The Prognostic Relevance of Computed Tomography-assessed Skeletal Muscle Index and Skeletal Muscle Radiation Attenuation in Patients With Gynecological Cancer

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Is the endometrial evaluation routinely required in patients with adult granulosa cell tumors of the ovary?

Granulosa cell tumors (GCTs) are the most common estrogen-secreting ovarian tumors; perhaps due to the persistent hyperestrogenism, a wide spectrum of associated endometrial pathologies ranging from endometrial hyperplasia to carcinoma has been documented in patients with GCTs. The aim of this study is to evaluate the incidence of endometrial pathologies in a large series of GCT patients treated in MITO centers

Functional Interaction Between BRCA1 and DNA Repair in Yeast May Uncover a Role of RAD50, RAD51, MRE11A, and MSH6 Somatic Variants in Cancer Development

In this study, we determined if BRCA1 partners involved in DNA double-strand break (DSB) and mismatch repair (MMR) may contribute to breast and ovarian cancer development. Taking advantage the functional conservation of DNA repair pathways between yeast and human, we expressed several BRCA1 missense variants in DNA repair yeast mutants to identify functional interaction between BRCA1 and DNA repair in BRCA1-induced genome instability. The pathogenic p.C61G, pA1708E, p.M775R, and p.I1766S, and the neutral pS1512I BRCA1 variants increased intra-chromosomal recombination in the DNA-repair proficient strain RSY6. In the mre11, rad50, rad51, and msh6 deletion strains, the BRCA1 variants p.C61G, pA1708E, p.M775R, p.I1766S, and pS1215I did not increase intra-chromosomal recombination suggesting that a functional DNA repair pathway is necessary for BRCA1 variants to determine genome instability. The pathogenic p.C61G and p.I1766S and the neutral p.N132K, p.Y179C, and p.N550H variants induced a significant increase of reversion in the msh2Δ strain; the neutral p.Y179C and the pathogenic p.I1766S variant induced gene reversion also, in the msh6Δ strain. These results imply a functional interaction between MMR and BRCA1 in modulating genome instability. We also performed a somatic mutational screening of MSH6, RAD50, MRE11A, and RAD51 genes in tumor samples from 34 patients and identified eight pathogenic or predicted pathogenic rare missense variants: four in MSH6, one in RAD50, one in MRE11A, and two in RAD51. Although we found no correlation between BRCA1 status and these somatic DNA repair variants, this study suggests that somatic missense variants in DNA repair genes may contribute to breast and ovarian tumor development

DNA damage and repair biomarkers in cervical cancer patients treated with neoadjuvant chemotherapy: An exploratory analysis

Cervical cancer cells commonly harbour a defective G1/S checkpoint owing to the interaction of viral oncoproteins with p53 and retinoblastoma protein. The activation of the G2/M checkpoint may thus become essential for protecting cancer cells from genotoxic insults, such as chemotherapy. In 52 cervical cancer patients treated with neoadjuvant chemotherapy, we investigated whether the levels of phosphorylated Wee1 (pWee1), a key G2/M checkpoint kinase, and y-H2AX, a marker of DNA double-strand breaks, discriminated between patients with a pathological complete response (pCR) and those with residual disease. We also tested the association between pWee1 and phosphorylated Chk1 (pChk1), a kinase acting upstream Wee1 in the G2/M checkpoint pathway. pWee1, y-H2AX and pChk1 were retrospectively assessed in diagnostic biopsies by immunohistochemistry. The degrees of pWee1 and pChk1 expression were defined using three different classification methods, i.e., staining intensity, Allred score, and a multiplicative score. y-H2AX was analyzed both as continuous and categorical variable. Irrespective of the classification used, elevated levels of pWee1 and y-H2AX were significantly associated with a lower rate of pCR. In univariate and multivariate analyses, pWee1 and y-H2AX were both associated with reduced pCR. Internal validation conducted through a re-sampling without replacement procedure confirmed the robustness of the multivariate model. Finally, we found a significant association between pWee1 and pChk1. The message conveyed by the present analysis is that biomarkers of DNA damage and repair may predict the efficacy of neoadjuvant chemotherapy in cervical cancer. Further studies are warranted to prospectively validate these encouraging findings

Extra-Nuclear Signaling of Progesterone Receptor to Breast Cancer Cell Movement and Invasion through the Actin Cytoskeleton

Progesterone plays a role in breast cancer development and progression but the effects on breast cancer cell movement or invasion have not been fully explored. In this study, we investigate the actions of natural progesterone and of the synthetic progestin medroxyprogesterone acetate (MPA) on actin cytoskeleton remodeling and on breast cancer cell movement and invasion. In particular, we characterize the nongenomic signaling cascades implicated in these actions. T47-D breast cancer cells display enhanced horizontal migration and invasion of three-dimensional matrices in the presence of both progestins. Exposure to the hormones triggers a rapid remodeling of the actin cytoskeleton and the formation of membrane ruffles required for cell movement, which are dependent on the rapid phosphorylation of the actin-regulatory protein moesin. The extra-cellular small GTPase RhoA/Rho-associated kinase (ROCK-2) cascade plays central role in progesterone- and MPA-induced moesin activation, cell migration and invasion. In the presence of progesterone, progesterone receptor A (PRA) interacts with the G protein Gα13, while MPA drives PR to interact with tyrosine kinase c-Src and to activate phosphatidylinositol-3 kinase, leading to the activation of RhoA/ROCK-2. In conclusion, our findings manifest that progesterone and MPA promote breast cancer cell movement via rapid actin cytoskeleton remodeling, which are mediated by moesin activation. These events are triggered by RhoA/ROCK-2 cascade through partially differing pathways by the two compounds. These results provide original mechanistic explanations for the effects of progestins on breast cancer progression and highlight potential targets to treat endocrine-sensitive breast cancers

Pharmacological Treatment of Advanced, Persistent or Metastatic Endometrial Cancer: State of the Art and Perspectives of Clinical Research for the Special Issue “Diagnosis and Management of Endometrial Cancer”

Patients with metastatic or recurrent endometrial cancer (EC) not suitable for surgery and/or radiotherapy are candidates for pharmacological treatment frequently with unsatisfactory clinical outcomes. The purpose of this paper was to review the results obtained with chemotherapy, hormonal therapy, biological agents and immune checkpoint inhibitors in this clinical setting. The combination of carboplatin (CBDCA) + paclitaxel (PTX) is the standard first-line chemotherapy capable of achieving objective response rates (ORRs) of 43–62%, a median progression-free survival (PFS) of 5.3–15 months and a median overall survival (OS) of 13.2–37.0 months, respectively, whereas hormonal therapy is sometimes used in selected patients with slow-growing steroid receptor-positive EC. The combination of endocrine therapy with m-TOR inhibitors or cyclin-dependent kinase 4/6 inhibitors is currently under evaluation. Disappointing ORRs have been associated with epidermal growth factor receptor (EGFR) inhibitors, HER-2 inhibitors and multi-tyrosine kinase inhibitors used as single agents, and clinical trials evaluating the addition of bevacizumab to CBDCA + PTX have reported conflicting results. Immune checkpoint inhibitors, and especially pembrolizumab and dostarlimab, have achieved an objective response in 27–47% of highly pretreated patients with microsatellite instability-high (MSI-H)/mismatch repair (MMR)-deficient (-d) EC. In a recent study, the combination of lenvatinib + pembrolizumab produced a 24-week response rate of 38% in patients with highly pretreated EC, ranging from 64% in patients with MSI-H/MMR-d to 36% in those with microsatellite stable/MMR-proficient tumors. Four trials are currently investigating the addition of immune checkpoint inhibitors to PTX + CBDCA in primary advanced or recurrent EC, and two trials are comparing pembrolizumab + lenvatinib versus either CBDCA + PTX as a first-line treatment of advanced or recurrent EC or versus single-agent chemotherapy in advanced, recurrent or metastatic EC after one prior platinum-based chemotherapy