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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.

In this report we described the case of a BRCA1/2 (BRCA) molecular testing performed on tumor sample in a High Grade Serous Ovarian Cancer (HGSOC) patient with two different Next Generation Tumor Sequencing (NGTS) pipelines. The two clinical reports leaded to apparently different BRCA status, providing important foods for thought. After NGTS, the gene sequencing information (i.e., reads) are aligned to the reference gene sequences obtained from public databases, in order to provide an uniform nomenclature for unambiguous variant designation. However, the criteria adopted for variant reporting in tissue test are not always univocal. Particularly, this is the case of rare and unclassified BRCA variants for which the molecular evaluation may be a relevant challenge. Here we described a BRCA1 unclassified variant that may be re-evaluated in the context of alternative BRCA1 transcripts due to its different biological effect. We underlined that an in-depth knowledge of BRCA testing is mandatory for its appropriate use.

Several genes associated with hereditary ovarian cancer have been discovered as a result of the work done with next generation sequencing. It is estimated that approximately 23% of ovarian carcinomas have a hereditary predisposition. The most common hereditary condition is represented by germline mutations in BRCA1 or BRCA2 genes that account for 20–25% of high grade serous ovarian cancer. A number of other hereditary ovarian cancers are associated with different genes, with a crucial role in the DNA damage response pathway, such as the mismatch repair genes in Lynch syndrome, TP53 in Li-Fraumeni syndrome, STK11 in Peutz-Jeghers syndrome, CHEK2, RAD51, BRIP1, and PALB2. The goal of this manuscript is to summarize the published data regarding the molecular pathways involved in the pathogenesis of non-BRCA related hereditary ovarian cancer and to provide a tool that might be useful in discussing risk assessment, genetic testing, prevention strategies, as well as clinical and therapeutic implications for patients with ovarian cancer.

PTEN is a tumour suppressor gene, and its loss of function is frequently observed in both heritable and sporadic cancers. It is involved in a great variety of biological processes, including maintenance of genomic stability, cell survival, migration, proliferation and metabolism. A better understanding of PTEN activity and regulation has therefore emerged as a subject of primary interest in cancer research. Gynaecological cancers are variously interested by PTEN deregulation and many perspective in terms of additional prognostic information and new therapeutic approaches can be explored. Here, we present the most significant findings on PTEN in gynaecological cancers (ovarian, endometrial, cervical, vulvar and uterine cancer) focusing on PTEN alterations incidence, biological role and clinical implications.

Human papillomavirus (HPV) infection is the recognized cause of almost all cervical cancers. Despite the reduction in incidence due to a wide use of screening programs and a specific vaccine, the prognosis of cervical cancer remains poor, especially for late-stage and relapsed disease. Considering the elevated rates of PD-L1 expression in up to 80% of cervical cancers, a strong rationale supports the use of immunotherapy to restore the immune response against tumor. The aim of this review is to analyze the possible role of immune checkpoint inhibitors in cervical cancer treatment, with a particular focus on the rationale and on the results of phase I and II clinical trials. An overview of ongoing phase III studies with possible future areas of development is also provided.

Correspondence to Ms Anna Fagotti, Woman and Child's Health Department, Universita Cattolica del Sacro Cuore Facolta di Medicina e Chirurgia, Roma, Italy; annafagotti70@gmail.com We read with great interest the recently published ASCO guidelines regarding the need for genomic testing in patients with epithelial ovarian cancer.1 The authors made a notable effort to further the field as it pertains to germline and somatic mutations in patients with epithelial ovarian cancer and to personalize its management. Formalin-fixed, paraffin-embedded quality, different DNA extraction protocols, and level of DNA integrity testing may influence the quality of the extracted DNA, muddying sequencing and subsequent analysis.3 More recently, fresh frozen tissue has been proposed as an alternative procedure.4 5 This tissue handling seems to minimize damage to nucleotides, allowing extraction of high-quality DNA, enabling the identification of gBRCA large genomic rearrangements in tumor tissue.6 Indeed, 10 of 12 tBRCA wild-type samples were due to large genomic rearrangements, reported by Myriad test but not detected by Foundation Medicine Kit. With this regard, in 456 patients with high-grade serous carcinoma, we found that commitment of all professionals enables fresh-frozen, tissue-based BRCA testing to identify up to 32% of patients with the tBRCA mutation (including those with germline large genomic rearrangements), ruling out 6% of women who would have been missed if only gBRCA testing had been performed.7 Lastly, it remains unclear which is the most cost-effective approach.8 According to the ASCO guidelines,1 all patients with epithelial ovarian cancer with no gBRCA mutation will require tumor testing to unmask the presence of a somatic mutation.

BackgroundNeoadjuvant chemotherapy with interval debulking surgery represents an alternative treatment for advanced ovarian cancer. Currently, there are few data about the use of poly adenosine diphosphate-ribose polymerase inhibitors in the neoadjuvant setting.Primary ObjectiveTo evaluate whether the administration of olaparib in combination with standard chemotherapy in the neoadjuvant setting can improve tumor response.Study HypothesisThe addition of a poly adenosine diphosphate-ribose polymerase inhibitor to standard chemotherapy will achieve a higher response rate in BRCA mutated patients compared with standard chemotherapyTrial DesignThis is a multicenter, phase II, single arm, open label trial. Eligible patients will receive three cycles of weekly carboplatin plus paclitaxel, and intermittent olaparib administration. Responding patients will undergo an interval debulking surgery with pathological evaluation of response to chemotherapy.Major Eligibility CriteriaPatients must have histologically confirmed International Federation of Gynecology and Obstetrics stages III–IV primary ovarian, peritoneal, or fallopian tube cancers, high grade serous or endometrioid histology, not suitable for primary cytoreductive surgery with a documented BRCA1 or BRCA2 germline and/or somatic mutation.Primary EndpointRate of complete pathological response after three cycles of the experimental chemotherapy regimen.Sample SizeA total of 35 patients will be enrolled in the study.Estimated Dates for Completing Accrual and Presenting ResultsExpected complete 42 accrual in January 2022, with presentation of results by June 2022.Trial Registration Number NCT04261465

First - line treatment with bevacizumab should be offered to BRCA wild-type patients . 3 4 Dr Minucci Would you perform somatic BRCA testing, based on positive gBRCA test results? if so, why, how, and when? [...]in (-) gBRCA patients , the tBRCA testing conducted on a diagnostic biopsy or a primary staging or cytoreductive surgery, can identify the variants acquired as somatic mutations in addition to constitutional defect and, although a 3 % of discrepancy has been proposed, up to a 100 % concordance between tBRCA and gBRCA tests has been found when high - quality procedures are performed . 6 In addition, considering that now search ing for the largest genomic rearrangement from tumor analysis is possible, we underline that tBRCA may become the preferred method to detect both exclusive somatic and germline PVs, including copy number variations/large genomic rearrangements in HGSOC patients , replacing the gBRCA. 7 Only, in the event of a positive result, must the alteration be verified in peripheral blood in order to ascertain its constitutional origin. [...]at this time, genetic counseling is recommended both when genetic testing is offered to the patient and after genetic test results are disclosed. [...]somatic PVs in BRCA1 and BRCA2 are observed in approximately 3.5 % – 8.5 % and 2.5 % – 4 % of high-grade serous ovarian cancer patients without an underlying germline gPVs, respectively. 1 Moreover, tBRCA testing can provide useful information also to (+) gBRCA patients .

The advent of Precision Medicine has globally revolutionized the approach of translational research suggesting a patient-centric vision with therapeutic choices driven by the identification of specific predictive biomarkers of response to avoid ineffective therapies and reduce adverse effects. The spread of “multi-omics” analysis and the use of sensors, together with the ability to acquire clinical, behavioral, and environmental information on a large scale, will allow the digitization of the state of health or disease of each person, and the creation of a global health management system capable of generating real-time knowledge and new opportunities for prevention and therapy in the individual person (high-definition medicine). Real world data-based translational applications represent a promising alternative to the traditional evidence-based medicine (EBM) approaches that are based on the use of randomized clinical trials to test the selected hypothesis. Multi-modality data integration is necessary for example in precision oncology where an Avatar interface allows several simulations in order to define the best therapeutic scheme for each cancer patient.