Breast density, benign breast disease, and risk of breast cancer over time.

OBJECTIVES: Assessing the combined effect of mammographic density and benign breast disease is of utmost importance to design personalized screening strategies. METHODS: We analyzed individual-level data from 294,943 women aged 50-69 years with at least one mammographic screening participation in any of four areas of the Spanish Breast Cancer Screening Program from 1995 to 2015, and followed up until 2017. We used partly conditional Cox models to assess the association between benign breast disease, breast density, and the risk of breast cancer. RESULTS: During a median follow-up of 8.0 years, 3697 (1.25%) women had a breast cancer diagnosis and 5941 (2.01%) had a benign breast disease. More than half of screened women had scattered fibroglandular density (55.0%). The risk of breast cancer independently increased with the presence of benign breast disease and with the increase in breast density (p for interaction = 0.84). Women with benign breast disease and extremely dense breasts had a threefold elevated risk of breast cancer compared with those with scattered fibroglandular density and without benign breast disease (hazard ratio [HR] = 3.07; 95%CI = 2.01-4.68). Heterogeneous density and benign breast disease was associated with nearly a 2.5 elevated risk (HR = 2.48; 95%CI = 1.66-3.70). Those with extremely dense breast without a benign breast disease had a 2.27 increased risk (95%CI = 2.07-2.49). CONCLUSIONS: Women with benign breast disease had an elevated risk for over 15 years independently of their breast density category. Women with benign breast disease and dense breasts are at high risk for future breast cancer. KEY POINTS: • Benign breast disease and breast density were independently associated with breast cancer. • Women with benign breast disease had an elevated risk for up to 15 years independently of their mammographic density category.

Assessment of early therapy discontinuation and health-related quality of life in breast cancer patients treated with aromatase inhibitors: B-ABLE cohort study.

PURPOSE: The most frequent adverse effects of aromatase inhibitors (AI) are arthralgia and bone loss induction. These reduce the quality of life of patients and their adherence to the treatment. This study evaluates the early AI cessation caused by AI intolerance, and the evolution of joint pain and health-related quality of life (HRQoL) during AI treatment until 1-year after AI completion. METHODS: Data of 910 women diagnosed with early breast cancer and candidates for AI were recruited in B-ABLE cohort. AI discontinuation was analyzed by survival analysis, including Kaplan-Meier estimation and Cox regression. Patients were distributed in three groups of the study according to previous tamoxifen (TAM) exposure and length of AI treatment: TAM-2yAI, TAM-3yAI, and 5yAI. Evolution of joint pain and HRQoL in osteoporosis was evaluated using Visual Analog Scale (VAS) and ECOS-16 tests, respectively, from baseline to 1-year after AI completion through repeated-measures ANOVA. RESULTS: Risk of AI discontinuation was increased in patients previously exposed to tamoxifen compared to non-exposed (adjusted HR 5.30 [95% CI 2.23 to 12.57]). VAS and ECOS-16 scores of TAM-2yAI and TAM-3yAI groups increased during AI treatment, mainly during the first 3-12 months. After 1-year from AI completion, values tend to decrease to baseline levels. In 5yAI group, VAS and ECOS-16 levels increased at three months, and VAS remained significantly higher at 1-year post-treatment. CONCLUSIONS: AI therapy increased joint pain and reduced HRQoL, mainly during the first year of treatment. Patients previously treated with tamoxifen experienced greater pain when they switched to AI therapy and had an excess risk of discontinuation during the first 12 months. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03811509. Registered 28 January 2018-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03811509 .

Changes in metabolic risk, insulin resistance, leptin and adiponectin following a lifestyle intervention in overweight and obese breast cancer survivors.

Adiposity and physical activity are modifiable factors that could be important determinants of breast cancer (BC) prognosis through their effects on endogenous reproductive hormones, chronic inflammation and metabolic changes. Therefore, it is necessary to evaluate whether offering lifestyle interventions to BC survivors could affect the levels of certain biomarkers involved in these mechanisms. We designed a pre-post intervention study offering diet and exercise sessions over 12 weeks to 42 overweight/obese BC survivors. Before and after the intervention, we obtained dietary information, anthropometry and cardiorespiratory fitness (CRF) measurements and blood samples to measure metabolic risk, insulin resistance and adipokines biomarkers. Wilcoxon signed-rank tests and Spearman partial correlation coefficients were used to compare pre- and post-measurements and assess the correlations between changes in biomarkers and changes in anthropometry and CRF. Breast cancer survivors showed significant improvements in metabolic risk biomarkers and insulin resistance indicators along with a non-significant leptin decrease and a significant adiponectin decrease. The improvements in metabolic risk biomarkers, insulin resistance indicators and leptin were moderately correlated (0.32 ≤ |r| ≤ 0.55) with the decrease in body mass index and the increase in CRF. Diet and exercise interventions implemented in overweight/obese BC survivors may improve metabolic risk, insulin resistance and leptin biomarkers.

Non-canonical NF-κB pathway activation predicts outcome in borderline oestrogen receptor positive breast carcinoma.

BACKGROUND: NF-κB signalling appears deregulated in breast tumours. The purpose of this study was to determine whether the non-canonical NF-κB pathway, is activated in oestrogen receptor positive (ER+) breast cancer, to identify any correlation between its activity and the clinico-pathological phenotype and to explore whether NF-κB2 and RelB subunits and/or any of their target genes might be used as a predictive marker. METHODS: Two independent cohorts of ER+ early breast cancer patients treated with adjuvant endocrine therapy were included in the study. Activation of RelB and NF-κB2 subunits was determined in a training set of 121 patients by measuring DNA-binding activities in nuclear extracts from fresh frozen specimens by an ELISA-based assay. Samples of 15 ER- breast cancer patients were also included in the study. In a large validation cohort of 207 patients, nuclear immunostaining of RelB and NF-κB2 on formalin-fixed paraffin-embedded specimens was performed. Statistical correlation within clinico-pathological factors, disease-free survival (DFS) and overall survival (OS) was evaluated. Publicly available gene expression and survival data have been interrogated aimed to identify target genes. RESULTS: Activation of NF-κB2 and RelB was found in 53.7 and 49.2% of the 121 ER+ tumours analysed, with similar levels to ER- breast tumours analysed in parallel for comparisons. In the validation cohort, we obtained a similar proportion of cases with activation of NF-κB2 and RelB (59.9 and 32.4%), with a 39.6% of co-activation. Multiplexing immunofluorescence in breast cancer tissue confirmed an inverse spatial distribution of ER with NF-κB2 and RelB nuclear expression in tumour cells. Interestingly, NF-κB2 and RelB mRNA expression was inversely correlated with ER gene (ESR1) levels (P<0.001, both) and its activation was significantly associated with worse DFS (P=0.005 and P=0.035, respectively) in ER+ breast cancer. Moreover, the co-activation of both subunits showed a stronger association with early relapse (P=0.002) and OS (P=0.001). Finally, higher expression of the non-canonical NF-κB target gene myoglobin was associated with a poor outcome in ER+ breast cancer (DFS, P<0.05). CONCLUSIONS: The non-canonical NF-κB pathway activation is inversely associated with oestrogen receptor expression in ER+ breast cancer and predicts poor survival in this subgroup. The myoglobin gene expression has been identified as a possible surrogate marker of the non-canonical NF-κB pathway activation in these tumours.

An overview of randomized clinical trials in metastatic breast cancer: variables affecting regulatory drug approval.

The aim of this study was to analyse trial variables affecting drug approval in metastatic breast cancer (MBC). A literature search from 2000 to 2012 retrieved 66 phase III randomized controlled trials with reported primary endpoints in MBC and known outcomes in terms of approval. The influence of the primary endpoint, the line of therapy, crossover and the sample size was analysed. The primary endpoints used most frequently were progression-free survival (PFS) and time to progression or time to treatment failure (N=47; 71%). Overall survival (OS) was a primary endpoint in nine trials (14%). In 26 trials (39%), statistically significant results were found with respect to the primary endpoint, and in 13 trials (20%), this was found with respect to the secondary endpoint. Gains in OS were found in 12 trials (18%), whereas a benefit to PFS was found in 30 trials (46%). The average median OS was 23.1 months. Postprogression survival accounted for 64% of OS. Trials with crossover did not have OS as the primary endpoint. Trials that resulted in drug approval had a more pronounced gain in OS or PFS and had more patients than those without regulatory consequences. PFS was the main primary endpoint in randomized clinical trials in MBC and was significantly associated with drug approval. OS benefit was rarely achieved in trials where this was not the primary endpoint. The number of randomized patients, the primary endpoint and crossover are factors linked to regulatory requirements for approval, which should be considered in future trial designs.

Genetic determinants of aromatase inhibitor-related arthralgia: the B-ABLE cohort study.

A major side effect of aromatase inhibitor (AI) therapy is AI-related arthralgia (AIA), which often leads to therapy discontinuation. We aimed to identify genetic variants associated with AIA and therapy discontinuation in the first year of AI treatment. Our prospective cohort study included 343 postmenopausal women with early breast cancer starting AI therapy. Single nucleotide polymorphisms (SNPs) in candidate genes involved in estrogen and vitamin D signaling were selected. Univariate and multivariate linear/logistic regressions were fitted in order to asses the association between studied SNPs and AIA intensity (visual analogic scale score) at 3 and 12 months of follow-up, worsening pain, and therapy discontinuation. We also tested for a priori-defined interactions by introducing multiplicative terms in the regression equations. SNPs in CYP17A1 and VDR genes appeared significantly associated with AIA (P = 0.003, P = 0.012, respectively). One SNP in CYP27B1 gene was related to therapy discontinuation [P = 0.02; OR 0.29 (0.09-0.99)]. We revealed interactions between CYP27B1 and both CYP17A1 (P = 0.01) and VDR SNPs (P = 0.06). Furthermore, an additive effect on pain intensity was shown for unfavorable alleles, with two points higher mean absolute pain increase and up to 5.3-fold higher risk of worsening pain compared to favorable genotypes. SNPs in CYP17A1, VDR, and CYP27B1 genes predict the risk of AIA. Their determination would be useful to trigger the monitoring strategies in women at risk of therapy discontinuation.

Vitamin D threshold to prevent aromatase inhibitor-related bone loss: the B-ABLE prospective cohort study.

Aromatase inhibitor (AI)-related bone loss is associated with increased fracture rates. Vitamin D might play a role in minimising this effect. We hypothesised that 25-hydroxy-vitamin D concentrations [25(OH)D] after 3 months supplementation might relate to bone loss after 1 year on AI therapy. We conducted a prospective cohort study from January 2006 to December 2011 of a consecutive sample of women initiating AI for early breast cancer who were ineligible for bisphosphonate therapy and stayed on treatment for 1 year (N = 232). Serum 25(OH)D was measured at baseline and 3 months, and lumbar spine (LS) bone mineral density at baseline and 1 year. Subjects were supplemented with daily calcium (1 g) and vitamin D(3) (800 IU) and additional oral 16,000 IU every 2 weeks if baseline 25(OH)D was <30 ng/ml. Linear regression models were fitted to adjust for potential confounders. After 1 year on AI therapy, 232 participants experienced a significant 1.68 % [95 % CI 1.15-2.20 %] bone loss at LS (0.017 g/cm(2) [0.012-0.024], P < 0.0001). Higher 25(OH)D at 3 months protected against LS bone loss (-0.5 % per 10 ng/ml [95 % CI -0.7 to -0.3 %], adjusted P = 0.0001), and those who reached levels ≥40 ng/ml had reduced bone loss by 1.70 % [95 % CI 0.4-3.0 %; adjusted P = 0.005] compared to those with low 25(OH)D levels (<30 ng/ml). We conclude that improved vitamin D status using supplementation is associated with attenuation of AI-associated bone loss. For this population, the current Institute of Medicine target recommendation of 20 ng/ml might be too low to ensure good bone health.

Vitamin D threshold to prevent aromatase inhibitor-induced arthralgia: a prospective cohort study.

Aromatase inhibitor (AI)-associated arthralgia limits adherence to therapy in breast cancer. The pathophysiology may involve vitamin D status. We wished to establish the optimal concentration of 25(OH)D that prevents or minimizes arthralgia. We used a prospective cohort of 290 women starting AI in whom baseline vitamin D was measured. All received daily vitamin D(3) (800 IU) with calcium. Women with baseline 25(OH)D concentration <30 ng/ml also received 16,000 IU of D(3) orally every 2 weeks. The primary outcome was incident or worsening joint pain derived from baseline and 3-month visual analogic scale (VAS) for joint pain. Regression models were used to analyse the association between vitamin D concentrations at 3 months and pain adjusting for age, BMI, season when the sample was drawn, aromatase inhibitor (exemestane vs. letrozole/anastrozole), prior tamoxifen therapy, baseline NTX, and previous fracture. 90% of women had a 25(OH)D <30 ng/ml at baseline. After supplementation (daily 800 IU and additional 16,000 IU every 2 weeks), 50% of them still failed to reach adequate concentrations at 3 months. In the whole cohort, there was an increase in joint pain (mean 1.16 points SD 2.66; P < 0.001) and the increase was significantly (P = 0.02) attenuated in those that reached concentrations of 25(OH)D of ≥40 ng/ml, with a lower risk of incident arthralgia (OR 0.12 ** [0.03 to 0.40]). A target concentration of 40 ng/ml 25OHD may prevent development of AI arthralgia but higher loading doses are required to attain this level in women with deficiency at baseline.

Phase I/II study of biweekly vinorelbine and oxaliplatin as first-line treatment in patients with metastatic breast cancer.

The objective of this phase I/II study was to establish the recommended dose of biweekly vinorelbine and oxaliplatin in patients with metastatic breast cancer and to evaluate the efficacy and safety profile of this schedule as first-line treatment. Four different dose levels of vinorelbine and oxaliplatin were selected for the phase I study: (i) 25 and 80 mg/m²; (ii) 25 and 90 mg/m²; (iii) 25 and 100 mg/m²; and (iv) 30 and 90 mg/m²; respectively. At least three patients were treated at each dose level. Overall, 12 patients were included in the phase I trial. No dose-limiting toxicities occurred at any dose level. Therefore, the fourth dose level (30 mg/m² of vinorelbine and 90 mg/m² of oxaliplatin) every 2 weeks was selected for the phase II trial. In this part, 44 patients were included and 61% completed the eight 2-week cycles of study treatment. On an intention-to-treat basis, overall response rate was 59%, and median progression-free survival and overall survival were 9.2 months (95% confidence interval: 7.6-10.9) and 18.6 months (95% confidence interval: 14.4-22.9), respectively. The main severe toxicities were neutropenia (46%) and fatigue (14%). We conclude that the biweekly combination of vinorelbine and oxaliplatin at doses of 30 mg/m² and 90 mg/m², respectively, is highly active and well tolerated as first-line treatment for patients with metastatic breast cancer.

Mitogen-activated protein kinase phosphatase-1 in human breast cancer independently predicts prognosis and is repressed by doxorubicin.

PURPOSE: Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) dephosphorylates mitogen-activated protein kinase [extracellular signal-regulated kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and p38], mediates breast cancer chemoresistance, and is repressible by doxorubicin in breast cancer cells. We aimed to characterize doxorubicin effects on MKP-1 and phospho-MAPKs in human breast cancers and to further study the clinical relevance of MKP-1 expression in this disease. EXPERIMENTAL DESIGN: Doxorubicin effects on MKP-1, phospho-ERK1/2 (p-ERK1/2), phospho-JNK (p-JNK), and phospho-p38 were assayed in a panel of human breast cancer cells by Western blot and in human breast cancer were assayed ex vivo by immunohistochemistry (n = 50). MKP-1 expression was also assayed in a range of normal to malignant breast lesions (n = 30) and in a series of patients (n = 96) with breast cancer and clinical follow-up. RESULTS: MKP-1 was expressed at low levels in normal breast and in usual ductal hyperplasia and at high levels in in situ carcinoma. MKP-1 was overexpressed in approximately 50% of infiltrating breast carcinomas. Similar to what was observed in breast cancer cell lines, ex vivo exposure of breast tumors to doxorubicin down-regulated MKP-1, and up-regulated p-ERK1/2 and p-JNK, in the majority of cases. However, in a proportion of tumors overexpressing MKP-1, doxorubicin did not significantly affect MKP-1 or phospho-MAPKs. With regard to patient outcome, MKP-1 overexpression was an adverse prognostic factor for relapse both by univariate (P < 0.001) and multivariate analysis (P = 0.002). CONCLUSIONS: MKP-1 is overexpressed during the malignant transformation of the breast and independently predicts poor prognosis. Furthermore, MKP-1 is repressed by doxorubicin in many human breast cancers.

Effectiveness and safety of a novel dexamethasone mouthwash formulation in managing stomatitis in cancer patients.

OBJECTIVE: To present a new dexamethasone mouthwash formulation and  analyze its effectiveness and safety among patients receiving stomatitis-producing antineoplastic agents. METHOD: Prospective observational study conducted in a university hospital between March 2017 and November 2019. Consecutive patients starting everolimus were enrolled. Patients were instructed to rinse dexamethasone mouthwash formulation twice daily until discontinuation of everolimus. A second cohort of patients with existing stomatitis induced by  high probability of producing stomatitis chemotherapy therapies was also  recruited to assess treatment effectiveness. Effectiveness and safety of dexamethasone mouthwash formulation was assessed. RESULTS: Dexamethasone mouthwash formulation was prescribed in nine patients as prophylaxis. Six patients were diagnosed with breast cancer, two with neuroendocrine tumor and one with renal cell carcinoma. Four patients developed mild stomatitis (grade 1-2) and three patients  discontinued everolimus due to other treatment-related adverse events. In  addition, dexamethasone mouthwash formulation was prescribed as treatment in five patients with existing stomatitis. All patients achieved a significant reduction in the severity of stomatitis after starting the  dexamethasone mouthwash formulation. In both cohorts, dexamethasone  mouthwash formulation was well tolerated and neither dose reduction nor  discontinuation related to stomatitis was required. CONCLUSIONS: Dexamethasone mouthwash formulation could be considered as a  suitable alternative for stomatitis management.

Objetivo: Describir una nueva formulación de enjuague bucal con dexametasona y analizar su efectividad y seguridad en pacientes que reciben agentes antineoplásicos que producen estomatitis.Método: Estudio observacional prospectivo realizado en un hospital universitario entre marzo de 2017 y noviembre de 2019. Se incluyeron los pacientes que  iniciaron everolimus. El tratamiento consistió en enjuagar con solución oral de  dexametasona dos veces al día hasta la interrupción del tratamiento con  everolimus. Se reclutó una segunda cohorte de pacientes con estomatitis  inducida por otros agentes antineoplásicos con alta probabilidad de provocar  estomatitis. Se evaluó la efectividad y seguridad del enjuague bucal con  dexametasona.Resultados: Se reclutaron nueve pacientes en profilaxis con formulación de  enjuague bucal con dexametasona; seis pacientes presentaban un diagnóstico  de cáncer de mama, dos de tumor neuroendocrino y uno de carcinoma renal.  Cuatro pacientes desarrollaron estomatitis leve (grado 1-2) y tres pacientes  descontinuaron everolimus por otros eventos adversos relacionados con el  tratamiento. Se prescribió enjuague bucal con dexametasona en cinco pacientes  con estomatitis existente como tratamiento. Todos los pacientes lograron una  reducción significativa de la gravedad de la estomatitis tras iniciar el enjuague  bucal con dexametasona. En general, el nuevo enjuague bucal con  dexametasona fue bien tolerado y no se requirieron reducción de dosis ni  interrupción debido a estomatitis.Conclusiones: La nueva formulación de enjuague bucal con dexametasona podría considerarse una alternativa adecuada para el manejo de la estomatitis.

Thromboembolic, cardiovascular and overall mortality risks of aromatase inhibitors, compared with tamoxifen treatment: an outpatient-register-based retrospective cohort study.

BACKGROUND: Tamoxifen (TAM) and aromatase inhibitor (AI) therapies have been associated with increased risk of thromboembolic and cardiovascular events, respectively, in addition to other side effects. This study analysed the risk of these events and the overall survival (OS) benefit in breast cancer patients treated with AI, compared with TAM-treated patients, in a large population-based cohort. METHODS: This observational cohort study included women diagnosed with breast cancer and treated with TAM or AI. Data were extracted from primary care records in a population database (SIDIAP, System for the Development of Research in Primary Care). Incidence rates of study outcomes are reported. Survival analyses included Kaplan-Meier estimation and Cox proportional hazards models. Sensitivity analysis was carried out, using Fine and Gray models to account for competing risk of death. Confounding was minimized using propensity score adjustment and inverse probability weighting (IPW) adjustment. RESULTS: Data from 3082 postmenopausal women treated with TAM, and 18,455 treated with AI, were available. Adjusted hazard ratios (HRs) [95% confidence interval (CI)] for AI users, compared with TAM group, were 0.93 (95%CI 0.69-1.26) for thromboembolic events (TEEs); 1.13 (95%CI 0.79-1.63) for cardiovascular events, and 0.76 (95%CI 0.70-0.82) for mortality. Additional analyses using competing risk analysis had similar results, while IPW adjustment showed a potential risk of pulmonary embolism (PE) [2.26 (95%CI 1.02-4.97)] in AI-treated patients. CONCLUSIONS: AI users had >20% lower all-cause mortality compared with TAM users, without increasing risk to experience cardiovascular and TEEs. This would locate AI therapy on the first line in clinical practice. Thus, AI might be the most preferable option in adjuvant hormonal therapy choice.

Increased Fracture Risk in Women Treated With Aromatase Inhibitors Versus Tamoxifen: Beneficial Effect of Bisphosphonates.

Aromatase inhibitors have been associated with accelerated bone loss and an increased risk of osteoporotic fractures. Currently, bisphosphonates are recommended to reduce fracture risk in these patients. The aim of this study is to evaluate the fracture risk in breast cancer patients receiving aromatase inhibitors, compared to tamoxifen users, and to assess the effectiveness of oral bisphosphonates in reducing fracture risk. We performed an observational cohort study up to 10 years of follow-up. Data were extracted from primary care records in a population database. Women diagnosed with breast cancer between 2006 and 2015 and treated with tamoxifen or aromatase inhibitors (n = 36,472) were stratified according to low (without osteoporosis diagnosis nor bisphosphonates exposure) or high (with osteoporosis and/or treated with bisphosphonates) fracture risk. Cox models were used to calculate hazard ratios (HR [95% CI]) of fracture from the propensity score-matched patients. Sensitivity analyses account for competing risk of death were performed (subdistribution hazard ratio [SHR] [95% CI]). In postmenopausal women, fracture risk in aromatase inhibitor users showed an HR 1.40 [95% CI,1.05 to 1.87] and SHR 1.48 [95% CI, 1.11 to 1.98], compared to tamoxifen. Observing aromatase inhibitors patients at high risk of fracture, bisphosphonate-treated patients had an HR 0.73 [95% CI, 0.51 to 1.04] and SHR 0.69 [95% CI, 0.48 to 0.98] compared to nontreated. In conclusion, fracture risk in postmenopausal women during aromatase inhibitor treatment, in real-life conditions, was >40% compared to tamoxifen, corroborating previous randomized controlled trials results. In high-risk patients, bisphosphonate users had lower significant fracture incidence during aromatase inhibitor therapy than nonbisphosphonate users. Monitoring fracture risk and related risk factors in aromatase inhibitor patients is advisable. © 2019 American Society for Bone and Mineral Research.

A single-nucleotide polymorphism in the aromatase gene is associated with the efficacy of the aromatase inhibitor letrozole in advanced breast carcinoma.

PURPOSE: To evaluate the efficacy of treatment with the aromatase inhibitor letrozole in breast cancer patients segregated with respect to DNA polymorphisms of the aromatase gene CYP19. PATIENTS AND METHODS: Postmenopausal patients (n = 67) with hormone receptor-positive metastatic breast cancer were treated with the aromatase inhibitor letrozole. PCR allelic discrimination was used to examine three single-nucleotide polymorphisms (SNP) in DNA obtained from breast carcinoma tissue. Two SNPs analyzed (rs10046 and rs4646) were located in the 3' untranslated region and one (rs727479) was in the intron of the aromatase CYP19 gene. The primary end point of treatment efficacy was time to progression (TTP). RESULTS: Median age was 62 years and median number of metastatic sites was 2. Observed allelic SNP frequencies were rs10046, 71%; rs4646, 46%; and rs727479, 63%. Of the 67 patients, 65 were evaluable for efficacy. Median TTP was 12.1 months. We observed no relationship between TTP and the rs10046 or rs727479 variants. In contrast, we found that TTP was significantly improved in patients with the rs4646 variant, compared with the wild-type gene (17.2 versus 6.4 months; P = 0.02). CONCLUSION: In patients with hormone receptor-positive metastatic breast cancer treated with the aromatase inhibitor letrozole, the presence of a SNP in the 3' untranslated region of the CYP19 aromatase gene is associated with improved treatment efficacy. Testing for the CYP19 rs4646 SNP as a predictive tool for breast cancer patients on antiaromatase therapy deserves prospective evaluation.

Epidemiologic study to assess patient involvement in choice of adjuvant chemotherapy for breast cancer (PROSA Study).

INTRODUCTION: The objective of the current study was to assess patient involvement in adjuvant chemotherapy choice, reasons for treatment choice and satisfaction with the chosen treatment, given that improvement in breast cancer survival has been accompanied by a greater demand for disease information from patients. MATERIAL AND METHODS: An epidemiologic, prospective, multicentre study was conducted with patients aged over 18 diagnosed with breast cancer stages I, II and III. The study, which was conducted prior to these patients initiating adjuvant chemotherapy, was based on a baseline visit and a follow-up visit. Data on sociodemographic and clinical variables were collected and a survey was administered to assess both the reasons for choosing particular treatments and ultimate satisfaction with the chosen treatment. Statistical procedures included a descriptive analysis, bivariate tests and logistic regression. RESULTS: A total of 613 patients were recruited with a mean (SD) age of 53.3 (10.8) years. Most patients had stage II breast cancer (53.9%) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (82.8%). Of these patients, 58.3% were treated with taxanes (48.2% docetaxel, doxorubicin and cyclophosphamide) and 41.7% without (43.5% 5-fluorouracil, epirubicin and cyclophosphamide). At the baseline visit and final visit, 73.8% and 72.6% of patients, respectively, were aware of their diagnosis and prognosis. A total of 77.1% patients (64.7% who had followed their physician's advice) were involved in treatment choice and this involvement was directly related to improved ECOG performance status and information. A total of 78.7% of patients were very satisfied or satisfied with their treatment and 5.4% of patients refused to continue treatment (with 39.3% giving toxicity as the reason). CONCLUSIONS: Although a high proportion of patients were involved in choosing their treatment, this involvement was not related to greater treatment satisfaction. Further research in routine clinical settings is needed in order to assess other factors related to choice of adjuvant chemotherapy, treatment satisfaction and long-term effectiveness (3-5 years).

High Numbers of Circulating CD57+ NK Cells Associate with Resistance to HER2-Specific Therapeutic Antibodies in HER2+ Primary Breast Cancer.

Natural killer (NK) cells can orchestrate effective antitumor immunity. The presence of tumor-infiltrating NK cells in diagnostic biopsies predicts pathologic complete response (pCR) to HER2-specific therapeutic antibodies in patients with primary breast cancer. Here, we analyzed whether diversity in circulating NK cells might influence tumor infiltration and HER2-specific therapeutic antibody efficacy. We found that numbers of circulating CD57+ NK cells inversely correlated with pCR to HER2-specific antibody treatment in patients with primary breast cancer independently of age, traditional clinicopathologic factors, and CD16A 158F/V genotype. This association was uncoupled from the expression of other NK-cell receptors, the presence of adaptive NK cells, or changes in major T-cell subsets, reminiscent of cytomegalovirus-induced immunomodulation. NK-cell activation against trastuzumab-coated HER2+ breast cancer cells was comparable in patients with high and low proportions of CD57+ NK cells. However, circulating CD57+ NK cells displayed decreased CXCR3 expression and CD16A-induced IL2-dependent proliferation in vitro Presence of CD57+ NK cells was reduced in breast tumor-associated infiltrates as compared with paired peripheral blood samples, suggesting deficient homing, proliferation, and/or survival of NK cells in the tumor niche. Indeed, numbers of circulating CD57+ were inversely related to tumor-infiltrating NK-cell numbers. Our data reveal that NK-cell differentiation influences their antitumor potential and that CD57+ NK cells may be a biomarker useful for tailoring HER2 antibody-based therapeutic strategies in breast cancer.

Alkylphenolic compounds and risk of breast and prostate cancer in the MCC-Spain study.

BACKGROUND: Alkylphenolic compounds are chemicals with endocrine disrupting properties that have been widely used in industry with important changes in their usage over time. Few epidemiologic studies have evaluated the effect of alkylphenolic compounds on human health. OBJECTIVES: We investigated whether occupational exposure to alkylphenolic compounds is associated with breast and prostate cancer. METHODS: We carried out a population-based case-control study including 1513 incident cases of breast cancer, 1095 of prostate cancer, and 3055 controls, frequency matched by sex, age and region. Occupational exposure to alkylphenolic compounds was estimated using a recently developed job-exposure matrix, which considered different scenarios of exposure and different subtypes of alkylphenolic compounds. RESULTS: History of occupational exposure to alkylphenolic compounds was modestly associated with breast cancer (OR = 1.23; 95% CI = 1.01-1.48). Within the different scenarios, the occupational use of domestic tensioactives was positively associated with breast cancer (OR = 1.28; 95% CI = 1.02-1.60), while occupational exposure in other scenarios showed mostly a suggestion of a similar positive associations. Exposure to nonylphenol ethoxylates was positively associated with breast cancer (OR = 1.21; 95% CI = 1.00-1.47), while exposure to other compounds was uncommon. In general, we did not observe associations between alkylphenolic compounds and prostate cancer, except for a positive association among men occupationally exposed to cosmetic, hair and personal hygiene products. CONCLUSIONS: Our findings suggest a modest association between breast cancer risk and occupational exposure to alkylphenolic compounds, and no associations between these compounds and prostate cancer risk. These findings warrant further corroboration in other studies.

Vitamin D levels in Mediterranean breast cancer patients compared with those in healthy women.

OBJECTIVES: To evaluate the vitamin D status of postmenopausal women with early estrogen-receptor-positive breast cancer and to compare it with that of healthy postmenopausal women from the same Mediterranean region. STUDY DESIGN AND OUTCOME MEASURES: Data from 691 breast cancer (BC) patients in the B-ABLE cohort were analyzed after recent cancer intervention (recent-BC) or after a minimum of two years since this intervention (long-term-BC). Patients were also stratified by previous chemotherapy exposure (ChT+ and ChT-). Plasma levels of 25-hydroxyvitamin D [25(OH)D] (25(OH)D) were compared with data from 294 healthy women (non-BC) by linear regression to estimate ß-coefficients using non-BC participants as the reference group. Age, body mass index and season of blood extraction were selected as potential confounders. RESULTS: Of the recent-BC patients, 23.7% had 25(OH)D deficiency, compared with 17.7% of the long-term-BC group, and just 1.4% of the non-BC participants. Most of the women were located in the insufficient 25(OH)D category regardless of study group. BC patients had significantly lower 25(OH)D levels than non-BC participants (adjusted ß-coefficients: -4.84 [95%CI -6.56 to -3.12] in recent-BC, and -2.05 [95%CI -4.96 to -0.14] in long-term-BC). Among BC patients, the lowest 25(OH)D levels were found in the recent-BC (ChT+) group (p < 0.001). No differences were found between the long-term-BC (ChT-), long-term-BC (ChT+) and recent-BC (ChT-) groups. Among the BC ChT+ patients, the recent-BC group had significantly lower 25(OH)D levels than the long-term-BC group (p < 0.001). CONCLUSION: Severely reduced 25(OH)D levels were detected in patients with breast cancer, particularly after recent chemotherapy. These 25(OH)D levels had partially recovered over the long term, but still remained much lower than in the healthy population.

Bone health evaluation one year after aromatase inhibitors completion.

INTRODUCTION: Breast cancer patients treated with aromatase inhibitors (AIs) experience increased bone loss during their treatment. However, there is little information about bone mineral density (BMD) after completing AI-treatment. The present study aimed to assess BMD changes one year after AI-therapy completion. METHODS: Data were collected from 864 postmenopausal women treated with AI during 5 years (5y-AI group), or during 2-3 years after taking tamoxifen therapy (pTAM-AI group). Participants with osteoporosis were treated with oral bisphosphonates (BP). BMD changes in lumbar spine (LS), femoral neck (FN) and total hip (TH) between baseline, end of treatment, and at one year post-treatment were assessed using repeated-measures ANOVA. RESULTS: At the end of AI-treatment, 382 patients had available BMD values and 316 also had post-treatment BMD values. As expected, BMD levels were decreased at AI-completion in non-BP treated patients. After one year, LS BMD increased in both groups (5y-AI: +2.11% [95%CI: 1.55 to 2.68], p < 0.001; pTAM-AI: +1.00% [95%CI: 0.49 to 1.51], p < 0.001) compared with the end of AI-therapy, while values at FN and TH remained stable. On the other hand, BMD values of BP-treated patients were increased or maintained at the end of AI-treatment and also at post-treatment. CONCLUSIONS: At one year after AI-completion, FN and TH BMD remained reduced in non-BP treated women, while LS BMD was recovered in the 5y-AI group and partially recovered in the pTAM-AI group. BP treatment increased or maintained BMD values at the end of therapy and at one year post-treatment.

Cancer Genome Interpreter annotates the biological and clinical relevance of tumor alterations.

While tumor genome sequencing has become widely available in clinical and research settings, the interpretation of tumor somatic variants remains an important bottleneck. Here we present the Cancer Genome Interpreter, a versatile platform that automates the interpretation of newly sequenced cancer genomes, annotating the potential of alterations detected in tumors to act as drivers and their possible effect on treatment response. The results are organized in different levels of evidence according to current knowledge, which we envision can support a broad range of oncology use cases. The resource is publicly available at http://www.cancergenomeinterpreter.org .