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PolyADP-ribose polymerase (PARP) inhibitors (PARPis) represent the first clinically approved drugs able to provoke “synthetic lethality” in patients with homologous recombination-deficient (HRD) tumors. Four PARPis have just received approval for the treatment of several types of cancer. Besides, another three additional PARPis underlying the same mechanism of action are currently under investigation. Despite the success of these targeted agents, the increasing use of PARPis in clinical practice for the treatment of different tumors raised the issue of PARPis resistance, and the consequent disease relapse and dismal prognosis for patients. Several mechanisms of resistance have been investigated, and ongoing studies are currently focusing on strategies to address this challenge and overcome PARPis resistance. This review aims to analyze the mechanisms underlying PARPis resistance known today and discuss potential therapeutic strategies to overcome these processes of resistance in the future.

Background This study was designed to evaluate the positron emission tomography–laparoscopy-based method in the prediction of complete/optimal cytoreduction in platinum sensitive recurrent epithelial ovarian cancer patients. Methods We analysed 223 consecutive recurrent epithelial ovarian cancer patients. Inclusion criteria were absence of extra-abdominal disease and Eastern Cooperative Oncology Group Performance Status ≤2. Complete and optimal secondary cytoreduction are defined as macroscopic absence or less than 1 cm of residual tumor at the end of surgery. Results Laparoscopy was feasible in 210 of 223 patients (94.2 %). Laparoscopy stated 127 (60.5 %) possible cytoreductions and 83 (39.5 %) systemic chemotherapies. In the same population, AGO score evaluation avowed 150 possible cytoreduction (71.5 %) and 60 unresectable women (28.5 %). Overall, 115 of 210 patients (54.7 %) underwent successful secondary cytoreduction: complete and optimal cytoreduction was obtained in 103 (89.5 %) and 12 (10.5 %) patients, respectively. Laparoscopy obtained a positive predictive value of 91.3 %. Laparoscopy recovered to secondary cytoreduction 13 of 60 patients (21.7 %) deemed as not resectable according to AGO score. Forty-eight of 150 AGO score positive patients (32 %) were judged nonresectable by laparoscopy. Conclusions This study confirmed that laparoscopy could be effective for the selection of platinum-sensitive recurrent epithelial ovarian cancer patients suitable for complete cytoreduction.

Ovarian cancer treatment strategy is mainly based on three pillars: cytoreductive surgery, platinum-based chemotherapy, and targeted therapies. The latter in the last decade has provided a remarkable improvement in progression free patients and, hopefully, in overall survival. In particular, poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors exploit BRCA 1/2 mutations and DNA damage response deficiencies, which are believed to concern up to 50% of high grade epithelial ovarian cancer cases. While these agents have an established role in ovarian cancer treatment strategy in BRCA mutated and homologous recombination deficient patients, an appropriate predictive molecular test to select patients is lacking in clinical practice. At the same time, the impressive results of immunotherapy in other malignancies, have opened the space for the introduction of immune-stimulatory drugs in ovarian cancer. Despite immune checkpoint inhibitors as a monotherapy bringing only modest efficacy when assessed in pretreated ovarian cancer patients, the combination with chemotherapy, anti-angiogenetics, PARP inhibitors, and radiotherapy is believed to warrant further investigation. We reviewed literature evidence on PARP inhibitors and immunotherapy in ovarian cancer treatment.

ObjectiveNext-generation sequencing (NGS) analysis has become an essential tool for endometrial carcinoma management. Moreover, molecular-driven therapies play an increasingly remarkable role in the era of precision oncology. This study aims to determine the clinical relevance of NGS testing in endometrial carcinoma management by analyzing the clinical benefit of NGS-driven targeted therapies.MethodsA single-center retrospective study was conducted on 25 endometrial carcinoma patients who underwent Foundation Medicine CDx assay at Fondazione Policlinico Universitario Agostino Gemelli, IRCCS (Rome, Italy). Tumor samples were analyzed by Foundation One CDx. A descriptive analysis of tumor genome profiles was performed. Assessment of clinical benefit according to RECIST 1.1 criteria was analyzed for patients who received a tailored treatment according to actionable targets identified by NGS testing.ResultsOut of 25 endometrial carcinoma patients, 11 received targeted therapy. One patient was excluded from the clinical benefit assessment because of COVID-19-related death 1 month after starting the treatment. Eight of the remaining 10 patients benefited from targeted therapies, with an overall clinical benefit rate of 80%. A targeted agent belonging to the PI3K pathway was given to seven patients, with evidence of three partial responses (42.9%), three stable diseases (42.9%), and one progressive disease (14.2%) according to RECIST 1.1 criteria. One complete response (33.3%), one stable disease (33.3%), and one progressive disease (33.3%) were observed in the three patients treated with poly(ADP-ribose) polymerase (PARP) inhibitors according to their homologous recombination deficiency (HRD) status.ConclusionThis study highlights the importance of characterizing the mutation profile of patient tumors through NGS. Our findings suggest a clinical benefit of using NGS-driven targeted therapies in endometrial carcinoma patients. However, this personalized approach could benefit the health system in terms of cost-effectiveness by reducing the costs of inappropriate, ineffective, and often expensive treatments.

Introduction/BackgroundCervical cancer is the fourth most common cancer in women worldwide and almost 50% of cases are diagnosed in women younger than 35 years old. According to international guidelines, fertility sparing treatment in young patients is evaluated in early-stage disease with tumors <4 cm, negative nodes and non-aggressive histological subtype. Glassy cell cervical carcinoma (GCCC) is an extremely rare poorly differentiated carcinoma, characterized by aggressive behavior and poor prognosis and with no indication of fertility sparing approach. We reported our experience with GCCC with focus on conservative treatment.MethodologyWe collected clinical data, survival analysis, relapse rates of patients with diagnosis of GCCC from two institutes between 2000 and 2021.ResultsA total of twentyone cases were identified and collected, regardless of the stage. Median age was 48 years old (range 29–67). According to the 2009 FIGO staging system most patients had a stage IIB (8, 38%). Radical hysterectomy was performed in 12 cases (57%) and adjuvant treatment was proposed based on pathological risk factors. Nine patients (43%) underwent neoadjuvant treatment. Relapse was reported in six (28%) patients with a median time of 6 months (range 1–21) and 62% (13) died of disease. After counseling two nulliparous young patients with FIGO stage Ib1 opted for fertility sparing approach. Both of them had pregnancy during follow-up time. One patient performed cerclage due to cervical insufficiency at 13 weeks and had a vaginal delivery at 37 weeks. The other one decided for a cesarean section after 37 weeks. Obstetrics outcome was excellent. Currently, the patients have no evidence of disease.ConclusionGCCC is a very aggressive histological subtype with poor outcome. Radical hysterectomy is the standard of care in an early stage due at the unfavorable prognosis. For our experience fertility sparing surgery may be considered as an option for well selected patients.DisclosuresNothing to declare.

Purpose To assess the rate of bilateral sentinel lymph node (SLN) detection with indocyanine green (ICG), to evaluate the sensitivity and the negative predictive value of cervical cancer patients undergoing open radical hysterectomy; to compare open versus minimally invasive SLN biopsy performance and to assess factors related to no/unilateral SLN mapping. Methods We retrospectively reviewed consecutive patients with FIGO 2018 stage IA1 with lymph-vascular space involvement to IIB and IIIC1p cervical carcinoma who underwent SLN mapping with ICG followed by systematic pelvic lymphadenectomy between 05/2017 and 06/2020. Patients were divided according to surgical approach for statistical analysis. Results Eighty-five patients met inclusion criteria. Twenty-seven (31.8%) underwent open and 58 (68.2%) underwent minimally invasive SLN mapping. No difference in any SLN mapping (laparotomy 92.6% and minimally invasive 91.4%) or in SLN bilateral detection (laparotomy 72.0% and minimally invasive 84.9%) ( p  = 0.850 and p  = 0.222, respectively), in median number of SLNs mapped and retrieved (2 in both groups, p  = 0.165) and in site of SLN mapping per hemi-pelvis (right side, p  = 0273 and left side, p  = 0.618) was evident between open and minimally invasive approach. Per-patient sensitivity of SLN biopsy in laparotomy was 83.3% (95% CI 35.9–99.6%) and the negative predictive value was 95.0% (95% CI 76.0–99.1%). No difference in per-patient sensitivity was noted between two approaches ( p  = 0.300). None of the analyzed variables was associated with no/unilateral SLN mapping. Conclusion The use of ICG to detect SLN in cervical cancer treated with open surgery allows a bilateral detection, sensitivity and negative predictive value comparable to minimally invasive surgery with potential advantages of ICG compared to other tracers.

ObjectiveCorrelation between BRCA1/2 (BRCA) pathogenic variants and the response to poly (ADP-ribose) polymerase inhibitors (PARPi) has been recognized in patients with ovarian cancer. Moreover, data on the clinical implications of variants of unknown significance are lacking. The aim of this study was to evaluate differences in survival outcomes in patients with BRCA variants of unknown significance, mutated, and wild type relapsed ovarian cancer treated with PARPi.MethodsPatients with ovarian cancer whose somatic BRCA testing was available and who were receiving PARPi as maintenance treatment at the first recurrence between January 2014 and January 2021 were included in the present study and analyzed. Patients were divided into three groups according to BRCA mutational status (variant of unknown significance, mutated, and wild type). Progression-free survival was assessed in each study group.ResultsOf 67 patients identified, 20 (29.9%), 24 (35.8%), and 23 (34.3%) had BRCA variant of unknown significance, mutated, and wild type, respectively. Patients received PARPi as maintenance treatment at the time of the first relapse after a complete response or partial response to platinum-based chemotherapy without differences in the previous platinum-free interval among the analyzed groups. The median progression-free survival of patients with BRCA mutation was significantly longer than for those with BRCA wild type or variant of unknown significance (not reached vs 4 months vs 7 months, respectively; p<0.001). Additionally, no significant difference was found between patients with BRCA wild type and BRCA variant of unknown significance (p=0.50).ConclusionOur study suggests that carriers of BRCA variant of unknown significance have survival outcomes comparable to patients with BRCA wild type and shorter progression-free survival than women harboring BRCA pathogenic variants.

ObjectivesThe treatment choice in locally advanced cervical cancer (LACC) ranges from concurrent chemoradiation to neoadjuvant chemotherapy followed by radical surgery (RS); however, the rates of 5-year Progression Free Survival (PFS) (55%) and Overall Survival (OS) (63%) remain largely disappointing. Up to 92% of CC display high PD-L1 levels; therefore, the addition of anti-PD-1 immunotherapy may improve LACC prognosis. MITO CERV 3 trial aims at exploring the addition of Pembrolizumab to standard chemotherapy in PD-L1 positive patients (PDL1>1%).MethodsMITO CERV 3 is a single arm multicenter phase II trial evaluating the role of Pembrolizumab in combination with chemotherapy in stage IB2-IIB (according to FIGO 2009 classification) CC patients. Patients will receive 3 cycles of neoadjuvant (NAD) Carboplatin AUC 5 + Paclitaxel 175 mg/mq + Pembrolizumab 200 mg q21, followed by RS in non-progressing patients. After surgery, only patients with clinicopathological high risk factors will receive 3 further cycles of adjuvant chemotherapy in combination with Pembrolizumab, followed by Pembrolizumab alone as maintenance until progression or unacceptable toxicity or for up to 35 cycles. The primary endpoint will be PFS. An exploratory analysis on tumor biopsies before and after NAD will be performed, to identify immunogenic and genetic markers of responsiveness or resistance to NAD treatment.ResultsTrial in progress: there are no available results at the time of submission.ConclusionsTrial in progress: there are no available conclusions at the time of submission.

ObjectivesThis is a single arm phase II trial evaluating Pembrolizumab as neoadjuvant treatment before surgical conization and/or partial or radical vulvectomy in patients with pre-neoplastic cervical and vulvar HPV- related high grade lesions. Primary objective of the study is to determine the efficacy of Pembrolizumab in leading histopathologic complete regression of cervical HSIL. Secondary objectives are: to determine the efficacy of Pembrolizumab in leading histopathologic complete regression of VIN 2–3; to evaluate the safety and tolerability of Pembrolizumab in patients with HPV-related pre-neoplastic vulvar and cervical lesions; to determine Pembrolizumab efficacy in the virologic clearance of HPV. Exploratory objectives are: to evaluate tissue immune responses to pembrolizumab in cervical and vulvar samples and to evaluate the influence of vaginal microbiome on Pembrolizumab response.MethodsPatients with histologically confirmed H-SIL and/or VIN 2–3 will be treated with Pembrolizumab 200 mg flat dose every 3 weeks for 5 cycles. Within 4 weeks from the last Pembrolizumab administration patients will be submitted to surgical conization (either cold knife conization or LEEP) and/or partial or radical vulvectomy. During the screening phase patients will receive blood and stool specimen’s collection. Genotyping for HPV will be performed at baseline, surgery and at safety follow up visit.ResultsTrial in progress: there are no available results at the time of submission.ConclusionsTrial in progress: there are no available conclusions at the time of submission