SEOM-GEICO clinical guideline on epithelial ovarian cancer (2023).

In recent years, the incorporation of new strategies to the therapeutic armamentarium has completely changed the outcomes of epithelial ovarian cancer (EOC). The identification of new predictive and prognostic biomarkers has also enabled the selection of those patients more likely to respond to targeted agents. Nevertheless, EOC is still a highly lethal disease and resistance to many of these new agents is common. The objective of this guideline is to summarize the most relevant strategies to manage EOC, to help the clinician throughout the challenging diagnostic and therapeutic processes and to provide evidence-based recommendations.

Long-term follow-up of efficacy and safety of selinexor maintenance treatment in patients with TP53wt advanced or recurrent endometrial cancer: A subgroup analysis of the ENGOT-EN5/GOG-3055/SIENDO study.

OBJECTIVE: To report long-term efficacy and safety of selinexor maintenance therapy in adults with TP53 wild-type (TP53wt) stage IV or recurrent endometrial cancer (EC) who achieved partial remission (PR) or complete remission (CR) following chemotherapy. METHODS: Analysis of the prespecified, exploratory subgroup of patients with TP53wt EC from the phase 3 SIENDO study was performed. Progression-free survival (PFS) benefit in patients with TP53wt EC and across other patient subgroups were exploratory endpoints. Safety and tolerability were also assessed. RESULTS: Of the 263 patients enrolled in the SIENDO trial, 113 patients had TP53wt EC; 70/113 (61.9%) had TP53wt/proficient mismatch repair (pMMR) EC, and 29/113 (25.7%) had TP53wt/deficient mismatch repair (dMMR) EC. As of April 1, 2024, the median PFS (mPFS) for TP53wt patients who received selinexor compared with placebo was 28.4 versus 5.2 months (36.8-month follow-up, HR 0.44; 95% CI 0.27-0.73). A benefit in mPFS was seen with selinexor versus placebo regardless of MMR status (patients with TP53wt/pMMR EC: 39.5 vs 4.9 months, HR 0.36; 95% CI 0.19-0.71; patients with TP53wt/dMMR EC: 13.1 vs 3.7 months, HR 0.49; 95% CI 0.18-1.34). Selinexor treatment was generally manageable, with no new safety signals identified. CONCLUSION: In the phase 3 SIENDO study, selinexor maintenance therapy showed a promising efficacy signal and a manageable safety profile in the prespecified subgroup of patients with TP53wt EC who achieved a PR or CR following chemotherapy. These results are being further evaluated in an ongoing randomized phase 3 trial (NCT05611931).

Immunotherapy Combined With Standard Therapies in Head and Neck Squamous Cell Carcinoma - A Meta-analysis.

Head and neck squamous cell carcinoma (HNSCC) is a deadly disease with a poor prognosis due to late diagnosis and limited treatment options. Immunotherapy (IT) is emerging as a promising approach, especially after the failure of standard of care therapies (STs). The objective of this systematic review and meta-analysis was to evaluate whether the addition of IT to STs improves outcomes for patients with HNSCC, including overall survival (OS), progression-free survival (PFS), and quality of life (QoL). This review employed the Population Intervention Comparison and Outcome (PICO) framework to identify relevant search terms in electronic databases, and also included supplementary hand searches. Six primary research articles were selected using the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) flow chart, and were critically appraised. Data extraction from these studies was conducted, and a meta-analysis was performed to aid in the generation of forest plots. The addition of IT to standard anticancer therapies was found to enhance patient outcomes, such as OS, PFS, and QoL. The toxicity profile of IT was acceptable, with minimal treatment-related deaths. The most frequently observed adverse events (AE) were related to the skin, followed by hematological toxicities. Based on our analysis, the addition of IT to STs is a suitable treatment option and is supported by current research. However, further studies are needed to investigate factors that influence treatment effectiveness and to develop optimal therapies. To achieve this, we recommend a comprehensive treatment approach that involves the multidisciplinary team (MDT) and patient assessment tools.

Primary results and characterization of patients with exceptional outcomes in a phase 1b study combining PARP and MEK inhibition, with or without anti-PD-L1, for BRCA wild-type, platinum-sensitive, recurrent ovarian cancer.

BACKGROUND: This phase 1b study (ClinicalTrials.gov identifier NCT03695380) evaluated regimens combining PARP and MEK inhibition, with or without PD-L1 inhibition, for BRCA wild-type, platinum-sensitive, recurrent ovarian cancer (PSROC). METHODS: Patients with PSROC who had received one or two prior treatment lines were treated with 28-day cycles of cobimetinib 60 mg daily (days 1-21) plus niraparib 200 mg daily (days 1-28) with or without atezolizumab 840 mg (days 1 and 15). Stage 1 assessed safety before expansion to stage 2, which randomized patients who had BRCA wild-type PSROC to receive either doublet or triplet therapy, stratified by genome-wide loss of heterozygosity status (<16% vs. ≥16%; FoundationOne CDx assay) and platinum-free interval (≥6 to <12 vs. ≥12 months). Coprimary end points were safety and the investigator-determined objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Potential associations between genetic parameters and efficacy were explored, and biomarker profiles of super-responders (complete response or those with progression-free survival [PFS] >15 months) and progressors (disease progression as the best response) were characterized. RESULTS: The ORR in patients who had BRCA wild-type PSROC was 35% (95% confidence interval, 20%-53%) with the doublet regimen (n = 37) and 27% (95% confidence interval, 14%-44%) with the triplet regimen (n = 37), and the median PFS was 6.0 and 7.4 months, respectively. Post-hoc analyses indicated more favorable ORR and PFS in the homologous recombination-deficiency-signature (HRDsig)-positive subgroup than in the HRDsig-negative subgroup. Tolerability was consistent with the known profiles of individual agents. NF1 and MKNK1 mutations were associated with sustained benefit from the doublet and triplet regimens, respectively. CONCLUSIONS: Chemotherapy-free doublet and triplet therapy demonstrated encouraging activity, including among patients who had BRCA wild-type, HRDsig-positive or HRDsig-negative PSROC harboring NF1 or MKNK1 mutations.

Paclitaxel alters melanogenesis and causes pigmentation in the skin of gynecological cancer patients.

BACKGROUND: Paclitaxel (PTX) is a microtubule-stabilizing antineoplastic that has been shown to damage healthy tissues like the skin. Hyperpigmentation can be found among the adverse effects caused by PTX, but the literature is limited and the mechanisms driving PTX-induced pigmentary alterations are unknown. OBJECTIVES: This study aimed to describe the pigmentary alterations caused by PTX and to determine the effects of PTX on melanocytes. METHODS: Pigmentary skin alterations were measured in 20 gynecological cancer patients under PTX treatment by using specific probes, which determine the melanin index and the pigmentation level. Melanocytes were incubated with paclitaxel to analyze melanogenesis markers gene expression, melanin content, and transcription factors activation. RESULTS: Paclitaxel induced alterations in the skin pigmentation with no visible clinical manifestations. Gynecological cancer patients under paclitaxel treatment had an increase in the melanin index and pigmentation levels. In vitro, PTX exposure to melanocytes increased the expression of melanogenesis markers, melanin content, and induced activation of ERK and MITF. CONCLUSIONS: The results suggest that PTX alters pigmentation in patients with no clinically visible manifestations, and these alterations might be driven by its capacity to stimulate melanogenesis on melanocytes through the MITF activation pathway.

Oral Selinexor as Maintenance Therapy After First-Line Chemotherapy for Advanced or Recurrent Endometrial Cancer.

PURPOSE: Selinexor inhibits exportin-1 (XPO1) resulting in nuclear accumulation of tumor suppressor proteins including p53 and has clinical activity in endometrial cancer (EC). The primary end point was to assess progression-free survival (PFS) with once-weekly oral selinexor in patients with advanced or recurrent EC. PATIENTS AND METHODS: ENGOT-EN5/GOG-3055/SIENDO was a randomized, prospective, multicenter, double-blind, placebo-controlled, phase III study at 107 sites in 10 countries. Patients 18 years or older with histologically confirmed EC were enrolled. All had completed a single line of at least 12 weeks of taxane-platinum combination chemotherapy and achieved partial or complete response. Patients were assigned to receive 80 mg oral selinexor once weekly or placebo with 2:1 random assignment (ClinicalTrials.gov identifier: NCT03555422). RESULTS: Between January 2018 and December 2021, 263 patients were randomly assigned, with 174 allocated to selinexor and 89 to placebo. The median PFS was 5.7 months (95% CI, 3.81 to 9.20) with selinexor versus 3.8 months (95% CI, 3.68 to 7.39) with placebo (hazard ratio [HR], 0.76 [95% CI, 0.54 to 1.08]; two-sided P = .126), which did not meet the criteria for statistical significance in the intent-to-treat population. Incorrect chemotherapy response stratification data for 7 (2.7%) patients were identified. In a prespecified exploratory analysis of PFS in audited stratification data, PFS for selinexor met the threshold for statistical significance (HR, 0.71; 95% CI, 0.499 to 0.996; two-sided P = .049). Furthermore, patients with the TP53 wild-type (wt) EC had a median PFS of 13.7 and 3.7 months with selinexor and placebo. The most common grade 3 treatment-related adverse events were nausea (9%), neutropenia (9%), and thrombocytopenia (7%). CONCLUSION: The significance level for PFS was only met in the audited analysis. However, a preliminary analysis of a prespecified exploratory subgroup of patients with TP53wt EC showed promising results with selinexor maintenance therapy.

An Open-label Phase I Study of GDC-0927 in Postmenopausal Women with Locally Advanced or Metastatic Estrogen Receptor-Positive Breast Cancer.

PURPOSE: GDC-0927 is a novel, potent, nonsteroidal, orally bioavailable, selective estrogen receptor (ER) degrader that induces tumor regression in ER+ breast cancer xenograft models. PATIENTS AND METHODS: This phase I dose-escalation multicenter study enrolled postmenopausal women with ER+/HER2- metastatic breast cancer to determine the safety, pharmacokinetics, and recommended phase II dose of GDC-0927. Pharmacodynamics was assessed with [18F]-fluoroestradiol (FES) PET scans. RESULTS: Forty-two patients received GDC-0927 once daily. The MTD was not reached. The most common adverse events (AE) regardless of causality were nausea, constipation, diarrhea, arthralgia, fatigue, hot flush, back pain, and vomiting. There were no deaths, grade 4/5 AEs, or treatment-related serious AEs. Two patients experienced grade 2 AEs of special interest of deep vein thrombosis and jugular vein thrombosis, both considered unrelated to GDC-0927. Following dosing, approximately 1.6-fold accumulation was observed, consistent with the observed half-life and dosing frequency. There were no complete or partial responses. Pharmacodynamics was supported by >90% reduction in FES uptake and an approximately 40% reduction in ER expression, suggesting ER degradation is not the mechanistic driver of ER antagonism. Twelve patients (29%) achieved clinical benefit; 17 patients (41%) showed a confirmed best overall response of stable disease. Baseline levels of ER and progesterone receptor protein and mutant ESR1 circulating tumor DNA did not correlate with clinical benefit. CONCLUSIONS: GDC-0927 appeared to be well tolerated with pharmacokinetics supporting once-daily dosing. There was evidence of target engagement and preliminary evidence of antitumor activity in heavily pretreated patients with advanced/metastatic ER+/HER2- breast cancer with and without ESR1 mutations.

Uterine sarcomas: clinical practice guidelines for diagnosis, treatment, and follow-up, by Spanish group for research on sarcomas (GEIS).

Uterine sarcomas are very infrequent and heterogeneous entities. Due to its rarity, pathological diagnosis, surgical management, and systemic treatment are challenging. Treatment decision process in these tumors should be taken in a multidisciplinary tumor board. Available evidence is low and, in many cases, based on case series or clinical trials in which these tumors have been included with other soft tissue sarcoma. In these guidelines, we have tried to summarize the most relevant evidence in the diagnosis, staging, pathological disparities, surgical management, systemic treatment, and follow-up of uterine sarcomas.

Clinical and molecular signature of survival and resistance to olaparib plus pegylated liposomal doxorubicin in platinum-resistant ovarian cancer: a stratified analysis from the phase II clinical trial ROLANDO, GEICO-1601.

OBJECTIVE: To determine the potential prognostic value of clinical and molecular biomarkers in the survival of patients with platinum-resistant ovarian cancer treated with olaparib and pegylated liposomal doxorubicin. METHODS: ROLANDO was a single-arm phase II trial that included patients with high-grade serous or endometrioid tumors and at least one previous platinum-resistant recurrence regardless of BRCA status. Patients received 6 cycles of pegylated liposomal doxorubicin every 28 days plus olaparib 300 mg twice daily. followed by olaparib 300 mg twice daily; monotherapy until progression or unacceptable toxicity. Prognostic factors including previous lines (and platinum-containing ones), BRCA mutation status, previous bevacizumab, CA-125 levels, and the neutrophil/lymphocyte ratio, lymphocyte/monocyte ratio, and platelet/lymphocyte ratio calculated at inclusion were analyzed through a multivariate logistic regression and factor analysis of mixed data. RESULTS: Thirty-one patients were included. Median age was 57 years (range 43-75), Eastern Cooperative Oncolgy Group performance status 0/1: 32.3%/67.7% and BRCA mutated: 16.1%. Prior treatment lines were >2 lines: 14 (45.2%) patients, ≥2 platinum lines: 21 patients (67.7%) and previous bevacizumab 19 (61.3%) patients. CA-125 was >2 upper limit normal in 24 (77.4%) patients. A high neutrophil/lymphocyte ratio was associated with worse overall survival by univariate/multivariate regression model (HR=11.18; 95% CI 1.1 to 114.5; p=0.042). No other factors were associated with overall survival in the multivariate model. A multifactorial signature based on clinical and molecular baseline characteristics was capable of defining six patient clusters. Three of these clusters had significantly better prognosis, with a median overall survival of 21.3 months (95% CI 12.2 to not reached). CONCLUSIONS: High neutrophil/lymphocyte ratio at platinum-resistant relapse indicated poor prognosis in patients treated with olaparib plus pegylated liposomal doxorubicin. A multifactorial clinical signature was more precise than single variables for implying the prognosis and may help in therapeutic assignment after further validation in large prospective cohorts.

Evaluation of Antineoplastic Delayed-Type Hypersensitivity Skin Reactions In Vitro.

Delayed-type hypersensitivity (DTH) is caused by a broad number of drugs used in clinic, and antineoplastic drugs show an elevated proportion of DTH, which potentially affects the quality of life of patients. Despite the serious problem and the negative economic impact deriving from market withdrawal of such drugs and high hospitalization costs, nowadays, there are no standard validated methods in vitro or in vivo to evaluate the sensitizing potential of drugs in the preclinical phase. Enhanced predictions in preclinical safety evaluations are really important, and for that reason, the aim of our work is to adapt in vitro DPRA, ARE-Nrf2 luciferase KeratinoSensTM, and hCLAT assays for the study of the sensitizing potential of antineoplastic agents grouped by mechanism of action. Our results reveal that the above tests are in vitro techniques able to predict the sensitizing potential of the tested antineoplastics. Moreover, this is the first time that the inhibition of the VEGFR1 pathway has been identified as a potential trigger of DTH.

Efficacy of niraparib by time of surgery and postoperative residual disease status: A post hoc analysis of patients in the PRIMA/ENGOT-OV26/GOG-3012 study.

OBJECTIVE: To evaluate the association between surgical timing and postoperative residual disease status on the efficacy of niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer at high risk of recurrence. METHODS: Post hoc analysis of the phase 3 PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) study of niraparib in patients with newly diagnosed primary advanced ovarian, primary peritoneal, or fallopian tube cancer with a complete/partial response to first-line platinum-based chemotherapy. Progression-free survival (PFS) was assessed by surgical status (primary debulking surgery [PDS] vs neoadjuvant chemotherapy/interval debulking surgery [NACT/IDS]) and postoperative residual disease status (no visible residual disease [NVRD] vs visible residual disease [VRD]) in the intent-to-treat population. RESULTS: In PRIMA (N = 733), 236 (32.2%) patients underwent PDS, and 481 (65.6%) received NACT/IDS before enrollment. Median PFS (niraparib vs placebo) and hazard ratios (95% CI) for progression were similar in PDS (13.7 vs 8.2 months; HR, 0.67 [0.47-0.96]) and NACT/IDS (14.2 vs 8.2 months; HR, 0.57 [0.44-0.73]) subgroups. In patients who received NACT/IDS and had NVRD (n = 304), the hazard ratio (95% CI) for progression was 0.65 (0.46-0.91). In patients with VRD following PDS (n = 183) or NACT/IDS (n = 149), the hazard ratios (95% CI) for progression were 0.58 (0.39-0.86) and 0.41 (0.27-0.62), respectively. PFS was not evaluable for patients with PDS and NVRD because of sample size (n = 37). CONCLUSIONS: In this post hoc analysis, niraparib efficacy was similar across PDS and NACT/IDS subgroups. Patients who had NACT/IDS and VRD had the highest reduction in the risk of progression with niraparib maintenance.

Prospective Real-World Gynaecological Cancer Clinical Registry with Associated Biospecimens: A Collaborative Model to Promote Translational Research between GEICO and the Spanish Biobank Network.

Patient registries linked to biorepositories constitute a valuable asset for clinical and translational research in oncology. The Spanish Group of Ovarian Cancer Research (GEICO), in collaboration with the Spanish Biobank Network (RNBB), has developed a multicentre, multistakeholder, prospective virtual clinical registry (VCR) associated with biobanks for the collection of real-world data and biological samples of gynaecological cancer patients. This collaborative project aims to promote research by providing broad access to high-quality clinical data and biospecimens for future research according to the needs of investigators and to increase diagnostic and therapeutic opportunities for gynaecological cancer patients in Spain. The VCR will include the participation of more than 60 Spanish hospitals entering relevant clinical information in harmonised electronic case report forms (eCRFs) in four different cohorts: ovarian, endometrial, cervical, and rare gynaecological cancers (gestational trophoblastic disease). Initial data for the cases included till December 2021 are presented. The model described herein establishes a real-world win-win collaboration between multicentre structures, promoted and supported by GEICO, that will contribute to the success of translational research in gynaecological cancer.

A phase III trial of alpelisib + trastuzumab ± fulvestrant versus trastuzumab + chemotherapy in HER2+ PIK3CA-mutated breast cancer.

ALPHABET is a randomized phase III trial assessing alpelisib + trastuzumab with or without fulvestrant in previously treated HER2-positive PIK3CA-mutated advanced breast cancer. Patients will be included in two cohorts according to hormone receptor (HR) status. In the experimental arms, patients in the HR-negative cohort will receive trastuzumab + alpelisib, and patients in the HR-positive cohort will receive the same treatment plus fulvestrant. Patients in the control arms will receive trastuzumab + physician's choice chemotherapy (eribuline, capecitabine or vinorelbine). Key eligibility criteria include 1-4 previous lines of anti-HER2 therapy and prior trastuzumab emtansine. The primary end point is investigator-assessed progression-free survival. The study aims to recruit a total of 300 patients.

ALPHABET is a clinical study investigating the potential use of alpelisib for the treatment of certain subtypes of breast cancer. Alpelisib is a novel drug that is given orally. It specifically targets a protein called PI3K. PI3K is hyperactivated in some tumors, allowing uncontrolled growth. This study is enrolling patients with HER2-positive advanced breast cancer whose tumor tests positive for a mutation in the PIK3CA gene, which encodes PI3K. Patients are allocated at random to receive either a combination treatment of trastuzumab (an anti-HER2-targeted therapy) with alpelisib or standard chemotherapy and trastuzumab without alpelisib. The efficacy of each treatment will be determined by comparing how long patients in each group live for without further tumor growth. Additional analyses will also look at the side effects experienced by patients, as well as their quality of life.

Paclitaxel Induces Epidermal Molecular Changes and Produces Subclinical Alterations in the Skin of Gynecological Cancer Patients.

BACKGROUND: Paclitaxel is a microtubule-stabilizing chemotherapeutic agent. Despite its widespread use, it damages healthy tissues such as skin. The goal of this study was to prove that the real impact of paclitaxel-induced skin toxicity could be underestimated because the adverse events might appear asymptomatic. METHODS: Gynecological cancer patients were recruited. Skin parameters measurements were taken after three and six paclitaxel cycles. Measurements were conducted using specific probes which measure hydration, transepidermal water loss (TEWL), sebum, elasticity and firmness, erythema, roughness, smoothness, skin thickness, and desquamation levels. Further, a 3D epidermis model was incubated with paclitaxel to analyze gene and protein expression of aquaporin 3, collagen type 1, elastin, and fibronectin. RESULTS: Paclitaxel induced alterations in the skin parameters with no visible clinical manifestations. Gynecological cancer patients under paclitaxel treatment had a decrease in hydration, TEWL, sebum, elasticity, and thickness of the skin, while erythema, roughness, and desquamation were increased. The molecular markers, related to hydration and the support of the skin layers, and analyzed in the 3D epidermis model, were decreased. CONCLUSIONS: Results suggest that paclitaxel modifies gene and protein expression of skin-related molecular markers, and impairs different physical, physiological, and biomechanical properties of the skin of cancer patients at a subclinical level.

Olaparib as first line in BRCA-mutated advanced ovarian carcinoma: Is it cost-effective in Spain?

OBJECTIVE: To estimate the cost-effectiveness of olaparib after being funded by the Spanish National Health Service (SNHS) as first-line monotherapy maintenance treatment in patients with advanced high-grade serous ovarian carcinoma (HGSOC) and BRCA mutations in Spain. METHODS: A semi-Markov model with one-month cycles was adapted to the Spanish healthcare setting, using the perspective of the SNHS, and a time horizon of 50 years. Two scenarios were compared: receiving olaparib vs. no maintenance treatment. The model comprised four health states and included the clinical results of the SOLO1 study, along with the direct healthcare costs associated with the use of first-line and subsequent treatment resources (2020 €). A discount rate of 3% was applied for future cost and quality-of-life outcomes. A probabilistic sensitivity analysis (PSA) was also carried out and a cost-effectiveness threshold of €25,000 per quality adjusted life year (QALY) was considered. RESULTS: The introduction of olaparib as a first-line maintenance treatment for advanced HGSOC patients with BRCA mutations implied a cost of €131,614.98 compared to €102,369.54 without olaparib (difference: €29,245.44), with an improvement of 2.00 QALYs (5.56 and 3.57, respectively). Therefore, olaparib is cost-effective for advanced HGSOC patients with BRCA mutations, with an incremental cost-effectiveness ratio of €14,653.2/QALY. The results from the PSA showed that 92.1% of the simulations fell below the €25,000/QALY threshold. The model showed that olaparib could improve the overall survival by 2 years, vs. no maintenance treatment. CONCLUSIONS: Olaparib as first-line maintenance treatment is cost-effective in advanced HGSOC patients with BRCA mutations in Spain.

Clinical behavior and outcomes of breast cancer in young women with germline BRCA pathogenic variants.

Young breast cancer (BC) patients carrying a germline BRCA pathogenic variant (mBRCA) have similar outcomes as non-carriers. However, the impact of the type of gene (BRCA1 vs. BRCA2) and hormone receptor status (positive [HR+] vs. negative [HR-]) on clinical behavior and outcomes of mBRCA BC remains largely unknown. This is an international, multicenter, hospital-based, retrospective cohort study that included mBRCA patients diagnosed, between January 2000 and December 2012, with stage I-III invasive early BC at age ≤40 years. From 30 centers worldwide, 1236 young mBRCA BC patients were included. Among 808 and 428 patients with mBRCA1 or mBRCA2, 191 (23.6%) and 356 (83.2%) had HR+tumors, respectively (P < 0.001). Median follow-up was 7.9 years. Second primary BC (P = 0.009) and non-BC malignancies (P = 0.02) were more frequent among mBRCA1 patients while distant recurrences were less frequent (P = 0.02). Irrespective of hormone receptor status, mBRCA1 patients had worse disease-free survival (DFS; adjusted HR = 0.76, 95% CI = 0.60-0.96), with no difference in distant recurrence-free interval (DRFI) and overall survival (OS). Patients with HR+ disease had more frequent distant recurrences (P < 0.001) and less frequent second primary malignancies (BC: P = 0.005; non-BC: P = 0.18). No differences in DFS and OS were observed according to hormone receptor status, with a tendency for worse DRFI (adjusted HR = 1.39, 95% CI = 0.94-2.05) in patients with HR+ BC. Type of mBRCA gene and hormone receptor status strongly impact BC clinical behavior and outcomes in mBRCA young patients. These results provide important information for patients' counseling on treatment, prevention, and surveillance strategies.

Melanoma of unknown primary: New perspectives for an old story.

Melanoma of unknown primary site (MUP) comprises 3-4 % of all melanomas. It mostly presents in lymph nodes (LNs), followed by subcutaneous sites, and visceral organs; nevertheless, there is a trend of increase in the relative incidence of visceral counterpart in recent years. Spontaneous regression of the primary lesion is a well-established theory, based on the evidence that melanoma can undergo regression at the primary site. MUP and stage-matched melanoma of known primary site (MKP) share similar prognostic factors. The survival rate of patients with MUP has been compared to those with stage-matched MKP. Multiple studies conducted before the era of novel therapy with immune checkpoint or BRAF/MEK inhibitors found improved survival in favor of MUP, whereas others reported equivalent or poorer outcomes. Here, we discuss the genetic and molecular features, epidemiology, diagnosis, prognostic factors, survival, and treatment of MUP in comparison with MKP, in the pre- and post-novel therapy era.

Pregnancy After Breast Cancer in Patients With Germline BRCA Mutations.

PURPOSE: Young women with germline BRCA mutations have unique reproductive challenges. Pregnancy after breast cancer does not increase the risk of recurrence; however, very limited data are available in patients with BRCA mutations. This study investigated the impact of pregnancy on breast cancer outcomes in patients with germline BRCA mutations. PATIENTS AND METHODS: This is an international, multicenter, hospital-based, retrospective cohort study. Eligible patients were diagnosed between January 2000 and December 2012 with invasive early breast cancer at age ≤ 40 years and harbored deleterious germline BRCA mutations. Primary end points were pregnancy rate, and disease-free survival (DFS) between patients with and without a pregnancy after breast cancer. Pregnancy outcomes and overall survival (OS) were secondary end points. Survival analyses were adjusted for guarantee-time bias controlling for known prognostic factors. RESULTS: Of 1,252 patients with germline BRCA mutations (BRCA1, 811 patients; BRCA2, 430 patients; BRCA1/2, 11 patients) included, 195 had at least 1 pregnancy after breast cancer (pregnancy rate at 10 years, 19%; 95% CI, 17% to 22%). Induced abortions and miscarriages occurred in 16 (8.2%) and 20 (10.3%) patients, respectively. Among the 150 patients who gave birth (76.9%; 170 babies), pregnancy complications and congenital anomalies occurred in 13 (11.6%) and 2 (1.8%) cases, respectively. Median follow-up from breast cancer diagnosis was 8.3 years. No differences in DFS (adjusted hazard ratio [HR], 0.87; 95% CI, 0.61 to 1.23; P = .41) or OS (adjusted HR, 0.88; 95% CI, 0.50 to 1.56; P = .66) were observed between the pregnancy and nonpregnancy cohorts. CONCLUSION: Pregnancy after breast cancer in patients with germline BRCA mutations is safe without apparent worsening of maternal prognosis and is associated with favorable fetal outcomes. These results provide reassurance to patients with BRCA-mutated breast cancer interested in future fertility.

NOTCH signalling in ovarian cancer angiogenesis.

The Notch signalling pathway is involved in the new vessel formation process by regulating tip and stalk cells, which are key cells in the sprout formation. This process is essential in both normal ovary and cancer angiogenesis and is regulated by Notch-VEGF crosstalk. Furthermore, Notch has been linked in ovary with stem cell maintenance and epithelial mesenchymal transition processes. Dysregulation of the Notch pathway is frequent in ovarian cancer (OC) and it has been associated with impaired survival and advanced stages or lymph node involvement. Notch also plays a role in chemoresistance to platinum. In this context, this pathway has emerged as an attractive target for precision medicine in OC. Two main targets of this pathway concentrate the clinical development of compounds blocking Notch: gamma secretase and Delta-like ligand 4. Most of the clinical trials including OC patients have been developed in phase I or phase Ib. Despite being in an early phase, both of these compounds, navicixizumab or demcizumab, two monoclonal antibodies targeting Dll4, showed promising efficacy data in platinum-resistant OC patients in recent studies. This review will focus on the mechanisms of the Notch pathway with special interest in angiogenesis regulation and the implication of Notch as a potential therapeutic target in OC.

A two-gene epigenetic signature for the prediction of response to neoadjuvant chemotherapy in triple-negative breast cancer patients.

BACKGROUND: Pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) varies between 30 and 40% approximately. To provide further insight into the prediction of pCR, we evaluated the role of an epigenetic methylation-based signature. METHODS: Epigenetic assessment of DNA extracted from biopsy archived samples previous to NAC from TNBC patients was performed. Patients included were categorized according to previous response to NAC in responder (pCR or residual cancer burden, RCB = 0) or non-responder (non-pCR or RCB > 0) patients. A methyloma study was performed in a discovery cohort by the Infinium HumanMethylation450 BeadChip (450K array) from Illumina. The epigenetic silencing of those methylated genes in the discovery cohort were validated by bisulfite pyrosequencing (PyroMark Q96 System version 2.0.6, Qiagen) and qRT-PCR in an independent cohort of TN patients and in TN cell lines. RESULTS: Twenty-four and 30 patients were included in the discovery and validation cohorts, respectively. In the discovery cohort, nine genes were differentially methylated: six presented higher methylation in non-responder patients (LOC641519, LEF1, HOXA5, EVC2, TLX3, CDKL2) and three greater methylation in responder patients (FERD3L, CHL1, and TRIP10). After validation, a two-gene (FER3L and TRIP10) epigenetic score predicted RCB = 0 with an area under the ROC curve (AUC) = 0.905 (95% CI = 0.805-1.000). Patients with a positive epigenetic two-gene score showed 78.6% RCB = 0 versus only 10.7% RCB = 0 if signature were negative. CONCLUSIONS: These results suggest that pCR in TNBC could be accurately predicted with an epigenetic signature of FERD3L and TRIP10 genes. Further prospective validation of these findings is warranted.