In the SOLO2 trial (ENGOT Ov-21; NCT01874353), maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer (PSROC) and BRCA mutation significantly improved progression-free ...survival (PFS) and prolonged overall survival (OS). Following disease progression on olaparib, efficacy of subsequent chemotherapy remains unknown.
We conducted a post-hoc hypothesis-generating analysis of SOLO2 data to determine the efficacy of different chemotherapy regimens following RECIST disease progression in patients who received olaparib or placebo. We evaluated time to second progression (TTSP) calculated from the date of RECIST progression to the next progression/death.
The study population comprised 147 patients who received chemotherapy as their first subsequent treatment after RECIST progression. Of these, 69 (47%) and 78 (53%) were originally randomized to placebo and olaparib arms, respectively. In the placebo-treated cohort, 27/69 and 42/69 received non-platinum and platinum-based chemotherapy, respectively, compared with 24/78 and 54/78, respectively, in the olaparib-treated cohort. Among patients treated with chemotherapy (N = 147), TTSP was significantly longer in the placebo than in the olaparib arm: 12.1 versus 6.9 months hazard ratio (HR) 2.17, 95% confidence interval (CI) 1.47-3.19. Similar result was obtained on multivariable analysis adjusting for prognostic factors at RECIST progression (HR 2.13, 95% CI 1.41-3.22). Among patients treated with platinum-based chemotherapy (n = 96), TTSP was significantly longer in the placebo arm: 14.3 versus 7.0 months (HR 2.89, 95% CI 1.73-4.82). Conversely, among patients treated with non-platinum-based chemotherapy (n = 51), the TTSP was comparable in the placebo and olaparib arms: 8.3 versus 6.0 months (HR 1.58, 95% CI 0.86-2.90).
Following progression from maintenance olaparib in the recurrent setting, the efficacy of platinum-based subsequent chemotherapy seems to be reduced in BRCA1/2-mutated patients with PSROC compared to patients not previously receiving poly (ADP-ribose) polymerase inhibitors (PARPi). The optimal strategy for patients who relapse after PARPi is an area of ongoing research.
•Progression on olaparib may diminish the efficacy of platinum-based subsequent chemotherapy for recurrent ovarian cancer.•The disease progression patterns are similar in patients receiving either olaparib or placebo.•Characterization of the mechanisms of resistance is crucial for the development of new treatments for these patients.
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 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.
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.
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.
•First PARPi trial to show clinically meaningful OS benefit in HRD+ (BRCA/non-BRCA) newly diagnosed advanced ovarian cancer.•5-Year OS rate in HRD+ disease was 66% with olaparib + bevacizumab versus 48% with placebo + bevacizumab.•Forty-six percent of HRD+ patients receiving olaparib + bevacizumab were progression free at 5 years, versus 19% on bevacizumab alone.•No new safety signals were observed, and the incidence of myelodysplastic syndrome/acute myeloid leukemia remained low.•Maintenance olaparib + bevacizumab as a standard of care may enhance potential for cure for HRD+ disease in this setting.
To evaluate the role of laparoscopic (LPS) and laparotomic (LPT) re-staging in patients with incompletely surgically staged ovarian granulosa cell tumors (OGCT).
We conducted a medical chart ...retrospective analysis of all patients with sex cord stromal tumors (SCSTs) who were managed in our division between March 1994 and March 2017. After a complete review of surgical and pathological notes, patients with incomplete staging were restaged according to the FIGO guidelines. Statistical analysis was conducted using Statistical Package version 20.0 for Windows (SPSS, Inc., Chicago, Illinois).
Out of a total of 170 patients SCSTs, 84 patients (49,5%) received primary surgery that included a hysterectomy; 86 patients (50,5%) underwent fertility-sparing surgery. Eighty-one patients (48%) with diagnosis of OGCT were incompletely surgically staged at another institution. We evaluated our results in terms of laparoscopic approach (56 patients) and open treatment (25 patients). Among the IA patient's group, 1 was upstaged to IIB stage and 2 to IIIB; among patients with IC stage, 1 was upstaged to IIA, 2 to IIB and 1 to IIIB stage. Adjuvant chemotherapy was given to the upstaged patients with final stage IIB-IIIC. No statistically significant difference between laparoscopy and open-surgery was detected in terms of upstaged patients after second surgery (p = 0,36).
According to our series, laparoscopic restaging compared to the open approach seems to be a feasible and efficient technique to complete surgical staging in patients with GCTs incorrectly staged. Surgical restaging seems to upstage a considerable number of OGCT, mainly in the initial stage IC group of patients. However, the impact of restaging on final outcome and survival remains to be demonstrated.
•Ovarian granulosa cell tumor (OGCT) represents 3% to 5% of all ovarian neoplasms.•FIGO stage is one of the most important prognostic factors in OGCTs.•Re-staging operation is a reoperation after incomplete evaluation during initial surgery.•To our knowledge, there is no report concerning laparoscopic and laparotomic restaging of OGCT published to date.•Surgical restaging seems to have a role in the management of OGCT, mainly in initial stage IC group of patients.
Homologous recombination repair (HRR) enables fault-free repair of double-stranded DNA breaks. HRR deficiency is predicted to occur in around half of high-grade serous ovarian carcinomas. Ovarian ...cancers harbouring HRR deficiency typically exhibit sensitivity to poly-ADP ribose polymerase inhibitors (PARPi). Current guidelines recommend a range of approaches for genetic testing to identify predictors of sensitivity to PARPi in ovarian cancer and to identify genetic predisposition.
To establish a European-wide consensus for genetic testing (including the genetic care pathway), decision making and clinical management of patients with recently diagnosed advanced ovarian cancer, and the validity of biomarkers to predict the effectiveness of PARPi in the first-line setting. The collaborative European experts’ consensus group consisted of a steering committee (n = 14) and contributors (n = 84). A (modified) Delphi process was used to establish consensus statements based on a systematic literature search, conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.
A consensus was reached on 34 statements amongst 98 caregivers (including oncologists, pathologists, clinical geneticists, genetic researchers, and patient advocates). The statements concentrated on (i) the value of testing for BRCA1/2 mutations and HRR deficiency testing, including when and whom to test; (ii) the importance of developing new and better HRR deficiency tests; (iii) the importance of germline non-BRCA HRR and mismatch repair gene mutations for predicting familial risk, but not for predicting sensitivity to PARPi, in the first-line setting; (iv) who should be able to inform patients about genetic testing, and what training and education should these caregivers receive.
These consensus recommendations, from a multidisciplinary panel of experts from across Europe, provide clear guidance on the use of BRCA and HRR deficiency testing for recently diagnosed patients with advanced ovarian cancer.
•This publication provides European consensus recommendations from a multidisciplinary panel of experts from across Europe.•PRISMA guidelines and a systematic review of the literature were used to guide and support the consensus statements.•The statements provide guidance on BRCA and HRR deficiency testing for recently diagnosed patients with ovarian cancer.•The statements also provide considerations on how testing should be carried out in the clinic.•We believe that consensus documents are an effective means of focussing the opinions of a wide group of experts.
This open-label, multicentre, phase 2 trial evaluated the efficacy and tolerability of the mammalian target of rapamycin inhibitor ridaforolimus in women with advanced endometrial cancer.
Women with ...measurable recurrent or persistent endometrial cancer and documented disease progression were treated with ridaforolimus 12.5 mg intravenously once daily for 5 consecutive days every 2 weeks in a 4-week cycle. The primary end point was clinical benefit response, defined as an objective response or prolonged stable disease of 16 weeks or more.
In all, 45 patients were treated with single-agent ridaforolimus. Clinical benefit was achieved by 13 patients (29%), including 5 (11%) with confirmed partial responses and 8 (18%) with prolonged stable disease. All patients with clinical benefit response received ridaforolimus for more than 4 months. In this heavily pretreated population, the 6-month progression-free survival was 18%. Ridaforolimus was generally well tolerated: adverse events were predictable and manageable, consistent with prior studies in other malignancies. Overall, the most common adverse events were diarrhoea (58%) and mouth sores (56%); most common grade 3 or higher adverse events were anaemia (27%) and hyperglycaemia (11%).
Single-agent ridaforolimus has antitumor activity and acceptable tolerability in advanced endometrial cancer patients. Further clinical evaluation of ridaforolimus is warranted.
Immunotherapy has transformed the endometrial cancer treatment landscape, particularly for those exhibiting mismatch repair deficiency MMRd/microsatellite instability-hypermutated (MSI-H). A growing ...body of evidence supports the integration of immunotherapy with chemotherapy as a first-line treatment strategy. Recently, findings from ongoing trials such as RUBY (NCT03981796), NRG-GY018 (NCT03914612), AtTEnd (NCT03603184), and DUO-E (NCT04269200) have been disclosed.
This paper constitutes a review and meta-analysis of phase III trials investigating the role of immunotherapy in the first-line setting for advanced or recurrent endometrial cancer.
The pooled data from 2320 patients across these trials substantiate the adoption of chemotherapy alongside immunotherapy, revealing a significant improvement in progression-free survival compared to chemotherapy alone hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.62-0.79 across all patient groups. Progression-free survival benefits are more pronounced in MMRd/MSI-H tumors (n = 563; HR 0.33, 95% CI 0.23-0.43). This benefit, albeit less robust, persists in the MMR-proficient/microsatellite stable group (n = 1757; HR 0.74, 95% CI 0.60-0.91). Pooled data further indicate that chemotherapy plus immunotherapy enhances overall survival compared to chemotherapy alone in all patients (HR 0.75, 95% CI 0.63-0.89). However, overall survival data maturity remains low.
The incorporation of immunotherapy into the initial treatment for advanced and metastatic endometrial cancer brings about a substantial improvement in oncologic outcomes, especially within the MMRd/MSI-H subset. This specific subgroup is currently a focal point of investigation for evaluating the potential of chemotherapy-free regimens. Ongoing exploratory analyses aim to identify non-responding patients eligible for inclusion in clinical trials.
•Immunotherapy added to chemotherapy improves disease-free and overall survival in advanced and metastatic endometrial cancer.•Endometrial cancer is the malignancy with the highest prevalence of MMRd/MSI-H.•MMRd/MSI-H is an agnostic biomarker suggesting the efficacy of immunotherapy.•Immunotherapy plus chemotherapy improves progression-free survival even in the MMR-proficient population.
Class II bacteriocins are unmodified membrane-active peptides that act over a narrow spectrum of target bacteria. They bind a specific receptor protein on the membrane to form a pore, leading to ...membrane permeabilization and cell death. However, little is known about the molecular events triggering the pore formation after the bacteriocin recognizes the receptor. It is not clear yet if the pore is the same receptor forced into an open conformation or if the pore results from the bacteriocin insertion and oligomeric assembly in the lipid bilayer. In order to reveal which model is more suitable to explain the toxicity mechanism, in this work we use chimeric peptides, resulting from the fusion of the bitopic membrane protein EtpM with different class II bacteriocins: enterocin CRL35, pediocin PA-1 and microcin V. E. coli strains lacking the specific receptors for these bacteriocins were chosen as expression hosts. As these constructs display a lethal effect when they are heterologously expressed, they are called “suicide probes”. The results suggest that, indeed, the specific receptor would act as a docking molecule more than as a structural piece of the pore, as long as the bacteriocin is somehow anchored to the membrane. These set of chimeric peptides also represent an in vivo system that allows to study the interaction of the bacteriocins with real bacterial membranes, instead of model membranes. Hence, the effects of these suicide probes in membrane fluidity and transmembrane potential were also assessed, using fluorescence spectroscopy. The data show that the different suicide probes are able to increase phospholipid order and depolarize the membranes of receptor-free bacterial cells.
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•Suicide probes are hybrid peptides aimed to study bacteriocins mechanism of action.•Suicide probes are toxic for E. coli even in the absence of the specific receptor.•The receptor would act as an anchor allowing the bacteriocin assembly in the bilayer.•Membrane composition might be an important factor for bacteriocin activity.•Bacteriocins insertion affects bacterial membrane fluidity and membrane potential.
Porous materials can be modified with physical barriers to control the transport of ions and molecules through channels via an external stimulus. Such capability has brought attention toward drug ...delivery, separation methods, nanofluidics, and point-of-care devices. In this context, gated platforms on which access to an electrode surface of species in solution can be reversibly hindered/unhindered on demand are appearing as promising materials for sensing and microfluidic switches. The preparation of a reversible gated device usually requires mesoporous materials, nanopores, or molecularly imprinted polymers. Here, we show how the breath-figure method assembly of graphene oxide can be used as a simple strategy to produce gated electrochemical materials. This was achieved by forming an organized porous thin film of graphene oxide onto an ITO surface. Localized brushes of thermoresponsive poly(N-isopropylacrylamide) were then grown to specific sites of the porous film by in situ reversible addition-fragmentation chain-transfer polymerization. The gating mechanism relies on the polymeric chains to expand and contract depending on the thermal stimulus, thus modulating the accessibility of redox species inside the pores. The resulting platform was shown to reversibly hinder or facilitate the electron transfer of solution redox species by modulating temperature from the room value to 45 °C or vice versa.
Increased Vascular Endothelial Growth Factor Receptor (VEGF) expression in endometrial cancer (EC) is associated with a poor prognosis. Preliminary clinical data reported Bevacizumab effectiveness in ...EC both as single agent and in combination with chemotherapy.
In a phase II trial, patients with advanced (FIGO stage III-IV) or recurrent EC were randomized to receive Carboplatin-Paclitaxel standard dose for 6–8 cycles vs Carboplatin-Paclitaxel and Bevacizumab 15 mg/kg in combination with chemotherapy and maintenance until disease progression or unacceptable toxicity. The primary endpoint was progression free survival (PFS).
108 patients were randomized; PFS (10.5 vs 13.7 months, HR 0.84 p = 0.43), overall response rate (ORR 53.1% vs 74.4%) and overall survival (OS) (29.7 vs 40.0 months, HR 0.71 p = 0.24) resulted in a non-significant increase in Bevacizumab treated patients. The PFS increase became significant when an exploratory analysis with the Breslow test was used. Moreover, patients treated with Bevacizumab experienced a significant increase in 6-month disease control rate (70.4% vs 90.7%). Cardiovascular events were more frequent in the experimental arm (“de novo” grade ≥2 hypertension 21% vs 0% and grade ≥2 thromboembolic events 11% vs 2% in the Bevacizumab vs standard treatment arm, respectively).
Bevacizumab combined with chemotherapy in the treatment of advanced/recurrent EC failed to demonstrate a significant increase in PFS in the MITO END-2 trial. Nevertheless, these preliminary data suggests some effectiveness of the antiangiogenic agent which merits further exploration in a larger population with a better molecular characterization.
•Bevacizumab combined with chemotherapy does not increase PFS in comparison to chemotherapy in recurrent endometrial cancer.•Cardiovascular events were more frequent in the bevacizumab arm.•Secondary endpoint suggests activity of bevacizumab in endometrial cancer which merits further exploration.
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