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Hyperthermic intraperitoneal chemotherapy (HIPEC) at interval cytoreductive surgery for ovarian cancer improves overall survival but its role in recurrent disease is uncertain. We aimed to compare outcomes in patients treated with or without HIPEC during surgery for recurrent ovarian cancer. The multicentre, open-label, randomised, phase 3 CHIPOR trial was conducted at 31 sites in France, Belgium, Spain, and Canada, and enrolled patients with first relapse of epithelial ovarian cancer at least 6 months after completing platinum-based chemotherapy. Eligible patients were aged 18 years or older with WHO performance status of less than 2. After six cycles of platinum-based chemotherapy (and optional bevacizumab), patients amenable to complete cytoreductive surgery were randomly assigned centrally in a 1:1 ratio, using a web-based system and a minimisation procedure, during surgery to receive HIPEC (cisplatin 75 mg/m2 in 2 L/m2 of serum at 41±1°C for 60 min) or not, stratified by centre, completeness of cytoreduction score, platinum-free interval, and latterly, planned poly(ADP-ribose) polymerase inhibitor use. The primary endpoint was overall survival, analysed on an intention-to-treat basis in all randomly assigned patients. This ongoing trial is registered with ClinicalTrials.gov, NCT01376752. Between May 11, 2011, and May 14, 2021, 415 female patients were randomly assigned (207 HIPEC, 208 no HIPEC). At the primary analysis (median follow-up 6·2 years, IQR 4·1–8·1), 268 (65%) patients had died (126 [61%] of 207 in the HIPEC group; 142 [68%] of 208 in the no-HIPEC group). Overall survival was significantly improved with HIPEC (stratified hazard ratio 0·73, 95% CI 0·56–0·96; p=0·024). Median overall survival was 54·3 months (95% CI 41·9–61·7) with HIPEC versus 45·8 months (38·9–54·2) without. Grade 3 or worse adverse events within 60 days after surgery occurred in 102 (49%) of 207 patients receiving HIPEC versus 56 (27%) of 208 receiving no HIPEC, the most common being anaemia (47 [23%] vs 30 [14%]), hepatotoxicity (23 [11%] vs 18 [9%]), electrolyte disturbance (28 [14%] vs two [1%]), and renal failure (20 [10%] vs three [1%]). There were three deaths within 60 days of surgery, all in the no-HIPEC group. Adding HIPEC to cytoreductive surgery after response to platinum-based chemotherapy at first epithelial ovarian cancer recurrence significantly improved overall survival. When treating patients with late first relapse of high-grade serous or high-grade endometrioid ovarian cancer amenable to complete cytoreductive surgery at specialist centres, platinum-based HIPEC should be considered to extend overall survival. French National Cancer Institute and French League Against Cancer.

Endocrine therapy is the mainstay of treatment of estrogen-receptor-positive (ER+) breast cancer with an overall survival benefit. However, some adaptive mechanisms in the tumor emerge leading to the development of a resistance to this therapy. A better characterization of this process is needed to overcome this resistance and to develop new tailored therapies. Mechanisms of resistance to hormone therapy result in activation of transduction signal pathways, including the cell cycle regulation with cyclin D/CDK4/6/Rb pathway. The strategy of combined hormone therapy with targeted agents has shown an improvement of progression-free survival (PFS) in several phase II or III trials, including three different classes of drugs: mTOR inhibitors, PI3K and CDK4/6 inhibitors. A recent phase III trial has shown that fulvestrant combined with a CDK 4/6 inhibitor doubles PFS in aromatase inhibitor-pretreated postmenopausal ER+ breast cancer. Other combinations are ongoing to disrupt the interaction between PI3K/AKT/mTOR and cyclin D/CDK4/6/Rb pathways. Despite these successful strategies, reliable and reproducible biomarkers are needed. Tumor genomics are dynamic over time, and blood-based biomarkers such as circulating tumor DNA represent a major hope to elucidate the adaptive mechanisms of endocrine resistance. The optimal combinations and biomarkers to guide this strategy need to be determined.

Sex cord stromal tumors (SCST) are rare cancers of the ovarian area in adults. They constitute a heterogeneous group of tumors that develop from the sex cords and the ovarian stroma. These tumors are detected typically at an early stage, and they may recur as late as 30 years after the initial treatment. Because 70% of the patients present with stage I tumors, surgery represents the most important therapeutic arm. There are no data to support any kind of postoperative adjuvant treatment for patients with stage IA or IB SCSTs, given the indolent nature of these neoplasms and the overall good prognosis. The long natural history of the disease may lead to repeated surgical procedure should a relapse occurs. Platinum-based chemotherapy is currently used for patients with advanced stage SCSTs or recurrent disease, with an overall response rate of 63% to 80%. The indolent nature of SCSTs with the tendency for late recurrence requires long-term follow-up.

ObjectiveAdvanced or recurrent endometrial carcinoma (EC) represents a significant clinical challenge. This study aimed to evaluate patient (age and comorbidities) and disease (histological subtypes and stages) characteristics, treatment patterns and survival outcomes in a real-world French healthcare setting.Methods and analysisIn this national, multi-centre, retrospective observational cohort study, 200 patients with advanced or recurrent EC receiving first- or second-line chemotherapy during the year 2019 were analysed. Data collected included baseline characteristics, treatment regimens, real-world progression-free survival (rwPFS) and overall survival (OS).Results127 and 73 were included in the first and second lines, respectively. Endometrioid carcinoma was the most represented histological subtype (62.0%). Patients in the first line, of whom 31.5% had FIGO (Fédération Internationale de Gynécologie Obstétrique) IVB disease, mainly received a combination of carboplatin and paclitaxel (78.0%), while 131 patients receiving second-line therapy were mainly administered anthracycline (54.2%). Median rwPFS and OS were, respectively, 8.5 and 13.2 months for patients receiving first-line therapy and 4.0 and 9.4 months for patients receiving second-line therapy. In Cox analyses, a diagnosis of carcinosarcoma, the presence of liver metastases and stage IVB disease were associated with worse survival outcomes for patients recieving first-line chemotherapy. Non-platinum chemotherapy and liver metastases were associated with poorer survival in patients receiving second-line chemotherapy.ConclusionsThis study highlights the landscape of metastatic EC treatment in a real-world French setting before the availability of PD1 inhibitors, emphasising the discrepancy between clinical trial data and real-world outcomes. It underscores the necessity for further real-world studies to complement clinical trials for a comprehensive understanding of metastatic EC management.

Background Early access program (formerly cohort Temporary Authorization for Use) was granted for trastuzumab deruxtecan (T‐DXd) in France based on DESTINY‐Breast01 trial which demonstrated its efficacy and safety in HER2‐positive metastatic/unresectable breast cancer after ≥2 anti‐HER2‐based regimens received at metastatic stage. Methods This multicenter real‐world early access program included HER2‐positive metastatic/unresectable breast patients pretreated with at least two lines of anti‐HER2 regimens who received T‐DXd 5.4 mg/kg intravenously in monotherapy every 3 weeks. Results Four hundred and fifty‐nine patients (median age, 58 years; hormone receptor‐positive, 67%; brain metastases, 28.1%) received T‐DXd. Before inclusion, 81.7% of patients had radiation therapy and 76.5% had undergone surgery. Median number of prior metastatic treatment lines was four (range, 2–22); 99.8% patients had received trastuzumab, 94.8% trastuzumab emtansine and 79.3% pertuzumab. Follow‐up was performed from September 30, 2020 to March 30, 2021; when the early access program stopped, the median duration of T‐DXd treatment was 3.4 (range, 0–7.8) months. In 160 patients with available tumor assessment, objective response rate was 56.7% and 12.1% had progression. In 57 patients with available brain tumor assessment, complete or partial intracranial response was reported for 35.7% patients and 5.4% had progression. A total of 17 (3.7%) patients with interstitial lung disease (ILD) was reported with no cases of ILD‐related death. Conclusions In this early access program in patients with heavily pretreated HER2‐positive metastatic/unresectable breast cancer, T‐DXd had antitumor activity with a similar response to that reported in previous clinical studies. T‐DXd was well tolerated and no new safety signals were observed.

Background Ovarian cancer (OC) remains one of the most challenging and deadly malignancies facing women today. While PARP inhibitors (PARPis) have transformed the treatment landscape for women with advanced OC, many patients will relapse and the PARPi-resistant setting is an area of unmet medical need. Traditional immunotherapies targeting PD-1/PD-L1 have failed to show any benefit in OC. The CD47/TSP-1 axis may be relevant in OC. We aimed to describe changes in CD47 expression with platinum therapy and their relationship with immune features and prognosis. Methods Tumor and blood samples collected from OC patients in the CHIVA trial were assessed for CD47 and TSP-1 before and after neoadjuvant chemotherapy (NACT) and multiplex analysis was used to investigate immune markers. Considering the therapeutic relevance of targeting the CD47/TSP-1 axis, we used the CD47-derived TAX2 peptide to selectively antagonize it in a preclinical model of aggressive ovarian carcinoma. Results Significant reductions in CD47 expression were observed post NACT. Tumor patients having the highest CD47 expression profile at baseline showed the greatest CD4 + and CD8 + T-cell influx post NACT and displayed a better prognosis. In addition, TSP-1 plasma levels decreased significantly under NACT, and high TSP-1 was associated with a worse prognosis. We demonstrated that TAX2 exhibited a selective and favorable biodistribution profile in mice, localizing at the tumor sites. Using a relevant peritoneal carcinomatosis model displaying PARPi resistance, we demonstrated that post-olaparib (post-PARPi) administration of TAX2 significantly reduced tumor burden and prolonged survival. Remarkably, TAX2 used sequentially was also able to increase animal survival even under treatment conditions allowing olaparib efficacy. Conclusions Our study thus (1) proposes a CD47-based stratification of patients who may be most likely to benefit from postoperative immunotherapy, and (2) suggests that TAX2 is a potential alternative therapy for patients relapsing on PARP inhibitors.

Carcinosarcomas (also known as malignant mixed müllerian tumors) are rare and highly aggressive epithelial malignancies that contain both malignant sarcomatous and carcinomatous elements. Uterine carcinosarcomas (UCs) are uncommon with approximately more than 35% presenting with extra uterine disease at diagnosis. Up to 90% ovarian carcinosarcomas (OCs) will have disease that has spread beyond the ovary. Prognosis for localized stage disease is poor with a high risk of recurrences, both local and distant, occurring within 1 year. The survival of women with advanced UC or OC is worse than survival of endometrioid or high-grade serous histologies. No improvement in survival rates has been observed in the past few decades with an overall median survival of less than 2 years. Currently, there is no clear evidence to establish consensus guidelines for therapeutic management of carcinosarcomas. Until recently, gynecological carcinosarcomas were considered as a subtype of sarcoma and treated as such. However, carcinosarcomas are now known to be metaplastic carcinomas and so should be treated as endometrial or ovarian high-risk carcinomas, despite the lack of specific data. For UCs, a comprehensive approach to management is recommended with complete surgical staging followed by systemic chemotherapy in patients with both early and advanced stage disease. Active agents include paraplatin, cisplatin, ifosfamide, and paclitaxel. The combination of carboplatin-paclitaxel is the most commonly used regimen in the adjuvant and advanced setting. Adjuvant radiotherapy (external beam irradiation and/or vaginal brachytherapy) has not shown any overall survival benefit but has been reported to decrease local recurrences. For OCs and for other ovarian epithelial cancer, the mainstay of treatment remains cytoreductive surgical effort followed, even in early stage, by platinum-based chemotherapy, usually carboplatin-paclitaxel.

Background Patients treated for rare ovarian germ cell tumors (GCT) and sex cord stromal tumors (SCST) often experience long-term survival. Treatments include surgery with or without chemotherapy (CT), which can cause late side effects that negatively impact quality of life (QoL). This study assessed long-term QoL among GCT and SCST survivors compared to age-matched healthy women (HW), focusing on patients treated with CT. Methods Cancer-free GCT and SCST survivors (≥ 2 years post-treatment) were recruited from the INCa French Network TMRG. HW were recruited via the “Seintinelles” platform. Participants completed validated questionnaires assessing QoL (FACT-G/FACT-O), fatigue (MFI), anxiety/depression (HADS), insomnia (ISI), neurotoxicity (FACT/GOG-NTX), cognition (FACT-COG), and sexuality (FACT-O OCS). Clinically relevant differences were defined as ≥ 5% between groups. Results A total of 144 survivors (99 GCT and 45 SCST) were included and compared with 284 matched HW (median age: 35.2 years). The median time from the end of treatment was 6 years [Q1 3.5–Q3 9.3]. At inclusion, 42% of patients were menopausal compared to 17% of HW ( p  < 0.001), with reduced sexual QoL. Survivors reported more cognitive impairment (32% vs. 21%, p  = 0.025) and severe neurotoxicity (23% vs. 8%, p  < 0.001). QoL, fatigue, anxiety/depression, and insomnia scores were similar for patients and HW. Conclusions With a median of 6 years after CT, most GCT and SCST survivors reported similar overall QoL compared to HW but faced premature menopause, reduced sexual QoL, and persistent cognitive and neurotoxic effects. Trial registration number NCT03418844.

Background Olaparib, a poly(ADP-ribose) polymerase inhibitor, was approved by the European Commission in June 2019, following the results of the SOLO-1/GOG 3004 trial as maintenance monotherapy in adult patients with BRCA-mutated epithelial ovarian cancer. Objective This study aimed to provide a descriptive analysis of the first real-world data from patients with BRCA-mutated ovarian cancer who received olaparib as first-line maintenance monotherapy in the French cohort Temporary Authorisation for Use (Autorisation Temporaire d’Utilisation de cohorte, ATUc) programme from 11 March, 2019 to 16 January, 2020. Methods Eligible patients were aged 18 years and over with confirmed epithelial ovarian, primary peritoneal or Fallopian tube cancer and a deleterious or suspected deleterious germline or somatic BRCA 1/2 mutation. Patients were in complete or partial clinical response at the end of first-line platinum-based chemotherapy. Olaparib maintenance therapy was initiated within 8 weeks of the patients’ last dose of chemotherapy. Real-world data were collected through treatment access request forms completed by physicians. Clinical and safety data were collected monthly until the end of the ATUc programme. Results A total of 107 centres in metropolitan France and the French Overseas Departments and Territories requested the inclusion for 238 patients, of whom 194 received maintenance olaparib. In total, 87.6% of the primary tumour locations were ovary, the most common histology was high-grade serous (93.0%) and the most common International Federation of Gynaecology and Obstetrics (Fédération Internationale de Gynécologie et d’Obstétrique) stage was IIIC (56.8%). BRCA testing was performed in routine practice, prior to inclusion into the ATUc programme. All patients had a BRCA mutation: 52.5% had a somatic mutation, 38.4% had a germinal mutation and 9.1% had germinal and somatic mutations. Twenty-four (12%) patients experienced serious adverse drug reactions at the last safety follow-up (17 February, 2020). The most common were anaemia (12 [6%] patients), neutropenia (3 [2%] patients) and thrombocytopenia (3 [2%] patients). Conclusions The rapid enrolment into the ATUc programme highlighted the strong unmet need for patients with ovarian cancer and a BRCA mutation in first-line maintenance treatment. Olaparib was well tolerated and no new safety signals were observed in this real-world patient population.

Onapristone is a type I progesterone receptor (PR) antagonist, which prevents PR- mediated DNA transcription. Onapristone is active in multiple preclinical models and two prior studies demonstrated promising activity in patients with breast cancer. We conducted a study of extended release (ER) Onapristone to determine a recommended dose and explore the role of transcriptionally-activated PR (APR), detected as an aggregated subnuclear distribution pattern, as a predictive biomarker. An open-label, multicenter, randomized, parallel-group, phase 1 study (target n = 60; NCT02052128) included female patients ≥18 years with PRpos tumors. APR analysis was performed on archival tumor tissue. Patients were randomized to five cohorts of extended release (ER) onapristone tablets 10, 20, 30, 40 or 50 mg BID, or immediate release 100 mg QD until progressive disease or intolerability. Primary endpoint was to identify the recommended phase 2 dose. Secondary endpoints included safety, clinical benefit and pharmacokinetics. The phase 1 dose escalation component of the study is complete (n = 52). Tumor diagnosis included: endometrial carcinoma 12; breast cancer 20; ovarian cancer 13; other 7. Median age was 64 (36-84). No dose limiting toxicity was observed with reported liver function test elevation related only to liver metastases. The RP2D was 50 mg ER BID. Median therapy duration was 8 weeks (range 2-44), and 9 patients had clinical benefit ≥24 weeks, including 2 patients with APRpos endometrial carcinoma. Clinical benefit with excellent tolerance was seen in heavily pretreated patients with endometrial, ovarian and breast cancer. The data support the development of Onapristone in endometrial endometrioid cancer. Onapristone should also be evaluated in ovarian and breast cancers along with APR immunohistochemistry validation.