Controversies in the treatment of advanced ovarian cancer in the PARP inhibitors era: a Delphi consensus.

OBJECTIVE: Our aim was to reach a consensus on the management of the most controversial issues of advanced ovarian cancer. METHODS: Nominal group and Delphi techniques were used. A steering committee of 5 experts analyzed current management of advanced ovarian cancer, identified controversies, critically analyzed the evidence, and formulated guiding statements for clinicians. Subsequently, a panel of 15 experts was selected to test agreement with the statements through two Delphi rounds. Items were scored on a 4-point Likert scale from 1 (totally disagree) to 4 (totally agree). In the first and second rounds, consensus was considered if ≥70% of answers pertained to category 1 or category 4. RESULTS: Overall, 112 statements were incorporated in the following areas: 1) biomarkers and hereditary ovarian cancer; 2) first-line treatment; 3) recurrent disease when platinum might be the best option; and 4) post-poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors setting. In the first Delphi round, 37 statements reached consensus and did thus not pass to the second round. After the second round, another 18 statements reached consensus. Forty-six of the consensus were with the agreement and 9 with the disagreement. CONCLUSION: Through the methodology used, a consensus was reached in approximately half of the statements. The results of this work may be useful in addressing the most controversial issues on the management of advanced ovarian cancer.

PSA Kinetics as Prognostic Markers of Overall Survival in Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Abiraterone Acetate.

BACKGROUND: Abiraterone acetate (AA) is widely used in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). However, a significant percentage of patients will still progress, highlighting the need to identify patients more likely to benefit from AA. Parameters linked to prostate-specific antigen (PSA) kinetics are promising prognostic markers. We have examined clinical and PSA-related factors potentially associated with overall survival (OS) in patients treated with AA. METHODS: Between 2011 and 2014, 104 patients with mCRPC treated with AA after progression to docetaxel at centers of the Catalan Institute of Oncology were included in this retrospective study. Patients were assessed monthly. Baseline characteristics and variables related to PSA kinetics were included in univariate and multivariate analyses of OS. RESULTS: Median OS was 16.4 months (range 12.4-20.6) for all patients. The univariate analysis identified the following baseline characteristics as significantly associated with OS: ECOG PS, location of metastases, time between starting androgen deprivation therapy and starting AA, time between stopping docetaxel treatment and starting AA, neutrophil-lymphocyte ratio (NLR), alkaline phosphatase levels, and PSA levels. Factors related to PSA kinetics associated with longer OS were PSA response >50%, early PSA response (>30% decline at four weeks), PSA decline >50% at week 12, PSA nadir <2.4ng/mL, time to PSA nadir >140 days, the combination of PSA nadir and time to PSA nadir, and low end-of-treatment PSA levels. The multivariate analysis identified ECOG PS (HR 37.46; p<0.001), NLR (HR 3.7; p<0.001), early PSA response (HR 1.22; p=0.002), and time to PSA nadir (HR 0.39; p=0.002) as independent prognostic markers. CONCLUSION: Our results indicate an association between PSA kinetics, especially early PSA response, and outcome to AA after progression to docetaxel. Taken together with other factors, lack of an early PSA response could identify patients who are unlikely to benefit from AA and who could be closely monitored with a view to offering alternative therapies.

Efficacy and safety of trabectedin in metastatic uterine leiomyosarcoma: A retrospective multicenter study of the Spanish ovarian cancer research group (GEICO).

OBJECTIVE: We assessed trabectedin in patients with advanced uterine leiomyosarcoma (uLMS) in real-life clinical practice given according to the marketing authorization. METHODS: Thirty-six women from 11 tertiary hospitals across Spain who received trabectedin after anthracycline-containing regimen/s were retrospectively analyzed. The primary endpoint was progression-free survival (PFS). RESULTS: Median PFS and overall survival (OS) since starting trabectedin treatment were 5.4 (95%CI: 3.5-7.3) and 18.5 months (95%CI: 11.5-25.6), respectively. Median OS was significantly higher (P = 0.028) in patients receiving trabectedin in ≤ 2nd line (25.3 months) than in ≥ 3rd (15.1 months) and with ECOG performance status ≤ 1 at trabectedin start (19.8 months) than ECOG 2-3 (6.0 months, P = 0.013). When calculating OS since diagnosis, patients had longer OS with localized disease at diagnosis (87.4 months) vs. locally advanced (30.0 months) or metastatic (44.0 months, P = 0.041); and patients who received adjuvant therapy (87.4 months) compared with those who did not (30.0 months, P = 0.003), especially when receiving radiochemotherapy (106.7 months, P = 0.027). One patient (2.8%) had a complete response (CR) and nine patients (25.0%) achieved a partial response (PR) for an objective response rate of 27.8% with median response duration of 11 months (range: 4-93). Eighteen patients (50.0%) had disease stabilization for a disease control rate (DCR) of 77.8%. More patients receiving trabectedin in 1st-line of advanced disease achieved CR (16.7%) and PR (50.0%) than those in ≥ 2nd line/s (0.0% and 20.0%), whereas the DCR was similar across treatment lines. Reversible neutropenia was the most common grade 3/4 laboratory abnormality (19.4%). CONCLUSIONS: Trabectedin confers clinical benefit in patients with recurrent/metastatic uLMS, given after failure to an anthracycline-based regimen being comparable to those reported in clinical trials and with a manageable safety profile.

Tumors defective in homologous recombination rely on oxidative metabolism: relevance to treatments with PARP inhibitors.

Mitochondrial metabolism and the generation of reactive oxygen species (ROS) contribute to the acquisition of DNA mutations and genomic instability in cancer. How genomic instability influences the metabolic capacity of cancer cells is nevertheless poorly understood. Here, we show that homologous recombination-defective (HRD) cancers rely on oxidative metabolism to supply NAD+ and ATP for poly(ADP-ribose) polymerase (PARP)-dependent DNA repair mechanisms. Studies in breast and ovarian cancer HRD models depict a metabolic shift that includes enhanced expression of the oxidative phosphorylation (OXPHOS) pathway and its key components and a decline in the glycolytic Warburg phenotype. Hence, HRD cells are more sensitive to metformin and NAD+ concentration changes. On the other hand, shifting from an OXPHOS to a highly glycolytic metabolism interferes with the sensitivity to PARP inhibitors (PARPi) in these HRD cells. This feature is associated with a weak response to PARP inhibition in patient-derived xenografts, emerging as a new mechanism to determine PARPi sensitivity. This study shows a mechanistic link between two major cancer hallmarks, which in turn suggests novel possibilities for specifically treating HRD cancers with OXPHOS inhibitors.

[Recommendations for biomarker testing in epithelial ovarian cancer. A national consensus statement by the Spanish Society of Pathology and the Spanish Society of Medical Oncology]. / Recomendaciones para la determinación de biomarcadores en cáncer de ovario epitelial. Consenso nacional de la Sociedad Española de Anatomía Patológica y de la Sociedad Española de Oncología Médica.

Advances in the understanding of the histological and molecular characteristics of ovarian cancer now allow 5subtypes to be identified, leading to a more refined therapeutic approach and improved clinical trials. Each of the subtypes has specific histological features and a particular biomarker expression, as well as mutations in different genes, some of which have prognostic and predictive value. CA125 and HE4 are examples of ovarian cancer biomarkers used in diagnosis and follow-up. Currently, somatic or germinal mutations on BRCA1 and BRCA2 genes are the most important biomarkers in epithelial ovarian cancer, having prognostic and predictive value. In this article, a group of experts from the Spanish Society of Medical Oncology and the Spanish Society of Pathology review the histological and molecular characteristics of the 5subtypes of ovarian cancer and describe the most useful biomarkers and mutations for diagnosis, screening and tailored treatment strategy.

Incomplete staging surgery as a major predictor of relapse of borderline ovarian tumor.

BACKGROUND: Borderline ovarian tumors (BOTs) are a subset of epithelial ovarian tumors with low malignant potential but significant risk of relapse (10% to 30%). Unfortunately, surgical prognostic factors for BOT relapse have not been clearly identified, probably due to the use of heterogeneous surgical definitions and limited follow-up. The aim of this study was to assess potential relapse risk factors using standard surgical definitions and long follow-up. METHODS: All patients diagnosed with BOT for a period of more than 10 years in a single institution were included in the analysis. Complete surgical staging was defined as the set of procedures that follow standard guidelines for staging surgery (except lymphadenectomy), performed either with one or two interventions. Fertility-sparing surgeries that preserved one ovary and the uterus but included all the remaining procedures were classified as complete staging. The relationship between potential risk factors and time to BOT relapse was assessed by log-rank tests corrected for multiple comparisons and Cox regression. RESULTS: Forty-six patients with a median follow-up of 5.4 years were included, of whom 91.3% had been diagnosed as FIGO stage I disease and 45.7% had received complete staging surgery. Five relapses were detected (10.9%), all of them in women who had been diagnosed with stage I disease and had received incomplete staging surgery. Log-rank tests confirmed the association between incomplete staging surgery and shorter time to BOT relapse. CONCLUSIONS: Complete staging surgery should be considered a cornerstone of BOT treatment in order to minimize the risk of relapse.

Neuroendocrine tumors: a population-based study of incidence and survival in Girona Province, 1994-2004.

BACKGROUND: Neuroendocrine tumors (NETs) belong to a rare and heterogeneous group of neoplasms with a wide range of aggressiveness. Little information is available about incidence and mortality of NETs in the World population. The objective of this study was to report the incidence and survival of these tumors in Girona Province. METHODS: We include all ICD-O3 codes that codified a NET, period 1994-2004. Data from malignant NETs came directly from the Girona Cancer Registry, and data from benign or with uncertain behavior NETs directly from the Anatomic-Pathological Laboratories. RESULTS: We identified 698 NETs, the most frequent were those aroused in the bronco-pulmonary system (65.75%), followed by the gastro-entero-pancreatics (GEP) (12.75%). Small cell lung carcinomas were the most frequent NETs of the bronco-pulmonary system (92.59%), with an age-standardized incidence rate (ASRw, world population standard) of 4.29/100,000 person-years. Carcinoid lung tumors had an ASRw of 0.32/100,000 person-years and a 5-year relative survival (RS) of 77%. The ASRw of GEP NETs was 1.07/100,000 person-years, and the 5-year RS was 95%. The 5-year RS of pancreas was 43%. Thyroid NETs had an ASRw of 0.17/100,000 person-years, and a 5-year RS of 75%. Pheocromocytomas had an ASRw of 0.47/100,000 person-years and a 5-year RS of 85%. Merkel cell carcinomas had an ASRw of 0.11/100,000 person-years, with a 5-year RS of 50%. CONCLUSION: To our knowledge, this is the first population-based study reporting incidence of NETs in Spain. Our data was consistent with other European reports. By providing the incidence and survival of NETs in Girona Province, this study contributes to a better understanding of these rare tumors.

CA-125 response patterns in patients with recurrent ovarian cancer treated with pegylated liposomal doxorubicin (PLD).

INTRODUCTION: : In recurrent ovarian cancer, CA-125 could be the only objective response criteria. This study analyzes response patterns regarding CA-125 in responders versus nonresponders and determines whether a specific cutoff value for CA-125 could predict clinical response, compared with response evaluation criteria in solid tumors, in patients receiving pegylated liposomal doxorubicin (PLD). METHODS: : Sixty-eight patients were identified, 78% were platinum resistant. Relative changes in CA-125 values were calculated, and response was defined as higher than 50% reduction in CA-125 from baseline. Receiver operating characteristic (ROC) curves were constructed based on CA-125 value after the first cycle of PLD to evaluate the most precise cutoff point for the decision model predicting response. RESULTS: : Fifty-three patients were assessable for response: 16 patients responded and 37 did not; the median increase of CA-125 was 0.20 (-63; 312) and 52 (-29; 620), respectively. Our ROC curve generated a cutoff value with a sensitivity of 35% (positive test, the proportion of patients who will not respond) and a predictive positive value of 80%. According to the predictive positive value, 20% of the responder patients will be identified as nonresponders; P = 0.025. CONCLUSIONS: : Our ROC analysis did not demonstrate any reliable CA-125 cutoff on response. Discontinuation of the therapy before cycle 3 may exclude some patients who will benefit from PLD.