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Erb-b2 receptor tyrosine kinase 2 (ERBB2)-activating mutations are therapeutically actionable alterations found in various cancers, including metastatic breast cancer (MBC). We developed multiplex digital PCR assays to detect and quantify ERBB2 mutations in circulating tumor DNA from liquid biopsies. We studied the plasma from 272 patients with hormone-receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) MBC to detect 17 ERBB2 mutations using a screening assay. The assay was developed on the three-color Crystal dPCR™ naica® platform with a two-step strategy for precise mutation identification. We found that nine patients (3.3%) harbored at least one ERBB2 mutation. The mutation rate was higher in patients with lobular histology (5.9%) compared to invasive breast carcinoma of no special type (2.6%). A total of 12 mutations were found with the following frequencies: L755S (25.00%), V777L (25.00%), S310Y (16.67%), L869R (16.67%), S310F (8.33%), and D769H (8.33%). Matched tumor samples from six patients identified the same mutations with an 83% concordance rate. In summary, our highly sensitive multiplex digital PCR assays are well suited for plasma-based monitoring of ERBB2 mutational status in patients with MBC., (© 2024 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Introduction: Cases of osteonecrosis of the jaw have been reported by dental surgeons to the pharmacovigilance center in Rennes, France, occurring among patients treated with palbociclib, a cyclin-dependent kinase 4/6 inhibitor. Although this event was not expected with the drug, a safety signal was raised. Describing a local case series, the aim of our study was to identify specific patterns that might suggest a triggering role for these drugs, and to discuss pathophysiological hypotheses., Materials and Methods: A retrospective case series of patients exposed to cyclin-dependent kinase 4/6 inhibitors between 2016 and 2020 with a diagnosis of osteonecrosis of the jaw at the Rennes Dental Care Center was analyzed. The descriptive analysis was conducted on patient demographics, breast cancer characteristics, osteonecrosis of the jaw, biological data, and exposure to cyclin-dependent kinase 4/6 inhibitors., Results: We identified eight cases, most of them at stages 0-1 (62.5%). Four patients were still exposed to palbociclib at the time of diagnosis and four had discontinued the treatment before the diagnosis. Chronological imputability could not be excluded given the drug's half-life and the variable intervals of dental monitoring from one patient to another. All patients had at least one dental osteonecrosis risk factor (including dental extraction, dentures, and denosumab exposure at the time of diagnosis). Neutropenia and mucositis were not systematically reported at the time of diagnosis. The anatomopathological characteristics were nonspecific., Conclusion: We did not identify a specific pattern that could suggest a triggering role of palbociclib in the development of ONJ., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: In the PAOLA-1/ENGOT-ov25 primary analysis, maintenance olaparib plus bevacizumab demonstrated a significant progression-free survival (PFS) benefit in newly diagnosed advanced ovarian cancer patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab, irrespective of surgical status. Prespecified, exploratory analyses by molecular biomarker status showed substantial benefit in patients with a BRCA1/BRCA2 mutation (BRCAm) or homologous recombination deficiency (HRD; BRCAm and/or genomic instability). We report the prespecified final overall survival (OS) analysis, including analyses by HRD status., Patients and Methods: Patients were randomized 2 : 1 to olaparib (300 mg twice daily; up to 24 months) plus bevacizumab (15 mg/kg every 3 weeks; 15 months total) or placebo plus bevacizumab. Analysis of OS, a key secondary endpoint in hierarchical testing, was planned for ∼60% maturity or 3 years after the primary analysis., Results: After median follow-up of 61.7 and 61.9 months in the olaparib and placebo arms, respectively, median OS was 56.5 versus 51.6 months in the intention-to-treat population [hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.76-1.12; P = 0.4118]. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 105 (19.6%) olaparib patients versus 123 (45.7%) placebo patients. In the HRD-positive population, OS was longer with olaparib plus bevacizumab (HR 0.62, 95% CI 0.45-0.85; 5-year OS rate, 65.5% versus 48.4%); at 5 years, updated PFS also showed a higher proportion of olaparib plus bevacizumab patients without relapse (HR 0.41, 95% CI 0.32-0.54; 5-year PFS rate, 46.1% versus 19.2%). Myelodysplastic syndrome, acute myeloid leukemia, aplastic anemia, and new primary malignancy incidence remained low and balanced between arms., Conclusions: Olaparib plus bevacizumab provided clinically meaningful OS improvement for first-line patients with HRD-positive ovarian cancer. These prespecified exploratory analyses demonstrated improvement despite a high proportion of patients in the placebo arm receiving poly(ADP-ribose) polymerase inhibitors after progression, confirming the combination as one of the standards of care in this setting with the potential to enhance cure., Competing Interests: Disclosure IRC reports honoraria (personal) from AbbVie, Agenus, Advaxis, Bristol Myers Squibb (BMS), PharmaMar, Genmab, Pfizer, AstraZeneca, Roche, GlaxoSmithKline (GSK), Merck Sharp & Dohme (MSD), Deciphera, Mersana, Merck Sereno, Novartis, Amgen, Tesaro, and Clovis; honoraria (institution) from GSK, MSD, Roche, and BMS; advisory/consulting fees from AbbVie, Agenus, Advaxis, BMS, PharmaMar, Genmab, Pfizer, AstraZeneca, Roche/Genentech, GSK, MSD, Deciphera, Mersana, Merck Sereno, Novartis, Amgen, Tesaro, and Clovis; research grant/funding (self) from MSD, Roche, and BMS; research grant/funding (institution) from MSD, Roche, BMS, Novartis, AstraZeneca, and Merck Sereno; and travel support from Roche, AstraZeneca, and GSK. AL reports grants from AstraZeneca and Sanofi; consulting fees from Seattle Genetics; honoraria/reimbursement and advisory board fees from AstraZeneca; advisory board fees or continuing medical education from Ability Pharma, Biocad, Clovis Oncology, GSK, Medscape, Merck Serono, MSD, TouchCongress, and Zentalis; support for attending meetings and/or travel from AstraZeneca, Clovis Oncology, GSK, and Roche; and participation on a data safety monitoring board or advisory board for ARIEL4 and TROPHIMMUNE. SP reports honoraria from AstraZeneca, Roche, MSD, Pfizer, Tesaro, Clovis Oncology, GSK, and PharmaMar; and research funding (institution) from Roche, MSD, AstraZeneca, and Pfizer. AGM reports advisory/consultancy fees (personal) from Alkermes, Amgen, AstraZeneca, Clovis Oncology, Eisai, Genmab, GSK, Hedera Dx, Illumina, ImmunoGen, MSD, Macrogenics, Mersana, Novartis, Oncoinvent, PharmaMar, Roche, Regeneron, Sotio, and Sutro; speaker bureau fees (personal) from AstraZeneca, Roche, GSK, MSD, Novocure, Takeda, Zai Lab, and Clovis; research grant/funding (institution) from Roche, Novartis, GSK, and Aravive; and steering committee member (personal) for MSD. CM reports honoraria/consulting fees (personal) from Roche, Novartis, Amgen, MSD, PharmaMar, AstraZeneca, GSK, and Seagen; participation on an advisory board from Roche, Novartis, Amgen, MSD, PharmaMar, AstraZeneca, GSK, and Seagen; and travel expenses from Roche and AstraZeneca. SN reports honoraria (self) from AstraZeneca, Chugai, Mochida, MSD, Takeda, and Terumo; and research grant (self) from AstraZeneca. IV reports consulting fees from Agenus, Akesobio, AstraZeneca, BMS, Deciphera Pharmaceuticals, Eisai, Elevar Therapeutics, F. Hoffmann-La Roche, Genmab, GSK, Immunogen, Jazzpharma, Karyopharm, Mersana, MSD, Novocure, Novartis, Oncoinvent, OncXerna, Sanofi, Seagen, Sotio, Verastem Oncology, and Zentalis; contracted research funding (via KULeuven) from Oncoinvent AS; corporate sponsored research funding from Amgen and Roche; and accommodation and travel expenses from Karyopharm. NC reports research grants from AstraZeneca, PharmaMar, and Roche; honoraria for lectures from AstraZeneca, Tesaro, Novartis, Clovis Oncology, MSD, GSK, and Eisai; honoraria for advisory boards from Roche, PharmaMar, AstraZeneca, Clovis Oncology, MSD, GSK, Tesaro, Pfizer, BIOCAD, ImmunoGen, Mersana Therapeutics, Eisai, and OncXerna Therapeutics; and is a steering committee member on ESMO clinical guidelines and a scientific committee chair for Acto Onlus. JM reports honoraria from AstraZeneca and GSK. FS reports honoraria from AstraZeneca, GSK Tesaro, MSD, Sandoz (Novartis), and Clovis Oncology; and institutional financial support from Roche, GSK Tesaro, AstraZeneca, Immunogen, MSD, Incyte, and Agenus. JS reports grants or contracts from Roche Pharma, AstraZeneca, Bayer, Clovis, GSK, Lilly, Tesaro, consulting fees from Tesaro, Merck, Pfizer, PharmaMar, Clovis Oncology, AstraZeneca, Roche Pharma, GSK, MSD, Eisai, Novocure, Oncoinvent, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Tesaro, GSK, PharmaMar, AstraZeneca, Clovis, Bayer, Roche, PharmaMar, Vifor Pharma, Hexal AG, Novartis Pharma. DL reports consultancy fees (personal) from AstraZeneca, Clovis Oncology, Genmab, GSK, Immunogen, MSD, PharmaMar, Novartis, and Seagen; membership on an advisory board (personal) from AstraZeneca, Clovis Oncology, Corcept, Genmab, GSK, Immunogen, MSD, Oncoinvest, PharmaMar, Seagen, and Sutro; research funding (institutional) from AstraZeneca, Clovis Oncology, Genmab, GSK, Immunogen, Incyte, MSD, Novartis, PharmaMar, Roche, and Seagen; and travel support from Roche, PharmaMar, AstraZeneca, Clovis Oncology, and GSK. EMGA reports consulting fees from AstraZeneca–MSD, Clovis Oncology, GSK–Tesaro, PharmaMar, and Roche; speaker bureau/expert testimony honorarium from AstraZeneca–MSD, PharmaMar, Roche, GSK–Tesaro, and Clovis Oncology; and travel support from Roche, GSK–Tesaro, and Baxter. GB reports consulting or advisory board roles for AstraZeneca, Roche, and GSK; and has received funding for medical conferences from AstraZeneca, Roche, and GSK. CLP reports advisory/consultancy honoraria from Pfizer, AstraZeneca, Roche, and Daiichi–Sanko; and other travel/accommodation/medical congress expenses from Roche, Novartis, Pfizer, Pierre Fabre, and MSD. PB reports honoraria from Roche, AstraZeneca, and GSK; and congress and travel support from GSK and PharmaMar. AL reports advisory board fees from AstraZeneca, MSD, and Tesaro; speaker honoraria from Clovis Oncology and Roche; and participation in a medical congress for Novartis, Pfizer, MSD, Lilly, and Roche. AB reports honoraria for lectures and advisory boards from AstraZeneca, Roche, and Tesaro. JM reports advisory board fees (personal) from Daiichi Sankyo, Gilead, and Eli Lilly; and non-financial traveling facilities from Pfizer. AEB reports advisory board fees from AstraZeneca, MSD, and GSK; speaker honoraria from AstraZeneca and Olympus; and participation in a medical congress for PharmaMar and AstraZeneca. MR reports advisory board fees (personal) from AstraZeneca, GSK, and Immunocore; advisory board fees and research grant (personal/institution) from MSD; and research grant (institution) from BMS. TWPS reports honoraria (advisory role, expert testimony and lectures, participation in clinical trials, other financial relationships, e.g. travel) from AstraZeneca, Daiichi-Sankyo, Exact Sciences, Gilead, GSK, Lilly, MSD, NCO, Novartis, Pfizer, Roche, and Seagen. CD reports participation on a data safety monitoring board or advisory board for MSD, Eisai, and AstraZeneca. DD reports consulting or advisory roles (personal) for AstraZeneca, GSK/Tesaro, Roche, Eisai Germany, and MSD Oncology; travel expenses from AstraZeneca; and honoraria from Roche, AstraZeneca, GSK/Tesaro, MSD, Intuitive Surgical, and KLS Martin. BY reports consulting fees (personal) from MSD, AstraZeneca, GSK–Tesaro, Bayer, Roche–Genentech, ECS Progastrin, Novartis, LEK, Amgen, Clovis Oncology, Merck Serono, BMS, SEAGEN, and Myriad. EPL reports lecture fees, speaker’s bureau fees, and travel support from AstraZeneca, Tesaro, and Roche; lecture fees from Clovis Oncology, Incyte, and Pfizer; and is employed by ARCAGY Research. PH reports honoraria from AstraZeneca, Roche, Clovis Oncology, Stryker, MSD Oncology, Zai Lab, Lilly, Sotio, Eisai, and GSK; consulting/advisory roles from AstraZeneca, Roche, Tesaro, Merck, GSK, Clovis Oncology, and Immunogen; and research funding (institution) from AstraZeneca, Roche, Genmab, GSK, Immunogen, and Clovis Oncology. All other authors have declared no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Gestational trophoblastic neoplasia (GTN) is a group of rare tumors characterized by abnormal trophoblastic proliferation following pregnancy including invasive moles, choriocarcinomas, and intermediate trophoblastic tumors (ITT). Although the treatment and follow-up of GTN has been heterogeneous, globally the emergence of expert networks has helped to harmonize its management., Areas Covered: We provide an overview of the current knowledge, diagnosis, and management strategies in GTN and discuss innovative therapeutic options under investigation. While chemotherapy has been the historical backbone of GTN treatment, promising drugs such as immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway and anti-angiogenic tyrosine kinase inhibitors are currently being investigated remodeling the therapeutical landscape of trophoblastic tumors., Expert Opinion: Chemotherapy regimens for GTN have potential long-term effects on fertility and quality of life, making innovative and less toxic therapeutic approaches necessary. Immune checkpoint inhibitors have shown promise in reversing immune tolerance in GTN and have been evaluated in several trials. However, immunotherapy is associated with rare but life-threatening adverse events and evidence of immune-related infertility in mice, highlighting the need for further research and careful consideration of its use. Innovative biomarkers could help personalize GTN treatments and reduce chemotherapy burden in some patients.

Background: Uterine clear cell carcinomas (CCC) represent less than 5% of uterine cancers. Their biological characteristics and clinical management remain uncertain. A multicenter study to explore both clinical and molecular features of these rare tumors was conducted., Methods: This multicenter retrospective national study was performed within the French TMRG (Rare Gynecologic Malignant Tumors) network. Clinical data and, when available, FFPE blocks were collected. Clinical features, treatments, and outcome (progression-free survival (PFS) and overall survival (OS)) were analyzed and correlated to the protein (tissue micro-array), RNA (Nanostring nCounter ® technology), and DNA (array-Comparative Genomic hybridization and target-next generation sequencing) levels using the tumor samples available., Results: Sixty-eight patients with uterine CCC were enrolled, 61 from endometrial localization and 5 with cervix localization. Median age at diagnosis was 68.9 years old (range 19-89.7). Most tumors were diagnosed at an early stage (78% FIGO stage I-II). Hysterectomy (performed in 90%) and lymph node dissection (80%) were the most frequent surgical treatment. More than 70% of patients received external beam radiotherapy and 57% received brachytherapy. Nearly half (46%) of the patients received chemotherapy. After a median follow-up of 24.7 months, median PFS was 64.8 months (95 CI [5.3-124.4]) and median OS was 79.7 (IC95 [31.0-128.4]). Low hormone receptor expression (13% estrogen-receptor positive), frequent PI3K pathway alterations (58% PTEN loss, 50% PIK3CA mutations), and P53 abnormalities (41%) were observed. Mismatch repair deficiency was identified in 20%. P16 expression was associated with shorter PFS (HR = 5.88, 95 CI [1.56-25], p = 0.009). Transcriptomic analyzes revealed a specific transcriptomic profile notably with a high expression of immune response-associated genes in uterine CCC displaying a very good overall prognosis., Conclusions: Uterine CCC reported to be potentially MSI high, hormone receptors negative, and sometimes TP53 mutated. However, some patients with immune response-associated features and better prognosis may be candidate to treatment de-escalation and immunotherapy., (© 2023. The Author(s).)

Background: Early detection of ESR1 mutations is a key element for better personalization of the management of patients with HR+/HER2- Metastatic Breast Cancer (MBC). Analysis of circulating tumor DNA from liquid biopsies is a particularly well-suited strategy for longitudinal monitoring of such patients., Materials and Methods: Using the naica® three-color digital PCR platform, we developed a screening assay allowing the detection of 11 ESR1 mutations and designed a sequential strategy for precise mutation identification. We then applied this strategy in the analysis of plasma circulating cell-free DNA from 109 HR+/HER2- MBC patients and performed a double-blind comparison study on a subset of patients with the multiplex assay used at the Institut Curie (IC) for the PADA-1 study., Results: Thirty-one patients (28.4%) harboured at least one ESR1 mutation, with the following frequencies: D538G (41.03%), Y537S (25.64%), E380Q (10.26%), Y537N (10.26%), "(536-540)" (7.69%), Y537C (2.56%), and L536R (2.56%). The presence of ESR1 mutation(s) was significantly associated with liver metastases (p = 0.0091). A very good agreement (91%) was observed with the IC assay., Conclusion: Our assays have proven to be robust and highly sensitive and are very well-suited for monitoring ESR1 mutations in the plasma of MBC patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Several studies have shown that emotional competence (EC) impacts cancer adjustment via anxiety and depression symptoms. The objective was to test this model for the quality of life (QoL) of partners: first, the direct effect of partners' EC on their QoL, anxiety and depression symptoms after cancer diagnosis (T1), after chemotherapy (T2) and after radiotherapy (T3); Second, the indirect effects of partners' EC at T1 on their QoL at T2 and T3 through anxiety and depression symptoms., Methods: 192 partners of women with breast cancer completed a questionnaire at T1, T2 and T3 to assess their EC (PEC), anxiety and depression symptoms (HADS) and QoL (Partner-YW-BCI). Partial correlations and regression analyses were performed to test direct and indirect effects of EC on issues., Results: EC at T1 predicted fewer anxiety and depression symptoms at each time and all dimensions of QoL, except for career management and financial difficulties. EC showed different significant indirect effects (i.e. via anxiety or depression symptoms) on all sub-dimensions of QoL, except for financial difficulties, according to the step of care pathway (T2 and T3). Anxiety and depression played a different role in the psychological processes that influence QoL., Conclusion: Findings confirm the importance of taking emotional processes into account in the adjustment of partners, especially regarding their QoL and the support they may provide to patients. It, thus, seems important to integrate EC in future health models and psychosocial interventions focused on partners or caregivers., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Cancer progression is driven in part by genomic alterations 1 . The genomic characterization of cancers has shown interpatient heterogeneity regarding driver alterations 2 , leading to the concept that generation of genomic profiling in patients with cancer could allow the selection of effective therapies 3,4 . Although DNA sequencing has been implemented in practice, it remains unclear how to use its results. A total of 1,462 patients with HER2-non-overexpressing metastatic breast cancer were enroled to receive genomic profiling in the SAFIR02-BREAST trial. Two hundred and thirty-eight of these patients were randomized in two trials (nos. NCT02299999 and NCT03386162) comparing the efficacy of maintenance treatment 5 with a targeted therapy matched to genomic alteration. Targeted therapies matched to genomics improves progression-free survival when genomic alterations are classified as level I/II according to the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) 6 (adjusted hazards ratio (HR): 0.41, 90% confidence interval (CI): 0.27-0.61, P < 0.001), but not when alterations are unselected using ESCAT (adjusted HR: 0.77, 95% CI: 0.56-1.06, P = 0.109). No improvement in progression-free survival was observed in the targeted therapies arm (unadjusted HR: 1.15, 95% CI: 0.76-1.75) for patients presenting with ESCAT alteration beyond level I/II. Patients with germline BRCA1/2 mutations (n = 49) derived high benefit from olaparib (gBRCA1: HR = 0.36, 90% CI: 0.14-0.89; gBRCA2: HR = 0.37, 90% CI: 0.17-0.78). This trial provides evidence that the treatment decision led by genomics should be driven by a framework of target actionability in patients with metastatic breast cancer., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The surgical specificities of advanced low-grade serous ovarian carcinoma (LGSOC) have been little investigated. Our objective was to describe surgical procedures/complications in primary (PDS) compared to interval debulking surgery (neoadjuvant chemotherapy and interval debulking surgery, NACT-IDS) and to assess the survival (progression-free (PFS) and overall survival (OS)) in patients with advanced LGSOC. We retrospectively analyzed advanced LGSOC from a nationwide registry (January 2000 to July 2017). A total of 127 patients were included (48% PDS and 35% NACT-IDS). Peritoneal carcinomatosis was more severe ( p = 0.01 to 0.0001, according to sites), surgery more complex ( p = 0.03) and late postoperative morbidity more frequent ( p = 0.03) and more severe in the NACT-IDS group. PFS and OS were similar in patients with CC0 and CC1 residual disease after PDS or IDS. Prognosis was poorest for NACT-IDS patients with CC2/CC3 resection (PFS: HR = 2.31, IC95% (1.3-4.58); p = 0.005; OS: HR = 4.98, IC95% (1.59-15.61); p = 0.006). NACT has no benefit in terms of surgical outputs in patients with advanced LGSOC. Patients with complete resection or minimal residual disease (CC0 and CC1) have similar prognoses. On the other hand, patients with CC2 and more residual disease have similar survival rates compared to nonoperated patients. Primary cytoreduction with complete or with minimal residuals should be preferred when feasible.

Objective: Emotional competence (EC) is considered a substantial resource in the adjustment of cancer patients, especially via its effect on anxiety and depression symptoms. This research aimed at assessing the impact of intrapersonal EC in young women (≤45 years) with breast cancer (YWBC) on their specific quality of life (i.e. subjective experience related to daily difficulties and perceived repercussions of the disease and treatments) related to chemotherapy, via anxiety and depression symptoms., Methods: Two hundred fifty YWBC from 24 French centers completed a self-reported questionnaire after diagnosis (T1) and after the chemotherapy phase (T2), comprising the Young Women Breast Cancer Inventory, the Profile of EC and the Hospital Anxiety and Depression Scale. The indirect effect of EC (T1) on subjective experience (T2) via anxiety and depression symptoms (T2) was tested using regressions and the Macro PROCESS., Results: Emotional competence predicted fewer anxiety and depression symptoms at T1 and T2, and a better subjective experience at T2 via fewer anxiety and depression symptoms. Depression symptoms appeared to be a stronger mediator than anxiety symptoms on four dimensions (Support from close relatives, feeling of couple cohesion, body image and sexuality, management of children and everyday life), whereas anxiety symptoms appeared to be a stronger mediator on two dimensions (negative affectivity and apprehension about the future, deterioration of relationships)., Conclusions: These results support the importance of developing psycho-affective interventions to reinforce the EC of YWBC during chemotherapy in order to facilitate the cognitive and emotional processes necessary for a better adjustment and subjective experience., (© 2022 John Wiley & Sons Ltd.)