Atezolizumab and chemotherapy for advanced or recurrent endometrial cancer (AtTEnd): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: At the time of AtTEnd trial design, standard treatment for advanced or recurrent endometrial cancer included carboplatin and paclitaxel chemotherapy. This trial assessed whether combining atezolizumab with chemotherapy might improve outcomes in this population. METHODS: AtTEnd was a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial done in 89 hospitals in 11 countries across Europe, Australia, New Zealand, and Asia. Enrolled patients were aged 18 years or older, and had advanced or recurrent endometrial carcinoma or carcinosarcoma, an Eastern Cooperative Oncology Group performance status of 0-2, and received no previous systemic chemotherapy for recurrence. Patients were randomly assigned (2:1) using an interactive web response system (block size of six) to either atezolizumab 1200 mg or placebo given intravenously with chemotherapy (carboplatin at area under the curve of 5 or 6 and paclitaxel 175 mg/m2 intravenously on day 1 every 21 days) for 6-8 cycles, then continued until progression. Stratification factors were country, histological subtype, advanced or recurrent status, and mismatch repair (MMR) status. Participants and treating clinicians were masked to group allocation. The hierarchically tested co-primary endpoints were progression-free survival (in patients with MMR-deficient [dMMR] tumours, and in the overall population) and overall survival (in the overall population). Primary analyses were done in the intention-to-treat population, defined as all randomly assigned patients who gave their full consent to participation in the study and data processing. Safety was assessed in all patients included in the intention-to-treat population who received at least one dose of study treatment. Here, we report the primary progression-free survival and the interim overall survival results. This study is ongoing and is registered with ClinicalTrials.gov, NCT03603184. FINDINGS: Between Oct 3, 2018, and Jan 7, 2022, 551 patients were randomly assigned to atezolizumab (n=362) or placebo (n=189). Two patients in the atezolizumab group were excluded from all analyses due to lack of consent. Median follow-up was 28·3 months (IQR 21·2-37·6). 81 (23%) patients in the atezolizumab group and 44 (23%) patients in the placebo group had dMMR disease by central assessment. In the dMMR population, median progression-free survival was not estimable (95% CI 12·4 months-not estimable [NE]) in the atezolizumab group and 6·9 months (6·3-10·1) in the placebo group (hazard ratio [HR] 0·36, 95% CI 0·23-0·57; p=0·0005). In the overall population, median progression-free survival was 10·1 months (95% CI 9·5-12·3) in the atezolizumab group and 8·9 months (8·1-9·6) in the placebo group (HR 0·74, 95% CI 0·61-0·91; p=0·022). Median overall survival was 38·7 months (95% CI 30·6-NE) in the atezolizumab group and 30·2 months (25·0-37·2) in the placebo group (HR 0·82, 95% CI 0·63-1·07; log-rank p=0·048). The p value for the interim analysis of overall survival did not cross the stopping boundary; therefore, the trial will continue until the required number of events are recorded. The most common grade 3-4 adverse events were neutropenia (97 [27%] of 356 patients in the atezolizumab group vs 51 [28%] of 185 in the placebo group) and anaemia (49 [14%] vs 24 [13%]). Treatment-related serious adverse events occurred in 46 (13%) patients in the atezolizumab group and six (3%) patients in the placebo group. Treatment-related deaths occurred in two patients (pneumonia in one patient in each group). INTERPRETATION: Atezolizumab plus chemotherapy increased progression-free survival in patients with advanced or recurrent endometrial carcinoma, particularly in those with dMMR carcinomas, suggesting the addition of atezolizumab to standard chemotherapy as first-line treatment in this specific subgroup. FUNDING: F Hoffmann-La Roche.

A Rare Association Between Osteomalacia, Phosphaturic Mesenchymal Tumor, and Ovarian Cancer: A Case Report and Literature Review.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by hypophosphatemia, bone mineralization disorders with increased risk of fragility fractures, muscle pain, and progressive weakness. TIO has been associated with increased production of the phosphaturic hormone Fibroblast Growth Factor 23 (FGF23) usually by mesenchymal tumors of soft tissue or bone (Phosphaturic Mesenchymal Tumors-PMTs). In rare cases TIO may be observed in association with other malignancies. We report the case of a 66-year-old woman with an occasional diagnosis of both a PMT and an ovarian cancer during the evaluation of TIO. We also systematically review the literature to discover possible correlations between osteomalacia, FGF23 production, and ovarian cancer. Four studies were eligible for the analysis. Two case reports described an association between TIO development and ovarian cancer, whereas the two case-control studies hypothesized a possible correlation between FGF/FGF receptor axis and cancer development. Although it does not provide conclusive evidence regarding the association between TIO and ovarian cancer, this case report highlights the possibility that in the diagnostic workup of suspected TIO, both FGF23-secreting tumors distinct from PMT and tumors unrelated to the clinical presentation of TIO could be identified. This information is important for guiding successful tumor staging and determining the necessity for surgical intervention and/or eventual adjuvant therapy.

Alpelisib for PIK3CA-mutated advanced gynecological cancers: First clues of clinical activity.

OBJECTIVE: Recurrent gynecological tumors (e.g., endometrial, and ovarian cancers) are incurable diseases; therefore, new treatment options are urgently needed. The PTEN-AKT-PI3K pathway is frequently altered in these tumors, representing a potential treatment target. Alpelisib is an α-specific PI3K inhibitor approved in PIK3CA-mutated advanced breast cancer. We report outcomes from a large series of patients with PIK3CA-mutated gynecological cancers prospectively treated with alpelisib within a controlled program. METHODS: From April 2021 to December 2022, 36 patients with PIK3CA-mutated advanced gynecological cancers received alpelisib 300 mg orally once daily. Objective response (ORR) and disease control (DCR) rates provided measure of the antitumor activity of alpelisib, the primary objective of the study. RESULTS: Included patients had endometrial (17/36 [47%]), ovarian (10/36 [28%]), or other gynecological cancers (9/36 [25%]). Most patients had received 2-3 prior systemic treatments (endometrial, 47·2%; ovarian, 60%; other, 56%), and presented with visceral metastases at baseline (82%, 70%, and 56%, respectively). Overall, 17 different PIK3CA mutations were found, including 53% in the kinase domain (most commonly H1047R) and 36% in the helical domain (most commonly E545K). Overall, the ORR was 28% and DCR was 61%, with the greatest benefit observed in patients with endometrial cancer (35% and 71%, respectively). CONCLUSION: Alpelisib represents an active treatment option in patients with recurrent gynecological cancers harboring a PIK3CA mutation. These findings support the need of biomarker-driven randomized trials of PI3K inhibitors in gynecological cancers.

PARP Inhibitors in Brain Metastases from Epithelial Ovarian Cancer through a Multimodal Patient Journey: Case Reports and Literature Review.

Epithelial ovarian cancer (EOC) is the deadliest gynecological malignancy worldwide. Brain metastasis (BM) is quite an uncommon presentation. However, the likelihood of central nervous system (CNS) metastasization should be considered in the context of disseminated disease. The therapeutic management of BMs is an unmet clinical need, to date. We identified, across different cancer centers, six cases of both BRCA wild-type and BRCA-mutated EOCs spreading to the CNS. They presented either with a single brain lesion or with multiple lesions and most of them had intracranial-only disease. All cases received Poly-ADP ribose polymerase inhibitor (PARPi) maintenance, as per clinical practice, for a long time within a multimodal treatment approach. We also provide an insight into the available body of work regarding the management of this intriguing disease setting, with a glimpse of future therapeutic challenges. Despite the lack of unanimous guidelines, multimodal care pathways should be encouraged for the optimal disease control of this unfortunate patient subset. Albeit not being directly investigated in BM patients, PARPi maintenance is deemed to have a valuable role in this setting. Prospective research, aimed to implement worthwhile strategies in the multimodal patient journey of BMs from EOC, is eagerly awaited.

The Impact of Neoadjuvant Chemotherapy on Ovarian Cancer Tumor Microenvironment: A Systematic Review of the Literature.

Immunotherapy, particularly the use of immune checkpoint inhibitors (ICIs), has shown limited efficacy in treating ovarian cancer (OC), possibly due to diverse T cell infiltration patterns in the tumor microenvironment. This review explores how neoadjuvant chemotherapy (NACT) impacts the immune landscape of OC, focusing on tumor-infiltrating lymphocytes (TILs), PD-1/PD-L1 expression, and their clinical implications. A comprehensive literature search across four databases yielded nine relevant studies. These studies evaluated stromal (sTILs) and intra-epithelial (ieTILs) TILs before and after NACT. sTIL responses varied, impacting prognostic outcomes, and ieTILs increased in some patients without clear survival associations. PD-L1 expression after NACT correlated with improved overall survival (OS), and increases in granzyme B+ and PD-1 correlated with longer progression-free survival (PFS). Remarkably, reduced FoxP3+ TILs post-NACT correlated with better prognosis. NACT often increases sTIL/ieTIL and CD8+ subpopulations, but their correlation with improved PFS and OS varies. Upregulation of co-inhibitory molecules, notably PD-L1, suggests an immunosuppressive response to chemotherapy. Ongoing trials exploring neoadjuvant ICIs and chemotherapy offer promise for advancing OC treatment. Standardized measurements assessing TIL density, location, and heterogeneity are crucial for addressing genetic complexity and immunological heterogeneity in OC.

Consensus statements and treatment algorithm to guide clinicians in the selection of maintenance therapy for patients with newly diagnosed, advanced ovarian carcinoma: Results of a Delphi study.

INTRODUCTION: Standard treatment of newly diagnosed, advanced ovarian carcinoma (OC) consists of cytoreductive surgery followed by platinum-based chemotherapy with or without bevacizumab. Maintenance therapy with PARP inhibitors and olaparib-bevacizumab has recently shown to significantly improve progression-free survival in the first-line setting. Some practical aspects of maintenance therapy, however, are still poorly defined. AIM OF THE STUDY: To provide guidance to clinicians in the selection of maintenance therapy for newly diagnosed, advanced ovarian carcinoma. METHODS: A board of six gynecologic oncologists with expertise in the treatment of OC in Italy convened to address issues related to the new options for maintenance treatment. Based on scientific evidences, the board produced practice-oriented statements. Consensus was reached via a modified Delphi study that involved a panel of 22 experts from across Italy. RESULTS: Twenty-seven evidence- and consensus-based statements are presented, covering the following areas of interest: use of biomarkers (BRCA mutations and presence of homologous recombination deficiency); timing and outcomes of surgery; selection of patients eligible for bevacizumab; definition of response to treatment; toxicity and contraindications; evidence of synergy of bevacizumab plus PARP inhibitor. Two treatment algorithms are also included, for selecting maintenance therapy based on timing and outcomes of surgery, response to platinum-based chemotherapy and biomarker status. A score for the assessment of response to chemotherapy is proposed, but its validation is ongoing. CONCLUSIONS: We provide here consensus statements and treatment algorithms to guide clinicians in the selection of appropriate and personalized maintenance therapy in the first-line setting of advanced OC management.

Synchronous Endometrial and Ovarian Carcinomas: Pathologic and Molecular Analysis Highlights the Monoclonal Origin of the Lesions.

The diagnosis of synchronous carcinomas, involving both the endometrium and ovaries, is not a rare finding in gynecologic pathology and represents a challenge with implications on tumor staging and therapeutic decision-making. A mono-institutional series of 11 metastatic and 6 paired synchronous endometrial and ovarian carcinomas were reviewed by 2 expert pathologists based on previously published histopathologic criteria. The series was investigated for DNA mismatch repair proteins, p53, and POLE status and was subject to DNA-based next-generation sequencing targeting 67 cancer-related genes. Out of 17 pairs, 16 featured the same histotype (10 endometrioid, 4 serous high-grade, and 2 clear cells). By using WHO 2020 criteria, 11 couples of tumors were confirmed as metastatic and 6 couples were confirmed as independent. Based on next-generation sequencing analysis, 16 of 17 cases (11 metastatic and 5 independent) of our series showed evidence of a clonal relationship between endometrial and ovarian carcinomas. In metastatic cases, the adverse outcome was associated with nonendometrioid/high-grade endometrioid histotype and with the p53-abnormal molecular subtype. Four cases originally fulfilling clinicopathological criteria of independent endometrial and ovarian carcinomas were clonally related, low-grade endometrioid histotype and POLE-mut, mismatch repair deficient, and no specific molecular profile molecular subtypes; no adverse event was recorded in this group. In summary, the molecular characterization of synchronous gynecologic carcinomas confirms their clonal origin in most cases. However, the results of our study point out that the clinical behavior of these tumors seems to be determined by the presence of high-risk WHO 2020 histologic criteria and molecular features (i.e. p53-abnormal), rather than the monoclonal origin.

Randomized phase II trial of weekly paclitaxel vs. cediranib-olaparib (continuous or intermittent schedule) in platinum-resistant high-grade epithelial ovarian cancer.

BACKGROUND: Previous findings showed that cediranib-olaparib increased PFS in women with recurrent platinum-sensitive ovarian cancer compared to olaparib alone. METHODS: BAROCCO trial randomized 123 patients: 80mg/m2 paclitaxel weekly up to 24 weeks (control), olaparib 300mg tablets twice daily together with 20mg cediranib daily (continuous schedule) or with 20mg cediranib 5 days/week (intermittent schedule) until progression. The primary objective was the PFS comparison between each experimental arm and the control (alpha one-sided 5%; power 80%; HR 0.5). RESULTS: The median platinum-free interval was 1.9 months, 60% of patients had been pretreated with 3 or more chemotherapy lines. Median PFS for paclitaxel, the continuous, and the intermittent schedules were 3.1, 5.6, and 3.8 months. The HR for PFS in the continuous arm vs control was 0.76 (90% CI: 0.50-1.14, p = 0.265). The HR for PFS in the intermittent arm vs control was 1.03 (90% CI: 0.68-1.55, p = 0.904). Treatment was discontinued due to adverse events in 15%, 20%, and 5% of patients in the control, continuous and intermittent arms. Grade ≥ 3 anemia and diarrhea and hypertension of any grade occurred only in the experimental arms, and peripheral neuropathies and alopecia only in the control arm. Five serious adverse drug reactions occurred and two were fatal: one in the control and one in the continuous arm. CONCLUSIONS: The combination of cediranib-olaparib was not superior to chemotherapy in terms of PFS in heavily pretreated platinum-resistant ovarian cancer patients. However, this oral doublet, is active and may offer a non-chemotherapy option in this difficult to treat population. CLINICAL TRIAL IDENTIFICATION: IRFMN-OVA-7289, EudraCT: 2016-003964-38, NCT03314740.

Sharing real-world experiences to optimize the management of olaparib toxicities: a practical guidance from an Italian expert panel.

Olaparib is the first poly(ADP-ribose) polymerase inhibitor approved as maintenance therapy of recurrent ovarian cancer (OC) patients with a BRCA mutation. To achieve the maximum clinical benefit, adherence to olaparib must be persistent. However, in clinical practice, this is challenged by the frequent suboptimal management of toxicities. In view of the expanding use of olaparib also in Italy, physicians must learn how to adequately and promptly manage drug toxicities not to unnecessarily interrupt or reduce the dose. The experts agreed that nausea,vomiting, anemia, and fatigue are the most frequent events experienced by OC patients on olaparib, and that these toxicities usually develop early during treatment, are mainly of grade 1-2 and transient and can be managed with simple non-pharmacological interventions. By sharing their real-world experiences, the panel prepared, for each toxicity, an algorithm organized by grade and besides the procedures indicated in the local label, included supportive care interventions based also on nutritional and lifestyle modifications and psycho-oncology consultation. Moreover, in view of the tablet entry into the Italian market, the full and reduced dosages of capsules and tablets were compared. This practical guidance is intended to be a tool to support especially less-experienced physicians in the management of these complex patients, with the aim to help preventing the worsening of patients' conditions and the unnecessary interruption/reduction of olaparib dosage, which may jeopardize treatment efficacy.

Use of scalp cooling device to prevent alopecia for early breast cancer patients receiving chemotherapy: A prospective study.

Chemotherapy-induced alopecia (CIA) affects the majority of patients receiving chemotherapy (CT) for early breast cancer. It is a highly distressing side effect of CT, with psychological and social impact. Primary aim of the present analysis was to assess the efficacy of scalp cooling with DigniCap® in preventing CIA. Success rate was defined as patients' self-reported hair loss <50% according to Dean scale. In this analysis, we reported success rate at 3 weeks after the first CT course and at 3 weeks after the last CT course. Secondary endpoints included self-reported tolerability and patients' judgment on scalp cooling performance. Consecutive early breast cancer patients admitted to Istituto Oncologico Veneto who were recommended to receive neoadjuvant or adjuvant CT, were eligible to undergo scalp cooling during the CT administration within this study. 135 patients were included: 74% received adjuvant CT and 26% neoadjuvant CT (P < .001). The type of CT was: docetaxel-cyclophosphamide (26%), paclitaxel (23%), epirubicin-cyclophosphamide followed by paclitaxel (32%), and paclitaxel followed by epirubicincyclophosphamide (19%). The rate of success in preventing alopecia was 77% (104/135) at 3 weeks from the start of CT and 60% (81/135) at 3 weeks from the end of treatment. Higher success rates were reported in non-anthracycline (71%) compared to anthracycline-containing CT regimens (54%; P < 0.001). Premature discontinuation of scalp cooling was reported in 29/135 patients (21.5%), including withdrawal for alopecia (16/29), for low scalp cooling tolerability (8/29) or both (5/29). Scalp cooling was generally well tolerated. These results overall suggest that the use of scalp cooling is effective in preventing alopecia in the majority of early breast cancer patients receiving neoadjuvant or adjuvant CT, especially for patients undergoing a taxane-based non-anthracycline regimen.