced stages, the standard treatment is radio-chemotherapy (RTCT) followed by brachytherapy. Nevertheless, the prognosis remains highly heterogeneous between patients., Objective: We investigated the prognostic value of HPV circulating tumor DNA (ctDNA) in locally advanced cervical cancers alongside that of Squamous Cell Carcinoma Antigen (SCC-A)., Methods: This single-center retrospective study included patients treated in curative intent for an IB3 to IVA squamous cell cervical cancer. Quantification of HPV ctDNA in serum collected at diagnosis was performed using a multiplex digital PCR assay for the simultaneous detection of 8 HPV genotypes., Results: Among the 97 patients included, 76 patients (78.4%) were treated by RTCT, followed by brachytherapy for 57 patients (60%). HPV ctDNA was detected in 59/97 patients at diagnosis (60.8%). This detection was associated with lymph node invasion (p=0.04) but not with tumor stage. A high level of SCC-A at diagnosis was associated with tumor stage (p=0.008) and lymph node invasion (p=0.012). In univariate analysis, better disease-free survival (DFS) was associated with optimal RTCT regimen (p=0.002), exposure to brachytherapy (p=0.0001) and a low SCC-A at diagnosis (continuous analysis, p=0.002). Exploratory analysis revealed that 3/3 patients (100%) whose HPV ctDNA was still detectable at the end of treatment relapsed, while 6/22 patients (27.3%) whose HPV ctDNA was negative at the end of treatment relapsed., Conclusion: HPV ctDNA detection at diagnosis of locally advanced cervical squamous cell carcinomas is frequent and related to node invasion, but not to DFS. The prognostic value of HPV ctDNA detection after treatment warrants specific studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Beaussire-Trouvay, Duhamel, Perdrix, Lévêque, Vion, Rovelet-Lecrux, Sarafan-Vasseur, Di Fiore, Crouzet, Leheurteur and Clatot.)

Objectives: The management of upper aerodigestive tract cancers is a complex specialty. It is essential to provide an update to establish optimal care. At the initiative of the INCa and under the auspices of the SFORL, the scientific committee, led by Professor Béatrix Barry, Dr. Gilles Dolivet, and Dr. Dominique De Raucourt, decided to develop a reference framework aimed at defining, in a scientific and consensus-based manner, the general principles of treatment for upper aerodigestive tract cancers applicable to all sub-locations., Methodology: To develop this framework, a multidisciplinary team of practitioners was formed. A systematic analysis of the literature was conducted to produce recommendations classified by grades, in accordance with the standards of the French National Authority for Health (HAS)., Results: The grading of recommendations according to HAS standards has allowed the establishment of a reference for patient care based on several criteria. In this framework, patients benefit from differentiated care based on prognostic factors they present (age, comorbidities, TNM status, HPV status, etc.), conditions of implementation, and quality criteria for indicated surgery (operability, resectability, margin quality, mutilation, salvage surgery), as well as quality criteria for radiotherapy (target volume, implementation time, etc.). The role of medical and postoperative treatments was also evaluated based on specific criteria. Finally, supportive care must be organized from the beginning and throughout the patients' care journey., Conclusion: All collected data have led to the development of a comprehensive framework aimed at harmonizing practices nationally, facilitating decision-making in multidisciplinary consultation meetings, promoting equality in practices, and providing a state-of-the-art and reference practices for assessing the quality of care. This new framework is intended to be updated every 5 years to best reflect the latest advances in the field., (Copyright © 2024 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Background: Liquid biopsy application is still challenging in glioblastoma patients and the usefulness of short-length DNA (slDNA) fragments is not established. The aim was to investigate slDNA concentration as a prognostic marker in unresected glioblastoma patients., Methods: Patients with unresected glioblastoma and treated by radiochemotherapy (RT/TMZ) were included. Plasmas were prospectively collected at three times: before (pre-) RT, after (post-) RT and at the time of progression. Primary objective was to investigate the impact on survival of slDNA concentration [slDNA] variation during RT/TMZ. Secondary objectives were to explore the association between tumor volume, corticosteroid exposition and [slDNA]; and the impact of slDNA detection at pre-RT on survival., Results: Thirty-six patients were analyzed: 11 patients (30.6 %) experienced [slDNA] decrease during RT/TMZ, 22 patients (61.1 %) experienced increase and 3 patients (8.3 %) had stability. Decrease of [slDNA] during RT/TMZ was associated with better outcome compared to increase or stability: median OS, since end of RT, of 13.2 months [11.4 - NA] vs 10.1 months [7.8 - 12.6] and 6.8 months [4.5 - NA], p = 0.015, respectively. slDNA detection at pre-RT time was associated with improved OS: 11.7 months in the slDNA(+) group versus 8.8 months in the slDNA(-) group, p = 0.004. [slDNA] was not associated with corticosteroids exposition or tumor volume. No influence on survival was observed for both whole cfDNA concentration or slDNA peak size., Conclusion: [slDNA] decrease during radiochemotherapy phase is a favorable prognostic marker on OS for unresected glioblastoma patients. Larger and independent cohorts are now required., Trial Registration: ClinicalTrial, NCT02617745. Registered 1 December 2015, https://clinicaltrials.gov/ct2/show/NCT02617745?term=glioplak&draw=2&rank=1., Competing Interests: Declaration of competing interest MF declares income received for research purposes from Servier® company, benefits for interventions from Seagen® and Novocure®, and payment of congress fees from Gilead® and Pfizer®. FC declares benefits for interventions from BMS®, Merck Serono®, MSD®, Gilead®, Astra Zeneca® and Novartis®, and payment of congress fees from Novartis®, Pfizer®, Merck® and Nutricia®. All these conflicts are outside the field of the submitted work. The other authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Inflammatory breast cancer (IBC) is a rare (1%-5%), aggressive form of breast cancer, accounting for approximately 10% of breast cancer mortality. In the localized setting, standard of care is neoadjuvant chemotherapy (NACT) ± anti-HER2 therapy, followed by surgery. Here we investigated associations between clinicopathologic variables, stromal tumor-infiltrating lymphocytes (sTIL), and pathologic complete response (pCR), and the prognostic value of pCR. We included 494 localized patients with IBC treated with NACT from October 1996 to October 2021 in eight European hospitals. Standard clinicopathologic variables were collected and central pathologic review was performed, including sTIL. Associations were assessed using Firth logistic regression models. Cox regressions were used to evaluate the role of pCR and residual cancer burden (RCB) on disease-free survival (DFS), distant recurrence-free survival (DRFS), and overall survival (OS). Distribution according to receptor status was as follows: 26.4% estrogen receptor negative (ER-)/HER2-; 22.0% ER-/HER2+; 37.4% ER+/HER2-, and 14.1% ER+/HER2+. Overall pCR rate was 26.3%, being highest in the HER2+ groups (45.9% for ER-/HER2+ and 42.9% for ER+/HER2+). sTILs were low (median: 5.3%), being highest in the ER-/HER2- group (median: 10%). High tumor grade, ER negativity, HER2 positivity, higher sTILs, and taxane-based NACT were significantly associated with pCR. pCR was associated with improved DFS, DRFS, and OS in multivariable analyses. RCB score in patients not achieving pCR was independently associated with survival. In conclusion, sTILs were low in IBC, but were predictive of pCR. Both pCR and RCB have an independent prognostic role in IBC treated with NACT., Significance: IBC is a rare, but very aggressive type of breast cancer. The prognostic role of pCR after systemic therapy and the predictive value of sTILs for pCR are well established in the general breast cancer population; however, only limited information is available in IBC. We assembled the largest retrospective IBC series so far and demonstrated that sTIL is predictive of pCR. We emphasize that reaching pCR remains of utmost importance in IBC., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Importance: Young women with breast cancer who have germline pathogenic variants in BRCA1 or BRCA2 face unique challenges regarding fertility. Previous studies demonstrating the feasibility and safety of pregnancy in breast cancer survivors included limited data regarding BRCA carriers., Objective: To investigate cumulative incidence of pregnancy and disease-free survival in young women who are BRCA carriers., Design, Setting, and Participants: International, multicenter, hospital-based, retrospective cohort study conducted at 78 participating centers worldwide. The study included female participants diagnosed with invasive breast cancer at age 40 years or younger between January 2000 and December 2020 carrying germline pathogenic variants in BRCA1 and/or BRCA2. Last delivery was October 7, 2022; last follow-up was February 20, 2023., Exposure: Pregnancy after breast cancer., Main Outcomes and Measures: Primary end points were cumulative incidence of pregnancy after breast cancer and disease-free survival. Secondary end points were breast cancer-specific survival, overall survival, pregnancy, and fetal and obstetric outcomes., Results: Of 4732 BRCA carriers included, 659 had at least 1 pregnancy after breast cancer and 4073 did not. Median age at diagnosis in the overall cohort was 35 years (IQR, 31-38 years). Cumulative incidence of pregnancy at 10 years was 22% (95% CI, 21%-24%), with a median time from breast cancer diagnosis to conception of 3.5 years (IQR, 2.2-5.3 years). Among the 659 patients who had a pregnancy, 45 (6.9%) and 63 (9.7%) had an induced abortion or a miscarriage, respectively. Of the 517 patients (79.7%) with a completed pregnancy, 406 (91.0%) delivered at term (≥37 weeks) and 54 (10.4%) had twins. Among the 470 infants born with known information on pregnancy complications, 4 (0.9%) had documented congenital anomalies. Median follow-up was 7.8 years (IQR, 4.5-12.6 years). No significant difference in disease-free survival was observed between patients with or without a pregnancy after breast cancer (adjusted hazard ratio, 0.99; 95% CI, 0.81-1.20). Patients who had a pregnancy had significantly better breast cancer-specific survival and overall survival., Conclusions and Relevance: In this global study, 1 in 5 young BRCA carriers conceived within 10 years after breast cancer diagnosis. Pregnancy following breast cancer in BRCA carriers was not associated with decreased disease-free survival., Trial Registration: ClinicalTrials.gov Identifier: NCT03673306.

Objective: Endocrine therapy is frequently administered in patients with hormone dependent (HR+) metastatic endometrial cancer. ESR1 mutations have emerged as a key mechanism of aromatase inhibitor (AI) resistance in HR + metastatic breast cancer and can be monitored using circulating tumor DNA (ctDNA). The aim of this study was to explore the incidence and clinical relevance of circulating ESR1 mutations in patients treated by AI or megestrol acetate (M) for advanced endometrial carcinoma., Methodology: This single-center retrospective study was performed at the Henri Becquerel Center (Rouen) and looked for circulating ESR1 gene mutations by droplet digital PCR (E380Q, L536R, Y537S, Y537N, Y537C, D538G, S463P) in patients with advanced HR + endometrial carcinoma treated between 2008 and 2020 for at least 30 days by AI or M. Analyses were performed before exposure and at progression/during endocrine therapy., Results: Twenty-two patients were included: 13 were treated with AI, 12 of whom progressed; 9 patients were treated with M, 8 of whom progressed. 68.1% of the patients had low-grade endometrial carcinoma and 54.5% had received chemotherapy in the metastatic setting. The median duration of treatment was 152 days (min 47 - max 629) with AI and 155 days (min 91-max 1297) with M. Under AI, there was no ESR1 mutation at baseline, and one Y537C mutation at progression with a variant allele frequency (VAF) of 0.14%. Under M, one patient had a Y537C (VAF 0.2%) at baseline that disappeared during treatment. Another patient had a Y537S mutation emergence at progression after 91 days of treatment (VAF 1.83%). There was no significant difference between the circulating DNA concentration before and after hormone therapy (p = 0.16)., Conclusion: ESR1 mutations do not seem to be involved in the mechanisms of resistance to AI or M in HR+ endometrial cancer. The clinical relevance of their detection is not demonstrated., (© 2023. The Author(s).)

Chemo-immunotherapy is the first-line standard of care for patients with PD-L1 positive metastatic triple-negative breast cancer (mTNBC). SYNERGY (NCT03616886) is a dose-finding phase I and a randomized phase II, open-label trial evaluating if targeting the immunosuppressive adenosine pathway can enhance the antitumor activity of chemo-immunotherapy. The phase I part included 6 patients with untreated locally-advanced or mTNBC to determine the safety and recommended phase II dose of the anti-CD73 antibody oleclumab in combination with the anti-PD-L1 durvalumab and 12 cycles of weekly carboplatin and paclitaxel. In the phase II part, 127 women were randomized 1:1 to receive chemo-immunotherapy, with (arm A) or without (arm B) oleclumab. The primary endpoint was the clinical benefit rate at week 24, defined as stable disease, partial or complete response per RECIST v1.1. Secondary endpoints included objective response rate, duration of response, survival outcomes (progression-free survival and overall survival), and safety. The trial did not meet its primary endpoint, as the 24-week clinical benefit rate was not significantly improved by adding oleclumab (43% vs. 44%, p = 0.61). Exploratory median progression-free survival was 5.9 months in arm A as compared to 7.0 months in arm B (p = 0.90). The safety profile was manageable in both arms., (© 2023. The Author(s).)

Purpose: Inflammatory breast cancer (IBC) is a rare breast cancer subtype. Chemorefractory nonmetastatic IBC, defined by locoregional progression under neoadjuvant chemotherapy, is a rare situation with few therapeutic options. Owing to the rarity of this clinical presentation and the lack of specific data, no specific management guidelines exist. We evaluated whether preoperative radiation therapy/chemoradiotherapy could achieve locoregional control after first-line neoadjuvant chemotherapy in patients with IBC., Methods and Materials: Patients with chemorefractory disease receiving preoperative radiation therapy were identified from a retrospective multicenter cohort of consecutive patients with IBC diagnosed between 2010 and 2017 at 7 oncology centers in France., Results: Overall, 18 patients among the 364 patients (5%) treated for IBC had progressive disease during neoadjuvant chemotherapy. These patients had aggressive tumors with lymph node involvement at diagnosis (n = 17; 94.4%), triple-negative subtype (n = 11; 61.1%), Scarff Bloom and Richardson grade 3 (n = 10; 55.6%), and high Ki67 (median, 56.0%). After preoperative radiation therapy, all patients had a complete (n = 1; 5.6%) or partial (n = 17; 94.4%) locoregional response. One patient (5.6%) experienced acute grade 3 dermatitis. Twelve (66.7%) patients underwent surgery as planned. The estimated median follow-up was 31 months. The median overall survival, disease-free survival, distant metastases-free survival, and locoregional recurrence-free survival were 19 months, 4.5 months, 5 months, and 6 months, respectively. Ultimate locoregional control was obtained for 11 patients (61.1%), and 13 patients (72.2%) experienced metastatic progression. Triple-negative subtype (hazard ratio [HR], 15.54; P = .011) and surgery (HR, 0.23; P = .030) were significantly associated with overall survival in the univariate analysis. In multivariate analyses, the triple-negative subtype remained a significant prognostic factor (HR, 13.04; P = .021) for overall survival., Conclusions: Preoperative radiation therapy is a feasible approach with acceptable toxicities. It allowed surgery and ultimate locoregional control in a majority of patients. The lack of translation into better survival has been a challenge, in part owing to the metastatic propensity of patients with chemorefractory IBC, especially in the overrepresented triple-negative population in this series., (Copyright © 2023 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Objectives: The suffering experienced by some patients at the end of their lives can lead to a wish to hasten death (WTHD). It is sometimes an existential suffering, refractory to palliative care even if well conducted, which leads to this desire. Since several years, in psychiatry, the rapid anti-suicidal effects of a single injection of ketamine have been proven. WTHD and suicidal ideation have similarities. The injection of a single dose of ketamine could have an efficiency on the desire to hasten death., Methods: We report the case of a woman with advanced breast cancer expressing a WTHD, treated by ketamine., Results: A 78-year-old woman expressed a WTHD (request for euthanasia) because of existential suffering following a loss of autonomy related to cancer. The suicide item was 4 on the Montgomery-Åsberg Depression Rating Scale (MADRS). She had no associated pain or depression. A single dose of intravenous ketamine 1 mg/kg over 40 min plus 1 mg of midazolam was injected. She had no adverse effects. From D1 post-injection to D3, the WTHD disappeared completely with a MADRS suicide item at 0. At D5, the WTHD started to reappear, and at D6, the previous speech was completely back., Significance of the Results: These results suggest an effect of ketamine on WTHD. This opens up the possibility of treating existential suffering at the end of life. The optimal dosage of this treatment would have to be determined as well as a maintenance of efficacy scheme.

Background: The presence of a breast nurse is recommended to advise and guide early breast cancer patients before and during chemotherapy/radiation therapy, and at the end of planned treatments. Nevertheless, some patients will need extra guidance. Little is known about the predisposing factors for additional requests., Aim and Objective: Determine time, reasons, and risk factors for breast nurse unplanned solicitations., Design and Methods: This monocentric retrospective study included all early breast cancer patients treated with chemotherapy during 1 year. Unplanned solicitations (in person, by phone, or by e-mail) were recorded in the medical file. They were extracted and stratified in four categories: treatment adverse events, medical condition, psychological support, and counselling., Results: 368 unplanned solicitations were observed for 265 patients, 140 patients (52.8%) asked for at least one unplanned solicitation and 57 (21.5%) asked for at least three. There was no significant difference between the four categories. Most of unplanned solicitations occurred significantly during chemotherapy, essentially after first docetaxel infusion (57% of calls). In univariate and multivariate analyses, anxiolytic treatment was significantly associated with more unplanned solicitations (OR = 2, p = 0.02), while a personal breast cancer history was associated with fewer unplanned solicitations (OR = 0.49, p = 0.05)., Conclusion: Breast nurse unplanned solicitations during adjuvant or neoadjuvant chemotherapy in early breast cancers are frequent. Even if patients with anxiolytic treatment have a slightly higher risk of solicitation, no typical profile of a patient who will need extra support exists. Because of its known toxicity, the first cycle of docetaxel is associated with a clear increase in solicitations. Despite physicians' consultations, breast nurses guidance, and leaflets on supportive care and treatments side effects, optimal patient management during early breast cancer remains challenging. Further randomized studies testing more customized tools are required to improve patient support., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2023 by S. Karger AG, Basel.)

Introduction: Lymphopenia has been correlated with poorer survival in patients with metastatic cancers treated with anti-PD-1 immunotherapy. Treatments such as chemotherapy, surgery or radiotherapy can induce lymphopenia. Radiation-induced lymphopenia is common and prolonged in head and neck cancer (HNSCC) patients. We evaluated the impact of lymphopenia, on efficacy of anti PD-1 nivolumab immunotherapy in HNSCC patients., Methods: a multicenter retrospective study included consecutive patients treated with nivolumab for recurrent/metastatic (R/M) HNSCC between January 2017 and June 2019. Lymphopenia was defined as lymphocyte counts below 1000 cells/mm 3 upon initiation of nivolumab. Logistical regression was performed on factors associated with lymphopenia and ROC analyses assessed association between lymphopenia and survival., Results: median age was 65. Of the 100 included patients, 60% had been treated by surgery, 67% had had first-line chemotherapy, and 89% loco-regional radiotherapy, 65% had concurrent chemotherapy with radiotherapy. Lymphopenia occurred in 56 (56%) patients upon initiation of nivolumab, with 29 (29%) patients having radiation-related lymphopenia. Prior locoregional radiotherapy was the only factor associated with lymphopenia upon initiation of nivolumab by logistical regression (OR 0.144 [0.029-0.706], p - 0.017). Lymphopenia upon initiation of nivolumab did not affect progression-free survival (PFS) (p - 0.815), overall survival (OS) (p - 0.783) or disease control rate (DCR) (p - 0.125). Locoregional symptomatology (HR - 2.37 [1.24-4.54], p - 0.009), metastatic symptomatology (HR - 4.74 [2.21-10.15], and persistent lymphopenia under nivolumab (HR 3.96 [1.19-13.17] p - 0.034) were associated with poorer OS in multivariate analysis., Conclusions: Lymphopenia upon initiation of nivolumab was not associated with poorer survival in R/M HNSCC patients, but persistence of lymphopenia during immunotherapy might be a prognostic marker of patient survival., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: We report long-term efficacy and overall survival (OS) results from a randomised, double-blind, phase 2 study (NCT02022098) investigating xevinapant plus standard-of-care chemoradiotherapy (CRT) vs. placebo plus CRT in 96 patients with unresected locally advanced squamous cell carcinoma of the head and neck (LA SCCHN)., Methods: Patients were randomised 1:1 to xevinapant 200 mg/day (days 1-14 of a 21-day cycle for 3 cycles), or matched placebo, plus CRT (cisplatin 100 mg/m 2 every 3 weeks for 3 cycles plus conventional fractionated high-dose intensity-modulated radiotherapy [70 Gy/35 F, 2 Gy/F, 5 days/week for 7 weeks]). Locoregional control, progression-free survival, and duration of response after 3 years, long-term safety, and 5-year OS were assessed., Results: The risk of locoregional failure was reduced by 54% for xevinapant plus CRT vs. placebo plus CRT but did not reach statistical significance (adjusted hazard ratio [HR] 0.46; 95% CI, 0.19-1.13; P = .0893). The risk of death or disease progression was reduced by 67% for xevinapant plus CRT (adjusted HR 0.33; 95% CI, 0.17-0.67; P = .0019). The risk of death was approximately halved in the xevinapant arm compared with placebo (adjusted HR 0.47; 95% CI, 0.27-0.84; P = .0101). OS was prolonged with xevinapant plus CRT vs. placebo plus CRT; median OS not reached (95% CI, 40.3-not evaluable) vs. 36.1 months (95% CI, 21.8-46.7). Incidence of late-onset grade ≥3 toxicities was similar across arms., Conclusions: In this randomised phase 2 study of 96 patients, xevinapant plus CRT demonstrated superior efficacy benefits, including markedly improved 5-year survival in patients with unresected LA SCCHN., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In node-negative breast cancer (NNBC), a high risk of recurrence is determined by clinico-pathological or tumor-biological assessment. Taxanes may improve adjuvant chemotherapy., Methods: NNBC 3-Europe, the first randomized phase-3 trial in node-negative breast cancer (BC) with tumor-biological risk assessment, recruited 4146 node-negative breast cancer patients from 2002 to 2009 in 153 centers. Risk assessment was performed by clinico-pathological factors (43%) or biomarkers (uPA/PAI-1, urokinase-type plasminogen activator/its inhibitor PAI-1). High-risk patients received six courses 5-fluorouracil (500 mg/m 2 ), epirubicin (100 mg/m 2 ), cyclophosphamide (500 mg/m 2 ) (FEC), or three courses FEC followed by three courses docetaxel 100 mg/m 2 (FEC-Doc). Primary endpoint was disease-free survival (DFS)., Results: In the intent-to-treat population, 1286 patients had received FEC-Doc, and 1255 received FEC. Median follow-up was 45 months. Tumor characteristics were equally distributed; 90.6% of tested tumors had high uPA/PAI-1-concentrations. Planned courses were given in 84.4% (FEC-Doc) and 91.5% (FEC). Five-year-DFS was 93.2% (95% C.I. 91.1-94.8) with FEC-Doc and 93.7% (91.7-95.3) with FEC. Five-year-overall survival was 97.0% (95.4-98.0) for FEC-Doc and 96.6% % (94.9-97.8) for FEC., Conclusions: With adequate adjuvant chemotherapy, even high-risk node-negative breast cancer patients have an excellent prognosis. Docetaxel did not further reduce the rate of early recurrences and led to significantly more treatment discontinuations.

Everolimus is the first oral targeted therapy widely used in advanced HR+/HER2- breast cancer. We sought to evaluate the impact of everolimus-based therapy on overall survival in the ESME-MBC database, a national metastatic breast cancer cohort that collects retrospective data using clinical trial-like methodology including quality assessments. We compared 1693 patients having received everolimus to 5928 patients not exposed to everolimus in the same period. Overall survival was evaluated according to treatment line, and a propensity score with the inverse probability of treatment weighting method was built to adjust for differences between groups. Crude and landmark overall survival analyses were all compatible with a benefit from everolimus-based therapy. Adjusted hazard ratios for overall survival were 0.34 (95% CI: 0.16-0.72, p = 0.0054), 0.34 (95% CI: 0.22-0.52, p < 0.0001), and 0.23 (95% CI: 0.14-0.36, p < 0.0001) for patients treated with everolimus in line 1, 2, and 3 and beyond, respectively. No clinically relevant benefit on progression-free survival was observed. Causes for everolimus discontinuation were progressive disease (56.2%), adverse events (27.7%), and other miscellaneous reasons. Despite the limitations inherent to such retrospective studies, these results suggest that adding everolimus-based therapy to the therapeutic sequences in patients with advanced HR+/HER2- breast cancer may favorably affect overall survival., Competing Interests: JSF declares consulting fees from Pfizer, Lilly, Novartis, AstraZeneca, Clovis Oncology, GSK, Gilead, Daiichi Sankyo, Seagen, Exact Science; honoraria for lectures from Lilly, Novartis, Gilead, Daiichi Sankyo, Seagen; travel support and meeting attendance from Pfizer, Milly, Novartis, AstraZeneca, Clovis Oncology, GSK, Gilead, Daiichi Sankyo, Seagen. AG declares Institutional research funding from MSD, BMS, Novartis, Boehringer Ingelheim, Roche Genentech, AstraZeneca, Sanofi, and Daiichi Sankyo. PC declares consulting fees and honoraria from Pfizer, Roche, Lilly; Institutional research funding from Novartis, Pfizer; travel support and meeting attendance from Roche, Pfizer, and Daiichi Sankyo. All other authors declare no conflicts of interest.

Background: Molecular factors influence relapse patterns in glioblastoma. The hotspot mutation located at position 289 of the extracellular domain of the epidermal growth factor receptor (EGFR A289mut ) is associated with a more infiltrative phenotype. The primary objective of this study was to explore the impact of the EGFR A289 mutation on the pattern of relapse after chemoradiotherapy-based treatment of patients suffering from newly diagnosed glioblastoma., Patients and Methods: An ancillary study from a prospective cohort of patients suffering from glioblastoma was conducted. All patients received radiotherapy and concomitant temozolomide. The population was divided into two groups according to EGFR A289 status (mutated versus wild-type). The primary endpoint was the overlap score (varying from 0 to 1) between the initial irradiated tumor volume (Vinit) and the relapse volume (Vr). Secondary endpoints explored the impact of EGFR A289mut on survival., Results: One hundred twenty-eight patients were included and analyzed: 11% had EGFR A289mut glioblastoma (n = 14/128). EGFR A289mut glioblastomas had a relapse pattern that was more marginal than EGFR A289wt glioblastomas: a median overlap score Vinit/Vr of 0.96 was observed in the EGFR A289mut group versus 1 in the EGFR A289wt group (P = 0.05). Half of the population with EGFR A289mut tumor (n = 7/14) had a marginal relapse (i.e. overlap score Vr/Vinit ≤ 0.95) compared to 23.7% (n = 27/114) in the EGFR A289wt group, P = 0.035. EGFR A289mut did not influence survival., Conclusion: We highlighted a link between the EGFR A289 mutation and the relapse pattern in glioblastoma. The independent role of EGFR A289mut and its clinical implication should now be explored in further studies., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Molecular documentation at relapse of high-grade glioma is an urgent need for patient care. A prospective pilot study was conducted to assess the rate of mutation detection using targeted deep sequencing on circulating tumor DNA from cerebrospinal fluid (CSF) after chemo-radiotherapy based treatment. Fifteen patients were included: 13 patients with glioblastoma, 1 patient with gliosarcoma and 1 patient with anaplastic astrocytoma. At progression, 10/15 patients (67%) had detectable mutations in the CSF. Among them, 5/10 patients harbored at least one common mutation between initial tumor and ctDNA. CSF protein level and cfDNA concentration were higher, although not significant, in the ctDNA positive group versus ctDNA negative group (1.17g/L vs. 0.79g/L). Molecular documentation obtained from ctDNA in CSF at the time of relapse is informative in around two-thirds of the patients., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

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.)

Objectives: Both peripherally inserted central catheters (PICCs) and implanted port catheters (PORTs) are commonly used for the delivery of immunochemotherapy. We compared the safety of the two types of devices in a homogeneous and monocentric population of diffuse large B-cell lymphoma (DLBCL) patients who were treated with first-line immunochemotherapy by evaluating the numbers of catheter-related venous thromboses (VTs) and infections that occurred in the six months after implantation according to the type of device., Methods: Using a propensity score, the adjusted relative risk (ARR) between the type of catheter and the occurrence of catheter-related complications (infection and/or VT) of interest was retrospectively determined., Results: 479 patients were enrolled (266 PORTs/213 PICCs), and 26 VTs (5.4%) and 30 infections (6.3%) were identified in the period following PICC/PORT implantation. The adjusted relative risk (ARR) of catheter-related complications (infection and/or VT) according to the type of device was 2.6 (95% CI =1.3-5.9, p = .0075). This risk increase associated with the PICC device was significant for both infections (ARR = 3.2; 95% CI = 1.3-10.9) and thrombosis (ARR = 4; 95% CI = 1.5-11.6)., Conclusion: Our study supports the preferential use of PORTs for the first line of treatment for DLBCL patients., (© 2022 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Objective: A precise evaluation of the disease extent is mandatory before surgery for early breast cancer (EBC). Contrast-enhanced mammography (CEDM) is a recent technique that may help define adequate surgery., Methods: This retrospective study included consecutive patients referred to a cancer center between November 2016 and July 2017 for biopsy-confirmed invasive EBC management. The primary objective was to evaluate the rate of surgical changes after incorporating the results of the preoperative staging examination, including CEDM., Results: A total of 231 patients were screened for inclusion, and 132 patients were included, corresponding to 134 lesions. The first surgical plan was modified for 33 patients (25%), which represented 34 lesions. For 8 patients (6%), the surgery was cancelled in preference for neoadjuvant chemotherapy; for 16 patients (12.1%), the primary tumor procedure was enlarged; and for 23 patients (17.4%) the lymph node management was modified. Surgery was changed only due to the CEDM results for 24 patients (18.5%) and consisted of a more invasive procedure due to a more extended, multifocal or multicentric lesion than seen on the standard imaging. Anatomopathological surgery piece findings were well correlated with contrast-enhanced mammography results. Overall, there was no increase in the delay between the planned date of surgery and the effective surgical procedure (median 0 days)., Conclusion: CEDM added to preoperative staging helped define better surgical management without increasing delay in the surgical procedure., Advances in Knowledge: CEDM is a reliable technique that should be considered as part of preoperative staging for EBC.

Background: Female patients undergoing anticancer treatment are at elevated risk of adverse ovarian outcomes including infertility and premature ovarian insufficiency (POI), which is associated with short- and long-term health risks. Anti-Müllerian hormone (AMH) is a key biomarker of ovarian reserve, but its role prior to and after cancer treatment is less well understood., Objective and Rationale: To conduct a systematic review evaluating AMH as a biomarker of ovarian reserve and POI before and after anticancer treatment, which has become a pressing clinical issue in reproductive medicine. There are a large number of observational studies, but differences in patient groups, cancer diagnoses and study design make this a confusing field that will benefit from a thorough and robust review., Search Methods: A systematic literature search for AMH in women with cancer was conducted in PubMed, Embase and Cochrane Central Register of Controlled Trials up to 1 April 2021. Bias review was conducted using the Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I) protocol along with qualitative assessment of quality. Exploratory subgroups were established based on age, cancer type and length of follow-up., Outcomes: Ninety-two publications (N = 9183 patients) were included in this analysis after quality and bias review. Reduced/undetectable AMH was consistently identified in 69/75 studies (92%) following chemotherapy or radiotherapy, with reductions ranging from 42% to concentrations below the limit of detection, and many reporting mean or median declines of ≥90%. Where longitudinal data were analysed (42 studies), a majority (33/42 (79%)) of studies reported at least partial recovery of AMH at follow-up, however, effect estimates were highly variable, reflecting that AMH levels were strongly impacted by anticancer treatment (i.e. the chemotherapy regimen used and the number of treatment cycles need), with recovery and its degree determined by treatment regimen, age and pre-treatment AMH level. In 16/31 (52%) publications, oligo/amenorrhoea was associated with lower post-treatment AMH consistent with impending POI, although menstruation and/or pregnancy were reported in patients with low or undetectable AMH. Long-term (>5 years) follow-up of paediatric patients following cancer treatment also found significantly lower AMH compared with control groups in 14/20 (70%) of studies, with very variable effect sizes from complete loss of AMH to full recovery depending on treatment exposure, as in adult patients., Wider Implications: AMH can be used to identify the damaging effect of cancer treatments on ovarian function. This can be applied to individual women, including pre-pubertal and adolescent girls, as well as comparing different treatment regimens, ages and pre-treatment AMH levels in populations of women. While there was evidence for its value in the diagnosis of POI after cancer treatment, further studies across a range of diagnoses/treatment regimens and patient ages are required to clarify this, and to quantify its predictive value. A major limitation for the use of AMH clinically is the very limited data relating post-treatment AMH levels to fertility, duration of reproductive lifespan or time to POI; analysis of these clinically relevant outcomes will be important in further research., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

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.

Purpose: Accurate diagnosis and prediction of loss of ovarian function after chemotherapy for premenopausal women with early breast cancer (eBC) is important for future fertility and clinical decisions regarding the need for subsequent adjuvant ovarian suppression. We have investigated the value of anti-mullerian hormone (AMH) as serum biomarker for this., Methods: AMH was measured in serial blood samples from 206 premenopausal women aged 40-45 years with eBC, before and at intervals after chemotherapy. The diagnostic accuracy of AMH for loss of ovarian function at 30 months after chemotherapy and the predictive value for that of AMH measurement at 6 months were analysed., Results: Undetectable AMH showed a high diagnostic accuracy for absent ovarian function at 30 months with AUROC 0.89 (96% CI 0.84-0.94, P < 0.0001). PPV of undetectable AMH at 6 months for a menopausal estradiol level at 30 months was 0.77. In multivariate analysis age, pre-treatment AMH and FSH, and taxane treatment were significant predictors, and combined with AMH at 6 months, gave AUROC of 0.90 (95% CI 0.86-0.94), with PPV 0.79 for loss of ovarian function at 30 months. Validation by random forest models with 30% data retained gave similar results., Conclusions: AMH is a reliable diagnostic test for lack of ovarian function after chemotherapy in women aged 40-45 with eBC. Early analysis of AMH after chemotherapy allows identification of women who will not recover ovarian function with good accuracy. These analyses will help inform treatment decisions regarding adjuvant endocrine therapy in women who were premenopausal before starting chemotherapy., (© 2022. The Author(s).)

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.)

Inflammatory breast cancer (IBC) is an aggressive BC subtype with poor outcomes. A targetable somatic PIK3CA mutation is reported in 30% of IBC, allowing for treatment by PI3Kα-specific inhibitors, such as alpelisib. The aim of this study was to evaluate the detection rate of circulating PIK3CA mutation in locally-advanced IBC (LAIBC) patients harbouring a PIK3CA mutation on initial biopsy. This monocentric retrospective study was based on available stored plasma samples and tumour biopsies at diagnosis from all LAIBC patients treated with neo-adjuvant chemotherapy (NCT) between 2008 and 2018 at the Centre Henri Becquerel. PIK3CA mutations (E542K, E545K, H1047R/L) were assessed by droplet digital PCR (ddPCR) in plasma samples and tumoral tissue at diagnosis. A total of 55 patients were included. Overall, 14/55 patients (25%) had a PIK3CA mutation identified on baseline biopsy (H1047R = 8; H1047L = 3; E545K = 2; E542K = 1). Among them, 11 (79%) patients had enough DNA for circulating DNA analyses, and corresponding circulating PIK3CA mutations were found in 6/11 (55%). Among the 41 patients without PIK3CA mutations on biopsy, 32 (78%) had enough DNA for circulating DNA analysis, and no circulating PIK3CA mutation was identified. Our results revealed no prognostic or predictive value of PIK3CA mutations at the diagnosis of non-metastatic IBC but highlighted the prognostic value of the cfDNA rate at diagnosis. Our study showed that a corresponding circulating PIK3CA mutation was identified in 55% of LAIBC patients with PIK3CA-mutated tumours, while no circulating mutation was found among patients with PI3KCA wild-type tumours., (© 2021. The Author(s).)

The tumor biopsy remains essential for breast cancer diagnosis and characterization. Indeed, the treatment is decided according to histological subtype, and according to the presence of targetable molecular alterations. Notably, the presence of hormone receptors, ERBB2 hyperexpression or the existence of PIK3CA or ESR1 mutations are among the alterations commonly investigated. But these biological characteristics are determined only partially by tumor biopsy, due to tumor heterogeneity or tumor plasticity that happens spontaneously or under treatment. Liquid biopsy, and in particular circulating tumor DNA and circulating tumor cells, is a non-invasive method to identify and characterize the presence of cancer in the blood. The aim of this review is to determine the value of liquid biopsy to enhance or replace the data provided by a tumor biopsy., (Copyright © 2021 Société FranÇaise du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés.)

Background: Knowledge is growing on the safety of assisted reproductive techniques (ART) in cancer survivors. No data exist, however, for the specific population of breast cancer patients harboring germline BRCA1/2 pathogenic variants., Patients and Methods: This is a multicenter retrospective cohort study across 30 centers worldwide including women diagnosed at ≤40 years with stage I-III breast cancer, between January 2000 and December 2012, harboring known germline BRCA1/2 pathogenic variants. Patients included in this analysis had a post-treatment pregnancy either achieved through use of ART (ART group) or naturally (non-ART group). ART procedures included ovulation induction, ovarian stimulation for in vitro fertilization or intracytoplasmic sperm injection, and embryo transfer under hormonal replacement therapy., Results: Among the 1424 patients registered in the study, 168 were eligible for inclusion in the present analysis, of whom 22 were in the ART group and 146 in the non-ART group. Survivors in the ART group conceived at an older age compared with those in the non-ART group (median age: 39.7 versus 35.4 years, respectively). Women in the ART group experienced more delivery complications compared with those in the non-ART group (22.1% versus 4.1%, respectively). No other apparent differences in obstetrical outcomes were observed between cohorts. The median follow-up from pregnancy was 3.4 years (range: 0.8-8.6 years) in the ART group and 5.0 years (range: 0.8-17.6 years) in the non-ART group. Two patients (9.1%) in the ART group experienced a disease-free survival event (specifically, a locoregional recurrence) compared with 40 patients (27.4%) in the non-ART group. In the ART group, no patients deceased compared with 10 patients (6.9%) in the non-ART group., Conclusion: This study provides encouraging safety data on the use of ART in breast cancer survivors harboring germline pathogenic variants in BRCA1/2, when natural conception fails or when they opt for ART in order to carry out preimplantation genetic testing., Competing Interests: Disclosure EdA has acted as a scientific advisory board member and has received honoraria from Roche/Genentech, Novartis, Seattle Genetics, Zodiacs, Libbs, Pierre Fabre, and Lilly; has received travel grants from Roche/GNE and GlaxoSmithKline (GSK)/Novartis; and has received research grants through his institution from Roche/GNE, AstraZeneca, GSK/Novartis, and Servier, outside the submitted work. FAP has acted as consultant for Ipsen, Roche Diagnostic, and Merck outside the submitted work. CRJ has acted as a scientific advisory board member and her institution has received honoraria from Bristol Myers Squibb (BMS), Theramex, and Roche; and her institution has received speaker's fees from Theramex and BMS, outside the submitted work. AS has acted as a consultant for Eli Lilly, Pfizer, Novartis, and Roche; has received speaker's fees from Teva, Roche, Pfizer, and Novartis; has received travel grants from Neopharm, Celgene, and Medison; and has received grant support from Novartis and Roche, outside the submitted work. CVG has acted as a consultant, as a scientific advisory board member, and has received speaker's fees from Roche, Novartis, Pfizer, Lilly, and Merck Sharp & Dohme (MSD); and has received research funding from AstraZeneca, Roche, and Pfizer, outside the submitted work. OCC has acted as a scientific advisory board member for Ascires Sistemas Genómicos; and has received grant support from Roche Diagnostics, Neomedic, and Takeda, outside the submitted work. KP has acted as a scientific advisory board member for AstraZeneca, Eli Lilly, Gilead Sciences, MSD, Novartis, Pierre Fabre, Roche, Teva, and Vifor Pharma; has acted as a consultant for AstraZeneca, Novartis, Pfizer, and Roche; has received speaker's fees from Eli Lilly, Medscape, MSD, Mundi Pharma, Novartis, Pfizer, and Roche; has received travel grants from AstraZeneca, Novartis, Pfizer, PharmaMar, and Roche, outside the submitted work. FP has acted as a scientific advisory board member and has received speaker's fees from Amgen, AstraZeneca, Daichi-Sankyo, Eisai, Eli Lilly, Ipsen, MSD, Novartis, Pierre-Fabre, Pfizer, Roche, Seagen, and Takeda; has received travel grants from Celgene, GlaxoSmithKline, and Roche; and has received research funding from AstraZeneca, Eisai, and Roche, outside the submitted work. ARF has received honoraria from Bayer, Daiichi Sankyo, Novartis, and Roche; and has received travel grants from Roche, outside the submitted work. JB has acted as consultant for AstraZeneca and Pfizer outside the submitted work. ID has acted as a scientific advisory board member and received grant from Roche; has received speaker's fees from Novartis; and has received travel grants from Theramex and Ferring, outside the submitted work. ML has acted as a consultant for Roche, Lilly, AstraZeneca, Exact Sciences, and Novartis; and has received honoraria from Sandoz, Roche, Lilly, Pfizer, Novartis, Ipsen, and Takeda, outside the submitted work. The remaining authors have no conflicts of interest to declare., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Immune checkpoint inhibitors are widely used in recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC). We aimed to describe response rates to taxanes after progression on nivolumab in R/M HNSCC patients., Methods: In this multicentric retrospective comparative study, we included patients treated with taxane monotherapy from 2014 to 2020. Patients were divided into two groups depending on whether they received nivolumab before taxanes (post-nivolumab group) or not (control group). The primary end-point was objective response rate (ORR) comparison between the two groups. The secondary end-points included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and PFS ratio (PFSr=PFS associated with taxanes divided by PFS associated with the previous line of treatment), a survival marker used for comparison of different treatment lines., Results: Between July 2014 and August 2020, 185 patients were included (114 in the control group and 71 in the post-nivolumab group). ORR was significantly higher in the post-nivolumab group (39.4% versus 26.3%, p = 0.03) as was DCR (69% versus 50%, P = 0.06). The median OS (7.5 months) and PFS (3.5 months) were not significantly different in the two groups, whereas PFSr was significantly improved in the post-nivolumab group (1.63 versus 1.11, P = 0.004)., Conclusion: Response and DCRs with taxanes are improved after prior exposure to nivolumab. Thus, taxane monotherapy could be a good choice as third-line therapy after nivolumab following a platinum-based first line. These results currently apply to patients without access to or potential benefit from first-line pembrolizumab., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Oral squamous cell carcinoma (OSCC) is the most frequent type of tumor arising from the oral cavity. Surgery is the cornerstone of the treatment of these cancers. Tumor biology has long been overlooked as an important contributor to the outcome of surgical procedures, but recent studies are challenging this concept. Molecular analyses of tumor DNA or RNA provide a rich source of information about the biology of OSCC., Methods: We searched for relevant articles using PubMed. We examined in particular the prospect of applying molecular methods for minimally invasive exploration of OSCC biology., Results: We examined five potential applications of genomics to the surgical management and study of OSCC: i) assessing oral potentially malignant lesions; ii) tumor staging prior to surgery; iii) predicting postoperative risk in locally advanced tumors; iv) measuring minimal residual disease and optimizing the longitudinal monitoring of OSCC; and v) predicting the efficacy of medical treatment., Conclusions: Genomic information can be harnessed in order to identify new biomarkers that could improve the staging, choice of therapy and management of OSCC. The identification of new biomarkers is awaited for better personalization of the surgical treatment of OSCC., (© 2021. The Author(s).)

Background: We previously reported that CEA kinetics are a marker of progressive disease (PD) in metastatic colorectal cancer (mCRC). This study was specifically designed to confirm CEA kinetics for predicting PD and to evaluate CA19-9, cell-free DNA (cfDNA), circulating tumour DNA (ctDNA) and circulating tumour cell (CTC) kinetics., Methods: Patients starting a chemotherapy (CT) with pre-treatment CEA > 5 ng/mL and/or CA19.9 > 30 UI/mL were prospectively included. Samples were collected from baseline to cycle 4 for CEA and CA19-9 and at baseline and the sixth week for other markers. CEA kinetics were calculated from the first to the third or fourth CT cycle., Results: A total of 192 mCRC patients were included. CEA kinetics based on the previously identified >0.05 threshold was significantly associated with PD (p < 0.0001). By dichotomising by the median value, cfDNA, ctDNA and CA19-9 were associated with PD, PFS and OS in multivariate analysis. A circulating scoring system (CSS) combining CEA kinetics and baseline CA19-9 and cfDNA values classified patients based on high (n = 58) and low risk (n = 113) of PD and was independently associated with PD (ORa = 4.6, p < 0.0001), PFS (HRa = 2.07, p < 0.0001) and OS (HRa = 2.55, p < 0.0001)., Conclusions: CEA kinetics alone or combined with baseline CA19-9 and cfDNA are clinically relevant for predicting outcomes in mCRC., Trial Registration Number: NCT01212510., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: To determine whether germline BRCA (g BRCA ) pathogenic variants are associated with decreased ovarian reserve., Materials and Methods: An individual patient-level data meta-analysis was performed using five data sets on 828 evaluable women who were tested for g BRCA . Of those, 250 carried g BRCA , whereas 578 had tested negative and served as controls. Of the women with g BRCA, four centers studied those affected with breast cancer (n = 161) and one studied unaffected individuals (n = 89). The data were adjusted for the center, age, body mass index, smoking, and oral contraceptive pill use before the final analysis. Anti-Müllerian hormone (AMH) levels in affected women were drawn before presystemic therapy., Results: The mean age of women with versus without g BRCA1/2 (34.1 ± 4.9 v 34.3 ± 4.8 years; P = .48) and with g BRCA1 versus g BRCA2 (33.7 ± 4.9 v 34.6 ± 4.8 years; P = .16) was similar. After the adjustments, women with g BRCA1/2 had significantly lower AMH levels compared with controls (23% lower; 95% CI, 4 to 38; P = .02). When the adjusted analysis was limited to affected women (157 with g BRCA v 524 without, after exclusions), the difference persisted (25% lower; 95% CI, 9 to 38; P = .003). The serum AMH levels were lower in women with g BRCA1 (33% lower; 95% CI, 12 to 49; P = .004) but not g BRCA2 compared with controls (7% lower; 95% CI, 31% lower to 26% higher; P = .64)., Conclusion: Young women with g BRCA pathogenic variants, particularly those affected and with g BRCA1 , have lower serum AMH levels compared with controls. They may need to be preferentially counseled about the possibility of shortened reproductive lifespan because of diminished ovarian reserve., Competing Interests: Matteo LambertiniConsulting or Advisory Role: Roche, Novartis, Lilly, AstraZenecaSpeakers' Bureau: Theramex, Takeda, Roche, Lilly, Novartis, Pfizer, Sandoz Erica WangConsulting or Advisory Role: OncoPepResearch Funding: Merck Florian ClatotHonoraria: Merck Serono, Bristol-Myers Squibb, AstraZenecaConsulting or Advisory Role: Lilly, Bristol-Myers Squibb, Roche, Merck SeronoResearch Funding: AstraZeneca, Roche DiagnosticsTravel, Accommodations, Expenses: Merck Serono, Roche, Bristol-Myers Squibb Beth Y. KarlanConsulting or Advisory Role: Roche Pharma AG, Merck, Mercy BioAnalyticsResearch Funding: VBL Therapeutics, AstraZenecaPatents, Royalties, Other Intellectual Property: US and EU patent on gene signatureOther Relationship: Elsevier Isabelle DemeestereConsulting or Advisory Role: RocheResearch Funding: Roche DiagnosticsTravel, Accommodations, Expenses: FerringNo other potential conflicts of interest were reported.

Background: Treatment strategies for metastatic breast cancer (MBC) have made great strides over the past 10 years. Real-world data allow us to evaluate the actual benefit of new treatments. ESME (Epidemio-Strategy-Medico-Economical)-MBC, a nationwide observational cohort (NCT03275311), gathers data of all consecutive MBC patients who initiated their treatment in 18 French Cancer Centres since 2008., Patients and Methods: We evaluated overall survival (OS) in the whole cohort (N = 20 446) and among subtypes: hormone receptor positive, human epidermal growth factor 2 negative (HR+/HER2-; N = 13 590), HER2+ (N = 3919), and triple-negative breast cancer (TNBC; N = 2937). We performed multivariable analyses including year of MBC diagnosis as one of the covariates, to assess the potential OS improvement over time, and we described exposure to newly released drugs at any time during MBC history by year of diagnosis (YOD)., Results: The median follow-up of the whole cohort was 65.5 months (95% CI 64.6-66.7). Year of metastatic diagnosis appears as a strong independent prognostic factor for OS [Year 2016 HR 0.89 (95% CI 0.82-0.97); P = 0.009, using 2008 as reference]. This effect is driven by the HER2+ subcohort, where it is dramatic [Year 2016 HR 0.52 (95% CI 0.42-0.66); P < 0.001, using 2008 as reference]. YOD had, however, no sustained impact on OS among patients with TNBC [Year 2016 HR 0.93 (95% CI 0.77-1.11); P = 0.41, using 2008 as reference] nor among those with HR+/HER2- MBC [Year 2016 HR 1.02 (95% CI 0.91-1.13); P = 0.41, using 2008 as reference]. While exposure to newly released anti-HER2 therapies appeared very high (e.g. >70% of patients received pertuzumab from 2016 onwards), use of everolimus or eribulin was recorded in less than one-third of HR+/HER2- and TNBC cohorts, respectively, whatever YOD., Conclusion: OS has dramatically improved among HER2+ MBC patients, probably in association with the release of several major HER2-directed therapies, whose penetrance was high. This trend was not observed in the other subtypes, but the impact of CDK4/6 inhibitors cannot yet be assessed., Competing Interests: Disclosure AG reports nonfinancial support from AstraZeneca, Roche, Pfizer, and Novartis, outside the submitted work. WJ reports grants, personal fees, and nonfinancial support from Astra Zeneca; personal fees and nonfinancial support from Eisai, Novartis, Roche, Pfizer, Eli Lilly, and Chugai; personal fees from MSD and BMS, outside the submitted work. P-HC reports grants and nonfinancial support from Roche and Pfizer, outside the submitted work. FC reports grants and personal fees from Merck Serono and BMS; nonfinancial support from Lilly; personal fees and nonfinancial support from Roche; and grants from AstraZeneca, outside the submitted work. ED reports personal fees and nonfinancial support from Novartis and Pfizer; and nonfinancial support from Lilly, outside the submitted work. TB reports personal fees and nonfinancial support from Roche and AstraZeneca; grants, personal fees, and nonfinancial support from Novartis and Pfizer; and personal fees from Seattle Genetics, outside the submitted work. DP reports personal fees from Laboratoire Roche, Pierre Fabre, Novartis, BMS, Eli-Lilly, Ipsen, MSD; personal fees and nonfinancial support from Laboratoire AstraZeneca; grants from Laboratoire MDS Avenir outside the submitted work and Laboratoire Roche (ESME program). SD reports grants and nonfinancial support from Pfizer, AstraZeneca, and Roche Genentech; grants from Novartis, Lilly, Puma, Myriad, Orion, Amgen, Sanofi, Genomic Health, GE, Servier, MSD, BMS, and Pierre Fabre, outside the submitted work. All remaining authors have nothing to disclose., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Solid tumors often establish a procoagulable state that can lead to venous thromboembolism (VTE). Although some of the key genes involved in this process are known, no previous study has compared the "coagulome", i.e., the expression of coagulation/fibrinolysis genes, across different primary tumor types. It is also unclear whether the coagulome is associated with specific characteristics of the tumor microenvironment (TME). We aimed to address this question., Methods: We analyzed the expression of the genes F3, PLAU, PLAT, PLAUR, SERPINB2, and SERPINE1 in 32 cancer types using data from The Cancer Genome Atlas (TCGA) and other freely available resources., Results: We identified specific expression patterns of procoagulant and fibrinolytic genes. The expression of the Tissue Factor (F3) was found to be tumor type dependent, with the highest expression in glioblastoma (GBM), a highly procoagulable tumor type. Conversely, high expression of the fibrinolysis gene cluster PLAU, PLAUR, SERPINE1 was consistently linked to the characteristics of the TME (monocytic infiltration) and high expression of important checkpoints of the immune response, such as PD-L2 and CD276/B7-H3., Conclusion: These tumor-specific patterns of expression might partially explain the differences in VTE risk among tumor types. We propose that biomarkers of coagulation fibrinolysis might provide valuable information about the TME in cancer patients.

Glioblastoma, the most frequent and aggressive primary malignant tumor, often presents with alterations in the telomerase reverse transcriptase promoter. Telomerase is responsible for the maintenance of telomere length to avoid cell death. Telomere lengthening is required for cancer cell survival and has led to the investigation of telomerase activity as a potential mechanism that enables cancer growth. The aim of this systematic review is to provide an overview of the available data concerning TERT alterations and glioblastoma in terms of incidence, physiopathological understanding, and potential therapeutic implications.