Noemia Afonso

Platinum/paclitaxel-based chemotherapy in advanced ovarian carcinoma: glutathione S-transferase genetic polymorphisms as predictive biomarkers of disease outcome

AbstractBackground. The glutathione S-transferases (GSTs) are a group of multifunctional enzymes that catalyze the conjugation of glutathione with a variety of electrophilic compounds, including cytotoxic agents. A significant percentage of normal individuals exhibit genetic polymorphism with a homozygous deletion (null genotype) of the genes, leading to absence of the enzyme. Methods. In the present study we analyzed GSTM1 and GSTT1 polymorphisms in the genomic DNA isolated from peripheral blood of patients with ovarian cancer treated with chemotherapy (paclitaxel and cisplatinum) after cytoreductive surgery and assessed its correlation with the clinical outcome of these patients. The median follow-up for the patients was 30 months. Results. The estimated 3-year survival rate was 59.8% for all patients and 20.8% for carriers of GSTM1-wt/GSTT1-wt (wt indicates wild type) genotype combination (37.7% for GSTM1-wt alone) compared with 83.1% for non-GSTM1-wt/GSTT1-wt genotype carriers (100% for GSTM1-null). The mean survival time was significantly better in patients who are carriers of the GSTM1-null genotype (40.5 vs. 33.5; P = 0.006) or carriers of non-GSTM1-wt/GSTT1-wt genotypes (55.4 vs. 30.7; P = 0.009). The progression-free interval was more favorable for GSTM1-null carriers (41.9 vs. 27.4; P = 0.024). Conclusion. The study suggests that characterization of the drug-metabolizing genetic individual profile can be of great interest in clinical oncology. It can define the optimal chemotherapy for each patient, improve the efficiency, and reduce the incidence of drug toxicity and poor drug responses.

Occupational risks for uveal melanoma results from a case-control study in nine European countries

Objective Uveal melanoma is a rare disease with poor prognosis and largely unknown etiology. We studied potential occupational risk factors.Methods A population based case-control study was undertaken during 1995–1997 in nine European countries using population and colon cancer controls with personal interviews. Occupational exposure to sunlight and artificial UV radiation was assessed with a job exposure matrix. In total, 320 uveal melanoma cases were eligible at pathology review, and 292 cases were interviewed, participation 91%. Out of 3357 population controls, 2062 were interviewed, 61%, and out of 1272 cancer controls 1094 were interviewed, 86%.Results Using population controls, occupational exposure to sunlight was not associated with an increased risk (RR=1.24, 95% CI=0.88−1.74), while an excess risk found with use of colon cancer controls was attributed to confounding factors. An excess risk in welders was restricted to the French part of the data. Cooks, RR=2.40; cleaners, RR 2.15; and laundry workers, RR=3.14, were at increased risk of uveal melanoma.Conclusion Our study does overall not support an association between occupational sunlight exposure and risk of uveal melanoma. The finding of an excess risk of eye melanoma in cooks in several European countries is intriguing.

Male breast cancer: Looking for better prognostic subgroups.

PURPOSE Male Breast Cancer (MBC) remains a poor understood disease. Prognostic factors are not well established and specific prognostic subgroups are warranted. PATIENTS/METHODS Retrospectively revision of 111 cases treated in the same Cancer Center. Blinded-central pathological revision with immunohistochemical (IHQ) analysis for estrogen (ER), progesterone (PR) and androgen (AR) receptors, HER2, ki67 and p53 was done. Cox regression model was used for uni/multivariate survival analysis. Two classifications of Female Breast Cancer (FBC) subgroups (based in ER, PR, HER2, 2000 classification, and in ER, PR, HER2, ki67, 2013 classification) were used to achieve their prognostic value in MBC patients. Hierarchical clustering was performed to define subgroups based on the six-IHQ panel. RESULTS According to FBC classifications, the majority of tumors were luminal: A (89.2%; 60.0%) and B (7.2%; 35.8%). Triple negative phenotype was infrequent (2.7%; 3.2%) and HER2 enriched, non-luminal, was rare (≤1% in both). In multivariate analysis the poor prognostic factors were: size >2 cm (HR:1.8; 95%CI:1.0-3.4 years, p = 0.049), absence of ER (HR:4.9; 95%CI:1.7-14.3 years, p = 0.004) and presence of distant metastasis (HR:5.3; 95%CI:2.2-3.1 years, p < 0.001). FBC subtypes were independent prognostic factors (p = 0.009, p = 0.046), but when analyzed only luminal groups, prognosis did not differ regardless the classification used (p > 0.20). Clustering defined different subgroups, that have prognostic value in multivariate analysis (p = 0.005), with better survival in ER/PR+, AR-, HER2-and ki67/p53 low group (median: 11.5 years; 95%CI: 6.2-16.8 years) and worst in PR-group (median:4.5 years; 95%CI: 1.6-7.8 years). CONCLUSION FBC subtypes do not give the same prognostic information in MBC even in luminal groups. Two subgroups with distinct prognosis were identified in a common six-IHQ panel. Future studies must achieve their real prognostic value in these patients.

Overall Survival Prediction for Women Breast Cancer Using Ensemble Methods and Incomplete Clinical Data

Breast Cancer is the most common type of cancer in women worldwide. In spite of this fact, there are insufficient studies that, using data mining techniques, are capable of helping medical doctors in their daily practice.

Abstract PD5-1: Results from the phase 2 trial of ridaforolimus, dalotuzumab, and exemestane compared to ridaforolimus and exemestane in advanced breast cancer

Introduction: The combination of a mammalian target of rapamycin (mTOR) inhibitor and an aromatase inhibitor has been shown to significantly increase progression-free survival (PFS) in patients with estrogen receptor-positive (ER+) advanced or metastatic breast cancer. Ridaforolimus is an alternative mTOR inhibitor with high potency and specificity. We hypothesized that triplet therapy with ridaforolimus, dalotuzumab (a humanized monoclonal antibody targeting the IGF-1 receptor [IGFR]), and exemestane (R/D/E) would be more effective than doublet therapy with ridaforolimus and exemestane (R/E). Methods: This phase 2, randomized, open-label trial enrolled 80 postmenopausal patients who had high-proliferation (KI67 staining) ER+ breast cancer that had progressed following treatment with a nonsteroidal aromatase inhibitor. Patients received either triplet therapy, at the previously determined maximum tolerated dose of oral ridaforolimus 10 mg QD×5, dalotuzumab 10 mg/kg/week IV, and oral exemestane 25 mg/day (R/D/E, n=40), or doublet therapy with R 30 mg QD×5 and E 25 mg/day (R/E, n=40). Dose increases of R to 20 or 40 mg QD×5 were permitted in the R/D/E or R/E arms, respectively, in the absence of grade ≥2 stomatitis after cycle 1. The R dose could be reduced in either arm for toxicity. The primary endpoint was PFS in the ITT population by central review. Adverse events (AE) of clinical interest (Tier 1) included stomatitis, pneumonitis, hearing loss, and hyperglycemia. Results: Baseline characteristics were balanced between treatment groups. The median PFS was 23.3 (95% CI, 8.71, 38.43) weeks for R/D/E versus 31.9 (95% CI, 16.00, 39.29) weeks in the R/E arm (hazard ratio, 1.18; 80% CI, 0.81-1.72; P=0.565). All patients experienced at least one AE. 5 (12.8%) and 3 (7.5%) patients in the R/D/E and R/E arms, respectively, discontinued the study because of AE. Serious drug-related AE occurred in 2.6% of the R/D/E arm and 15% of the R/E arm. Dose modifications due to AE occurred in 10.3% and 50% in the R/D/E and R/E arms, respectively (difference -39.7%; 95% CI, -56.7, -20.4). Tier 1 AE were primarily grade 1-2 in severity. Stomatitis occurred in 76.9% (30/39 patients) in the R/D/E arm vs 95.0% (38/40 patients) in the R/E arm (P=0.021), and grade 3-4 stomatitis was similar between arms (23.1% vs 25%). Pneumonitis occurred in 5.1% vs 22.5% (P=0.027) and hearing loss occurred in 1 patient in each treatment arm (2.6% vs 2.5%), all grade 1-2. Hyperglycemia occurred at a similar rate in both treatment arms (28.2% vs 27.5%), with grade 3-4 events in 4 (10.3%) and 3 (7.5%) patients in the R/D/E and R/E arms, respectively. Conclusions: The combination of R 10 mg QD×5, D, and E did not improve PFS when compared to R 30 mg QD×5 plus E. The incidence rates of AE were lower in the R/D/E arm than the R/E arm for most categories of adverse events, likely because of the higher dose of R in the R/E arm. The efficacy reported for R/E in this study is similar to that reported in previous studies evaluating mTOR inhibitors in combination with exemestane in ABC. Overlapping toxicities and lower doses likely contributed to the lack of improved PFS with the addition of the IGFR inhibitor to this combination. Citation Format: Hope S Rugo, Olivier Tredan, Jungsil Ro, Serafin Morales, Antonino Musolino, Noemia Afonso, Marta Ferreira, Kyong Hwa Park, Javier Cortes, Antoinette R Tan, Joanne L Blum, Lamar Eaton, Christine K Gause, Adelle (Zhen) Wang, Ellie Im, David J Mauro, Jose Baselga. Results from the phase 2 trial of ridaforolimus, dalotuzumab, and exemestane compared to ridaforolimus and exemestane in advanced breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD5-1.

Occupational exposure to endocrine-disrupting chemicals and the risk of uveal melanoma

OBJECTIVES We investigated the association between occupational exposure to endocrine-disrupting chemicals (EDC) and the risk of uveal melanoma using international data of a case-control study from nine European countries. METHODS After exclusion of proxy interviews, 280 cases and 3084 control subjects were included in the final analysis. Information on possible exposure to EDC was derived from 27 job-specific questionnaires (JSQ), which solicited detailed questions on occupational tasks. Relative risk estimates were based on the JSQ and potential exposure to a group of endocrine-disrupting agents. We constructed several exposure scores, taking into account intensity of exposure, use of personal protective equipment, and exposure duration. We calculated unconditional logistic regression analyses, adjusting for country, age, sex, eye color and a history of ocular damage due to intense ultraviolet (UV) exposure. RESULTS The overall exposure prevalence to EDC was low reaching a maximum of 11% for heavy metals with endocrine-disrupting properties. Although working in some industries was associated with increased melanoma risk [such as dry cleaning: odds ratio (OR) 6.15, 95% confidence interval (95% CI) 2.0-18.96 and working in the glass manufacturing industry: OR 3.49, 95% CI 1.10-11.10], agent-specific risks were not elevated. The strongest possible risk increase was observed for organic solvents with endocrine-disrupting properties (OR 1.31, 95% CI 0.78-2.21). Calculation of exposure scores did not indicate consistently elevated results with higher score values. Sensitivity analyses did not alter these results. CONCLUSION Occupational exposure to EDC was not associated with an increased risk for uveal melanoma.

Occupational exposure to electromagnetic fields and sex-differential risk of uveal melanoma

Objectives The association between occupational exposure to electromagnetic fields (EMF) and the risk of uveal melanoma was investigated in a case–control study in nine European countries. Methods Incident cases of uveal melanoma and population as well as hospital controls were included and frequency matched by country, 5-year birth cohort and sex. Subjects were asked whether they had worked close to high-voltage electrical transmission installations, computer screens and various electrical machines, or in complex electrical environments. Measurements of two Scandinavian job–exposure matrices were applied to estimate lifelong cumulative EMF exposure. Unconditional logistic regression analyses, stratified by sex and eye colour were calculated, adjusting for several potential confounders. Results 293 patients with uveal melanoma and 3198 control subjects were interviewed. Women exposed to electrical transmission installations showed elevated risks (OR 5.81, 95% CI 1.72 to 19.66). Positive associations with exposure to control rooms were seen among men and women, but most risk increases were restricted to subjects with dark iris colour. Application of published EMF measurements revealed stronger risk increases among women compared to men. Again, elevated risks were restricted to subjects with dark eye colour. Conclusion Although based on a low prevalence of exposure to potential occupational sources of EMF, our data indicate that exposed dark-eyed women may be at particular risk for uveal melanoma.

Insight into p95HER2 in Breast Cancer: Molecular Mechanisms and Targeted Therapies

Breast cancer afflicts more than 1.3 million people worldwide and is the main cause of cancer-related deaths among women. Many efforts are underway to develop new therapeutic and biomarker strategies for the management of this disease. Hormone receptors and human epidermal growth factor receptor 2 (HER2) are currently the most important molecular tools in this regard. Moreover, targeted therapies including trastuzumab in particular are the primary treatment in both the adjuvant and recurrent settings. However, many studies reported that selected patients may present with resistance to trastuzumab due to the presence of p95HER2 fragments. To address this challenge, drugs such as lapatinib and others described in recent patents promise alternative therapeutic options. We discuss the most recent patents related to HER2 and p95HER2 fragments for breast cancer treatment.

CYP2D6*4 polymorphism: A new marker of response to hormonotherapy in male breast cancer?

BACKGROUND Tamoxifen remains the standard hormonotherapy for Male breast cancer patients (MBC). Previous studies, in women, tried to evaluate the impact of CYP2D6 polymorphisms in tamoxifen efficacy with conflicting results. Herein we analyze the relation between CYP2D6*4 polymorphism and survival in MBC patients. PATIENTS AND METHODS Fifty-three patients, proposed to tamoxifen in adjuvant setting, were enrolled. Clinical information was collected from records and histological revision with additional immunochemistry analysis was done to better characterize the tumors. Comprehensive CYP2D6*4 genotyping from blood or tumor tissue was performed and translated into two predicted metabolic activity groups. RESULTS Patients included in the two CYP2D6*4 groups did not differ concerning to age, histological characteristics, and primary treatments performed. Median age at diagnosis was 63 years-old and patients were submitted at least to mastectomy and adjuvant hormonotherapy. Recurrence was observed in 7 patients (13.2%) and 13 patients (25.5%) died with a 5-year disease-free survival of 86.2%. The poorer metabolizer group had a high risk for recurrence (p = 0.034) and this outcome effect remains in different subgroups: in tumors larger than 2 cm (p < 0.001), nodal status, N0 vs N+ (p = 0.04) and in advanced stage, stage III (p < 0.001). Poorer metabolizer patients had also a worse overall survival when tumors were larger than 2 cm (p = 0.03). CONCLUSIONS In our series, there was an association between CYP2D6*4 polymorphism and a probability of recurrence, with a consistent effect in risk groups defined by classic prognostic factors. Multicentric studies with larger samples are needed to validate these results.

Relative dose intensity reduction in breast cancer adjuvant chemotherapy.

Abstract #4111 Introduction
 In breast cancer (BC), adjuvant chemotherapy has become a standard therapy, resulting in prolonged survival. This goal might be affected by chemotherapy dose reductions and delays that are not uncommon features.
 The aim of this study was to assess relative dose intensity (RDI) reduction risk factors and define predictive factors.
 Methods
 Data regarding BC patients (pts) under anthracycline based-chemotherapy regimens was collected, retrospectively, from two Portuguese centres, between 1998 and 2007, and combined into a database of 783 individuals. Primary G-CSF prophylaxis was not planned. DIEP® (Dose Intensity Evaluation Programme) software was developed to allow calculation of RDI, and includes demographic data, clinical and treatment characteristics, chemotherapy dose modifications and delays, haematological toxicities and patterns of use of G-CSF.
 Univariate and multivariate analysis was performed to identify factors related to RDI ≤ 90% in these patients. A value of P Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4111.