Association between selenium intake and breast cancer risk: results from the Women's Health Initiative.

PURPOSE: It has been hypothesized that selenium (Se) can prevent cancer, and that Se deficiency may be associated with an increased risk of breast cancer. However, findings from epidemiological studies have been inconsistent. The objective of this study was to assess the association between Se intake and risk of breast cancer in the Women's Health Initiative (WHI). METHODS: This study included 145,033 postmenopausal women 50-79 years who completed baseline questionnaires between October 1993 and December 1998, which addressed dietary and supplemental Se intake and breast cancer risk factors. The association between baseline Se intake and incident breast cancer was examined in Cox proportional hazards analysis. RESULTS: During a mean follow-up of 15.5 years, 9487 cases of invasive breast cancer were identified. Total Se (highest versus lowest quartile: HR 1.00, 95% CI 0.92-1.09, Ptrend = 0.66), dietary Se (highest versus lowest quartile: HR 0.99, 95% CI 0.89-1.08, Ptrend = 0.61), and supplemental Se (yes versus no: HR 0.99, 95% CI 0.95-1.03) were not associated with breast cancer incidence. CONCLUSIONS: This study indicates that Se intake is not associated with incident breast cancer among postmenopausal women in the United States. Further studies are needed to confirm our findings by using biomarkers such as toenail Se to reduce the potential for misclassification of Se status.

Pretreatment elevated prognostic nutritional index predicts a favorable prognosis in patients with prostate cancer.

BACKGROUND: The prognostic nutritional index (PNI), an immunity and nutrition based prognostic score, was correlated with clinical outcomes in different tumors. However, the prognostic significance of PNI has not been investigated in hormone sensitive prostate cancer (PCa). The objective of this study was to determine the prognostic significance of PNI in hormone sensitive PCa. METHODS: Two hundred eighty PCa patients undergoing androgen deprivation therapy (ADT) as first line therapy at three centers were enrolled. The serum albumin levels and peripheral lymphocyte count were measured at the time of diagnosis. PNI was calculated as 10 * serum albumin (g/dL) + 0.005 * total lymphocyte count (per mm3). Patients were categorized in two groups using a cut-off point of 50.2 as calculated by the receiver-operating curve analysis. Univariate and multivariate cox regression analyses were performed to evaluate PNI as a favorable prognostic factor for progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS). Prognostic accuracy was evaluated with the Harrell concordance index. RESULTS: Multivariate analyses identified PNI as an independent prognostic indicator with respect to PFS (hazard ratio (HR) = 0.521, p = 0.001), CSS (HR = 0.421, p = 0.002) and OS (HR = 0.429, p = 0.001). Patients with elevated PNI had better clinical outcomes. The addition of PNI to the final models improved predictive accuracy (c-index: 0.758, 0.830 and 0.782) for PFS, CSS and OS compared with the clinicopathological base models (c-index: 0.736, 0.801 and 0.752), which included Gleason score and incidence of metastasis. CONCLUSIONS: Elevated pretreatment PNI was a favorable prognostic indicator for PCa patients treated with ADT.

¿Qué hacer ante un pT0 en cáncer de próstata? Revisión a propósito de un caso / What to do with a pT0 in Prostate Cancer? Review of the Literature and Case Report

Introducción y Objetivos El cáncer de próstata es la segunda causa de mortalidad por cáncer en hombres en Colombia y en el mundo. El efecto "vanishing" en cáncer de próstata, es un fenómeno poco frecuente que se define como la ausencia de tumor en el estudio histológico postquirúrgico de pacientes llevados a prostatectomía radical como manejo curativo diagnóstico previo confirmado por biopsia o RTUP. Su incidencia en diferentes series llega hasta el 0,86%, por lo cual existen pocos estudios aleatorizados al respecto y aún no es clara la conducta con ese tipo de tumores. Reportamos un caso de un paciente con cáncer de próstata pT0 y realizamos una revisión de la literatura respecto del seguimiento y manejo que se deberían seguir al enfrentarnos a ese tipo de tumor. Métodos y Materiales Revisión de la literatura y reporte de caso clínico. Reporte de Caso Hombre de 58 años sintomático urinario, con PSA elevado por lo que se realizó biopsia transrectal de próstata, con resultado de adenocarcinoma de próstata confirmado por inmunohistoquímica. Al realizarse la prostatectomía radical no se encuentra tumor en la patología. En la literatura se encuentran factores asociados con la presencia del tumor cuando hay RTUP previa y uso de hormonoterapia neoadyuvante en el contexto de tumores de bajo volumen. A pesar de no encontrarse tumor en la patología, está descrita la recaída bioquímica y progresión clínica de esos tumores, por lo que debe realizarse el seguimiento usual para esa patología. Conclusiones El hallazgo de pT0 en cáncer de próstata, aunque poco frecuente, demanda una guía de manejo Proponemos la revisión de la patología con el protocolo descrito para reducir los falsos positivos y el seguimiento usual con los pasos estandarizados en las guías internacionales.

Introduction and Objectives Prostate cancer is the second leading cause of death related with cancer in men in Colombia and the world. "Vanishing" phenomenon in prostate cáncer is a rare event, where the post-surgical histologic review in patiets that underwent radical prostatectomy is negative, all of them with previous diagnosis of CaP by biopsy or TUR. The incidence of CaP in different series reaches 0.86%, whereby there are few randomized studies and the management and follow up of this type of tumors is not clear. In this article we report a case of a pT0 prostate cancer patient. We perform a systematic review of the literature to determine the medical behavior and medical follow up in cases presenting with pT0 prostate cancer. Materials and Methods Review of the literature & case report. Results Patient of 58 years old with medical history of recent progressive LUTS and high PSA levels that underwent a trans-rectal prostate biopsy with report of adenocarcinoma, that were confirmed by immunohistochemistry. In the pathology report after the radical prostatectomy no tumor cells were found. In the literature, there is reference about factors associated with pT0 prostate cancer in patients with previous RTUP and that were taken to hormonal coadjutant therapy in lesser degree tumors. Despite the absent of cancer findings in the pathology, it is well described biochemistry relapses and clinical progression of this tumors; usual protocol follow up must be made. Conclusion In patients with pT0 prostate cancer, even though to be a rare finding, must be studied and follow up with the steps mentioned above with the aim to reduce the false positive cases. Also the follow-ups steps must fully meet the requirements of standardized protocols guidelines.

Steroid sulfatase inhibition success and limitation in breast cancer clinical assays: An underlying mechanism.

Steroid sulfatase is detectable in most hormone-dependent breast cancers. STX64, an STS inhibitor, induced tumor reduction in animal assay. Despite success in phase І clinical trial, the results of phase II trial were not that significant. Breast Cancer epithelial cells (MCF-7 and T47D) were treated with two STS inhibitors (STX64 and EM1913). Cell proliferation, cell cycle, and the concentrations of estradiol and 5α-dihydrotestosterone were measured to determine the endocrinological mechanism of sulfatase inhibition. Comparisons were made with inhibitions of reductive 17ß-hydroxysteroid dehydrogenases (17ß-HSDs). Proliferation studies showed that DNA synthesis in cancer cells was modestly decreased (approximately 20%), accompanied by an up to 6.5% in cells in the G0/G1 phase and cyclin D1 expression reduction. The concentrations of estradiol and 5α-dihydrotestosterone were decreased by 26% and 3% respectively. However, supplementation of 5α-dihydrotestosterone produced a significant increase (approximately 35.6%) in the anti-proliferative effect of sulfatase inhibition. This study has clarified sex-hormone control by sulfatase in BC, suggesting that the different roles of estradiol and 5α-dihydrotestosterone can lead to a reduction in the effect of sulfatase inhibition when compared with 17ß-HSD7 inhibition. This suggests that combined treatment of sulfatase inhibitors with 17ß-HSD inhibitors such as the type7 inhibitor could hold promise for hormone-dependent breast cancer.

Fulvestrant for hormone-sensitive metastatic breast cancer.

BACKGROUND: Fulvestrant is a selective oestrogen receptor down-regulator (SERD), which by blocking proliferation of breast cancer cells, is an effective endocrine treatment for women with hormone-sensitive advanced breast cancer. The goal of such systemic therapy in this setting is to reduce symptoms, improve quality of life, and increase survival time. OBJECTIVES: To assess the efficacy and safety of fulvestrant for hormone-sensitive locally advanced or metastatic breast cancer in postmenopausal women, as compared to other standard endocrine agents. SEARCH METHODS: We searched the Cochrane Breast Cancer Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), and ClinicalTrials.gov on 7 July 2015. We also searched major conference proceedings (American Society of Clinical Oncology (ASCO) and San Antonio Breast Cancer Symposium) and practice guidelines from major oncology groups (ASCO, European Society for Medical Oncology (ESMO), National Comprehensive Cancer Network, and Cancer Care Ontario). We handsearched reference lists from relevant studies. SELECTION CRITERIA: We included for analyses randomised controlled trials that enrolled postmenopausal women with hormone-sensitive advanced breast cancer (TNM classifications: stages IIIA, IIIB, and IIIC) or metastatic breast cancer (TNM classification: stage IV) with an intervention group treated with fulvestrant with or without other standard anticancer therapy. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from trials identified in the searches, conducted 'Risk of bias' assessments of the included studies, and assessed the overall quality of the evidence using the GRADE approach. Outcome data extracted from these trials for our analyses and review included progression-free survival (PFS) or time to progression (TTP) or time to treatment failure, overall survival, clinical benefit rate, toxicity, and quality of life. We used the fixed-effect model for meta-analysis where possible. MAIN RESULTS: We included nine studies randomising 4514 women for meta-analysis and review. Overall results for the primary endpoint of PFS indicated that women receiving fulvestrant did at least as well as the control groups (hazard ratio (HR) 0.95, 95% confidence interval (CI) 0.89 to 1.02; P = 0.18, I2= 56%, 4258 women, 9 studies, high-quality evidence). In the one high-quality study that tested fulvestrant at the currently approved and now standard dose of 500 mg against anastrozole, women treated with fulvestrant 500 mg did better than anastrozole, with a HR for TTP of 0.66 (95% CI 0.47 to 0.93; 205 women) and a HR for overall survival of 0.70 (95% CI 0.50 to 0.98; 205 women). There was no difference in PFS whether fulvestrant was used in combination with another endocrine therapy or in the first- or second-line setting, when compared to control treatments: for monotherapy HR 0.97 (95% CI 0.90 to 1.04) versus HR 0.87 (95% CI 0.77 to 0.99) for combination therapy when compared to control, and HR 0.93 (95% CI 0.84 to 1.03) in the first-line setting and HR 0.96 (95% CI 0.88 to 1.04) in the second-line setting.Overall, there was no difference between fulvestrant and control treatments in clinical benefit rate (risk ratio (RR) 1.03, 95% CI 0.97 to 1.10; P = 0.29, I2 = 24%, 4105 women, 9 studies, high-quality evidence) or overall survival (HR 0.97, 95% CI 0.87 to 1.09, P = 0.62, I2 = 66%, 2480 women, 5 studies, high-quality evidence). There was no significant difference in vasomotor toxicity (RR 1.02, 95% CI 0.89 to 1.18, 3544 women, 8 studies, high-quality evidence), arthralgia (RR 0.96, 95% CI 0.86 to 1.09, 3244 women, 7 studies, high-quality evidence), and gynaecological toxicities (RR 1.22, 95% CI 0.94 to 1.57, 2848 women, 6 studies, high-quality evidence). Four studies reported quality of life, none of which reported a difference between the fulvestrant and control arms, though specific data were not presented. AUTHORS' CONCLUSIONS: For postmenopausal women with advanced hormone-sensitive breast cancer, fulvestrant is at least as effective and safe as the comparator endocrine therapies in the included studies. However, fulvestrant may be potentially more effective than current therapies when given at 500 mg, though this higher dosage was used in only one of the nine studies included in the review. We saw no advantage with combination therapy, and fulvestrant was equally as effective as control therapies in both the first- and second-line setting. Our review demonstrates that fulvestrant is a safe and effective systemic therapy and can be considered as a valid option in the sequence of treatments for postmenopausal women with hormone-sensitive advanced breast cancer.

A 16 Yin Yang gene expression ratio signature for ER+/node- breast cancer.

Breast cancer is one of the leading causes of cancer death in women. It is a complex and heterogeneous disease with different clinical outcomes. Stratifying patients into subgroups with different outcomes could help guide clinical decision making. In this study, we used two opposing groups of genes, Yin and Yang, to develop a prognostic expression ratio signature. Using the METABRIC cohort we identified a16-gene signature capable of stratifying breast cancer patients into four risk levels with intention that low-risk patients would not undergo adjuvant systemic therapy, intermediate-low-risk patients will be treated with hormonal therapy only, and intermediate-high- and high-risk groups will be treated by chemotherapy in addition to the hormonal therapy. The 16-gene signature for four risk level stratifications of breast cancer patients has been validated using 14 independent datasets. Notably, the low-risk group (n = 51) of 205 estrogen receptor-positive and node negative (ER+/node-) patients from three different datasets who had not had any systemic adjuvant therapy had 100% 15-year disease-specific survival rate. The Concordance Index of YMR for ER+/node negative patients is close to the commercially available signatures. However, YMR showed more significance (HR = 3.7, p = 8.7e-12) in stratifying ER+/node- subgroup than OncotypeDx (HR = 2.7, p = 1.3e-7), MammaPrint (HR = 2.5, p = 5.8e-7), rorS (HR = 2.4, p = 1.4e-6), and NPI (HR = 2.6, p = 1.2e-6). YMR signature may be developed as a clinical tool to select a subgroup of low-risk ER+/node- patients who do not require any adjuvant hormonal therapy (AHT).

Cardiac glycosides and breast cancer risk: A systematic review and meta-analysis of observational studies.

Cardiac glycosides are phytoestrogens and have been linked to the risk of estrogen sensitive cancers such as uterus cancer. However, the association between use of cardiac glycosides and risk of breast cancer remains unclear. We investigated the association between cardiac glycosides use and the risk of breast cancer by systematically reviewing the published literature and performing meta-analyses. A comprehensive literature search was performed using MEDLINE, EMBASE, Web of Science and SCOPUS to identify all relevant articles published up to November 2015. Risk estimates, and accompanying standard errors, for the association between cardiac glycoside use and breast cancer were extracted from identified studies. Meta-analysis models were used to calculate a combined hazard ratio (HR), and 95% confidence interval (CI), and to investigate heterogeneity between studies. In total, nine studies were identified investigating cardiac glycosides use and risk of developing breast cancer. Overall, there was evidence to suggest an association between cardiac glycosides use and breast cancer risk (HR = 1.34; 95% CI 1.25, 1.44; p < 0.001) with little variation in the association between studies (I2 = 16%, p for heterogeneity = 0.30). Results were little altered when analysis was restricted to studies with high quality scores or cohort studies. Overall, there was a 34% increase in breast risk with use of cardiac glycosides but it is unclear whether this association reflects confounding or is causal. Further observational studies are required to examine this association particularly for estrogen receptor positive breast cancer and to explore the role of potential confounding variables.

Statin Use at the Time of Initiation of Androgen Deprivation Therapy and Time to Progression in Patients With Hormone-Sensitive Prostate Cancer.

IMPORTANCE: Statin use has been associated with improved prostate cancer outcomes. Dehydroepiandrosterone sulfate (DHEAS) is a precursor of testosterone and a substrate for SLCO2B1, an organic anionic transporter. We previously demonstrated that genetic variants of SLCO2B1 correlated with time to progression (TTP) during receipt of androgen deprivation therapy (ADT). Statins also use SLCO2B1 to enter cells, and thus we hypothesized that they may compete with DHEAS uptake by the tumor cells. OBJECTIVE: To evaluate whether statin use prolongs TTP during ADT for hormone-sensitive prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: In vitro studies were performed using prostate cancer cell lines at an academic, comprehensive cancer center. Statin use was retrospectively analyzed in 926 patients who had received ADT for biochemical or metastatic recurrence or de novo metastatic prostate cancer between January 1996 and November 2013. MAIN OUTCOMES AND MEASURES: To determine whether statins interfere with DHEAS uptake, we performed in vitro studies using prostate cancer cell lines. Next, we queried our institutional clinical database to assess for an association between statin use and TTP during ADT using multivariable Cox regression analysis and adjusted for known prognostic factors. RESULTS: In vitro, we demonstrated that statins block DHEAS uptake by competitively binding to SLCO2B1. In our ADT cohort of 926 patients, 283 (31%) were taking a statin at ADT initiation. After a median follow-up of 5.8 years, 644 patients (70%) had experienced disease progression while receiving ADT. Median TTP during ADT was 20.3 months (95% CI, 18-24 months). Men taking statins had a longer median TTP during ADT compared with nonusers (27.5 [95% CI, 21.1-37.7] vs 17.4 [95% CI, 14.9-21.1] months; P < .001). The association remained statistically significant after adjusting for predefined prognostic factors (adjusted hazard ratio, 0.83 [95% CI, 0.69-0.99]; P = .04). The positive statin effect was observed for both patients with and without metastases (adjusted hazard ratio, 0.79 [95% CI, 0.58-1.07] for M0 disease and 0.84 [95% CI, 0.67-1.06] for M1 disease; P for interaction = .72). CONCLUSIONS AND RELEVANCE: Statin use at the time of ADT initiation was associated with a significantly longer TTP during ADT even after adjustment for known prognostic factors. Our in vitro finding that statins competitively reduce DHEAS uptake, thus effectively decreasing the available intratumoral androgen pool, affords a plausible mechanism to support the clinical observation of prolonged TTP in statin users.

Effect of Epilobium angustifolium and Serenoa repens extracts on regulation of non-genomic signaling pathway of kinases.

OBJECTIVES: Changes of kinase activity of non-genomic cellular signaling pathway may influence the effectiveness of pharmacotherapy in case of hormone-dependent tumors. Our study investigated a possible interaction at the molecular level between an aqueous herbal extract of Epilobium angustifolium as well as a lipid-sterolic fruit extract of Serenoa repens and synthetic drugs used in the treatment of hormone-dependent cancers. MATERIAL AND METHODS: E. angustifolium and Serenoa repens extracts were orally administered to testosterone-induced rats for 21 days. Changes of RafA/Mapk3/Mapk1 mRNA levels were analyzed by real-time quantitative PCR using target specific primers. RESULTS: The level of RafA mRNA slightly increased in rats receiving Epilobium angustifolium (p = 0.076) and Serenoa repens (p = 0.016) extracts. Administration of these extracts resulted in significantly elevated Mapk1 and Mapk3 transcripts in the investigated animals (p < 0.05 for each extract). The levels of Mapk1 and Mapk3 mRNA strongly increased (p < 0.05 for each extract) in animals receiving concomitantly testosterone and the extracts, while RafA transcription slightly decreased (p < 0.05), as compared to controls. CONCLUSIONS: The results of our study may indicate a potential effect of S. repens and E. angustifolium extracts on the functioning of non-genomic cellular signaling kinases pathway. We investigated safety of these extracts to detect possible drug interactions between synthetic drugs used in the treatment of proliferative changes in hormone-dependent reproductive organs and herbal preparations.

HAGE (DDX43) is a biomarker for poor prognosis and a predictor of chemotherapy response in breast cancer.

BACKGROUND: HAGE protein is a known immunogenic cancer-specific antigen. METHODS: The biological, prognostic and predictive values of HAGE expression was studied using immunohistochemistry in three cohorts of patients with BC (n=2147): early primary (EP-BC; n=1676); primary oestrogen receptor-negative (PER-BC; n=275) treated with adjuvant anthracycline-combination therapies (Adjuvant-ACT); and primary locally advanced disease (PLA-BC) who received neo-adjuvant anthracycline-combination therapies (Neo-adjuvant-ACT; n=196). The relationship between HAGE expression and the tumour-infiltrating lymphocytes (TILs) in matched prechemotherapy and postchemotherapy samples were investigated. RESULTS: Eight percent of patients with EP-BC exhibited high HAGE expression (HAGE+) and was associated with aggressive clinico-pathological features (Ps<0.01). Furthermore, HAGE+expression was associated with poor prognosis in both univariate and multivariate analysis (Ps<0.001). Patients with HAGE+did not benefit from hormonal therapy in high-risk ER-positive disease. HAGE+and TILs were found to be independent predictors for pathological complete response to neoadjuvant-ACT; P<0.001. A statistically significant loss of HAGE expression following neoadjuvant-ACT was found (P=0.000001), and progression-free survival was worse in those patients who had HAGE+residual disease (P=0.0003). CONCLUSIONS: This is the first report to show HAGE to be a potential prognostic marker and a predictor of response to ACT in patients with BC.

Effects of aromatase inhibitors and body mass index on steroid hormone levels in women with early and advanced breast cancer.

BACKGROUND: Aromatase inhibitors (AIs) are central to the management of oestrogen receptor-positive breast cancer in the adjuvant and metastatic setting. Levels of circulating steroid hormones (SHs) were measured in patients established on AIs to investigate: the influence of body mass index (BMI) in both the adjuvant and metastatic setting; the class of AI utilized in the adjuvant setting (steroidal versus non-steroidal); and differences in SH levels between women treated adjuvantly and those receiving a second-line AI for locally advanced/metastatic disease. METHODS: Plasma levels of androstenedione, 5-androstene-3ß,17ß-diol, dehydroepiandrosterone, oestradiol and testosterone were measured by radioimmunoassay in women with breast cancer who were receiving AIs in either an adjuvant or a metastatic setting. Differences between mean SH levels by class of AI, BMI, and second-line versus adjuvant therapy were assessed. RESULTS: Sixty-four women were receiving AI therapy, 45 (70 per cent) in an adjuvant setting and 19 (30 per cent) were taking a second-line AI. There was no significant correlation between BMI and SH levels. However, BMI was significantly higher in the second-line AI cohort compared with the adjuvant cohort (29.8 versus 26.2 kg/m2 respectively; P = 0.026). In the adjuvant setting, patients receiving a steroidal AI had significantly higher levels of all five hormones (P < 0.050). In the second-line AI cohort, oestradiol levels were significantly higher than in the adjuvant cohort (4.5 versus 3.3 pg/ml respectively; P = 0.022). Multivariable analysis adjusted for BMI confirmed the higher residual oestradiol level in the second-line AI group (P = 0.063) and a significantly higher androstenedione level (P = 0.022). CONCLUSION: Residual levels of SH were not significantly influenced by BMI. However, the significant differences in residual SH levels between the second-line and adjuvant AI cohort is of relevance in the context of resistance to AI therapy, and warrants further investigation.

[Legal value of the recomendations of good practice: example for breast cancer hormonotherapy]. / Valeur juridique des recommandations de bonne pratique: cas de l'hormonothérapie des cancers du sein.

On April 27th 2011, the French Supreme Administrative Court (Conseil d'État) granted the Recommendations for Good Practice set out by the French National Authority for Health (Haute Autorité de santé--[HAS]) a legal status, considering that they "must be regarded as (…) decisions which may be subject to an action for annulment". The judge came to this conclusion through a quasi-syllogistic reasoning. Firstly, the French Code of Medical Ethics requires physicians to care for their patients in accordance with established scientific knowledge. Secondly, the HAS recommendations recall in particular this established scientific knowledge. Treating patients according to established scientific knowledge requires then that physicians follow the HAS recommendations. While the case at bar does not directly involve liability for medical malpractice-since the applicant only sought to have an HAS recommendation declared void-it is nonetheless necessary to examine the impact of this ruling for health professionals. Indeed, this decision raises a number of concerns for everyday medical practice. Guidelines concerning the endocrine treatment of hormonodependant breast cancers are plentiful. In January 2010, the HAS and the French National Institute for Cancer (Institut national du cancer) issued a "Guide for long-term illnesses-Breast cancer" (Guide ALD - Cancer du sein). In addition to these nation-wide guidelines, the Regional Networks for Cancer (réseaux régionaux de cancérologie) issued their own recommendations. Other guidelines are also set out in the framework of consensus conferences, such as the Nice Saint-Paul-de-Vence (France) and St. Gallen (Switzerland) conferences. In the United States, the National Comprehensive Cancer Network (NCCN) and the American Society of Clinical Oncology (ASCO), and in Europe, the European Society of Medical Oncology (ESMO) make recommendations as well. Therefore, the HAS recommendations are hardly the sole source of information for physicians and these documents sometimes contradict each other. Besides, these can quickly become obsolete, what still limits their relevance. Nevertheless, in the judge's mind, there is no place for conflicting interpretations; scientific knowledge must be consistent, homogeneous and objective. However, the reality is quite the opposite. This simplistic vision shared by judges does not seem to grasp the complexity of everyday medical practice. After a critical reading of the Conseil d'État judgment, we shall consider the potential issues and concerns raised by this ruling in medical practice using the example of hormone therapy for breast cancer patients.

Effectiveness of primary androgen-deprivation therapy for clinically localized prostate cancer.

PURPOSE: Primary androgen-deprivation therapy (PADT) is often used to treat clinically localized prostate cancer, but its effects on cause-specific and overall mortality have not been established. Given the widespread use of PADT and the potential risks of serious adverse effects, accurate mortality data are needed to inform treatment decisions. METHODS: We conducted a retrospective cohort study using comprehensive utilization and cancer registry data from three integrated health plans. All men were newly diagnosed with clinically localized prostate cancer. Men who were diagnosed between 1995 and 2008, were not treated with curative intent therapy, and received follow-up through December 2010 were included in the study (n = 15,170). We examined all-cause and prostate cancer-specific mortality as our main outcomes. We used Cox proportional hazards models with and without propensity score analysis. RESULTS: Overall, PADT was associated with neither a risk of all-cause mortality (hazard ratio [HR], 1.04; 95% CI, 0.97 to 1.11) nor prostate-cancer-specific mortality (HR, 1.03; 95% CI, 0.89 to 1.19) after adjusting for all sociodemographic and clinical characteristics. PADT was associated with decreased risk of all-cause mortality but not prostate-cancer-specific mortality. PADT was associated with decreased risk of all-cause mortality only among the subgroup of men with a high risk of cancer progression (HR, 0.88; 95% CI, 0.78 to 0.97). CONCLUSION: We found no mortality benefit from PADT compared with no PADT for most men with clinically localized prostate cancer who did not receive curative intent therapy. Men with higher-risk disease may derive a small clinical benefit from PADT. Our study provides the best available contemporary evidence on the lack of survival benefit from PADT for most men with clinically localized prostate cancer.

Effects of adjuvant exemestane versus anastrozole on bone mineral density for women with early breast cancer (MA.27B): a companion analysis of a randomised controlled trial.

BACKGROUND: Treatment of breast cancer with aromatase inhibitors is associated with damage to bones. NCIC CTG MA.27 was an open-label, phase 3, randomised controlled trial in which women with breast cancer were assigned to one of two adjuvant oral aromatase inhibitors-exemestane or anastrozole. We postulated that exemestane-a mildly androgenic steroid-might have a less detrimental effect on bone than non-steroidal anastrozole. In this companion study to MA.27, we compared changes in bone mineral density (BMD) in the lumbar spine and total hip between patients treated with exemestane and patients treated with anastrozole. METHODS: In MA.27, postmenopausal women with early stage hormone (oestrogen) receptor-positive invasive breast cancer were randomly assigned to exemestane 25 mg versus anastrozole 1 mg, daily. MA.27B recruited two groups of women from MA.27: those with BMD T-scores of -2·0 or more (up to 2 SDs below sex-matched, young adult mean) and those with at least one T-score (hip or spine) less than -2·0. Both groups received vitamin D and calcium; those with baseline T-scores of less than -2·0 also received bisphosphonates. The primary endpoints were percent change of BMD at 2 years in lumbar spine and total hip for both groups. We analysed patients according to which aromatase inhibitor and T-score groups they were allocated to but BMD assessments ceased if patients deviated from protocol. This study is registered with ClinicalTrials.gov, NCT00354302. FINDINGS: Between April 24, 2006, and May 30, 2008, 300 patients with baseline T-scores of -2·0 or more were accrued (147 allocated exemestane, 153 anastrozole); and 197 patients with baseline T-scores of less than -2·0 (101 exemestane, 96 anastrozole). For patients with T-scores greater than -2·0 at baseline, mean change of bone mineral density in the spine at 2 years did not differ significantly between patients taking exemestane and patients taking anastrozole (-0·92%, 95% CI -2·35 to 0·50 vs -2·39%, 95% CI -3·77 to -1·01; p=0·08). Respective mean loss in the hip was -1·93% (95% CI -2·93 to -0·93) versus -2·71% (95% CI -4·32 to -1·11; p=0·10). Likewise for those who started with T-scores of less than -2·0, mean change of spine bone mineral density at 2 years did not differ significantly between the exemestane and anastrozole treatment groups (2·11%, 95% CI -0·84 to 5·06 vs 3·72%, 95% CI 1·54 to 5·89; p=0·26), nor did hip bone mineral density (2·09%, 95% CI -1·45 to 5·63 vs 0·0%, 95% CI -3·67 to 3·66; p=0·28). Patients with baseline T-score of -2·0 or more taking exemestane had two fragility fractures and two other fractures, those taking anastrozole had three fragility fractures and five other fractures. For patients who had baseline T-scores of less than -2·0 taking exemestane, one had a fragility fracture and four had other fractures, whereas those taking anastrozole had five fragility fractures and one other fracture. INTERPRETATION: Our results demonstrate that adjuvant treatment with aromatase inhibitors can be considered for breast cancer patients who have T-scores less than -2·0. FUNDING: Canadian Cancer Society Research Institute, Pfizer, Canadian Institutes of Health Research.

A phase II study of preoperative capecitabine in women with operable hormone receptor positive breast cancer.

Conventional preoperative chemotherapy regimens have only limited efficacy in hormone receptor positive (HR+) breast cancer and new approaches are needed. We hypothesized that capecitabine, which is effective in metastatic breast cancer, may be an active preoperative treatment for HR+ breast cancer. Women with HR+, HER2-negative operable breast cancer received capecitabine, 2000 mg/m(2) daily in divided doses for 14 days, followed by a 7-day rest period. Treatment was repeated every 21 days for a total of four cycles. The primary endpoint of the study was to determine the rate of pathological complete response (pCR). Because of slow accrual, the study was closed after 24 patients were enrolled. Three patients had a complete clinical response, and eight patients had a partial clinical response, for an overall clinical response rate of 45.8%. There were no cases of pCR. Of the 22 patients who had pathological response assessment by the Miller-Payne grading system, there were six grade 3 responses, and no grade 4 or 5 responses. Toxicity was manageable: the only grade 3 toxicities observed were one case each of diarrhea, palmar plantar erythrodysesthesia, hypokalemia, and mucositis. There was no association between baseline levels, or change in level from baseline to cycle 1, or from baseline to time of surgery, of thymidine phosphorylase (TYMP), thymidylate synthase (TYMS), dihydropyrimidine dehydrogenase (DPYD), or Ki67 and pathological, clinical, or radiographic response. Preoperative capecitabine is a well-tolerated regimen, but appears not lead to pCR when used as monotherapy in HR+ breast cancer.

A case of metastatic cancer with markedly elevated PSA level that was not detected by repeat prostate biopsy.

BACKGROUND: Prostate-specific antigen (PSA) is a widely used specific tumor marker for prostate cancer. We experienced a case of metastatic prostate cancer that was difficult to detect by repeat prostate biopsy despite a markedly elevated serum PSA level. CASE PRESENTATION: A 64-year-old man was referred to our hospital with lumbar back pain and an elevated serum PSA level of 2036 ng/mL. Computed tomography, bone scintigraphy, and magnetic resonance imaging showed systemic lymph node and osteoblastic bone metastases. Digital rectal examination revealed a small, soft prostate without nodules. Ten-core transrectal prostate biopsy yielded negative results. Androgen deprivation therapy (ADT) was started because of the patient's severe symptoms. Twelve-core repeat transrectal prostate biopsy performed 2 months later, and transurethral resection biopsy performed 5 months later, both yielded negative results. The patient refused further cancer screening because ADT effectively relieved his symptoms. His PSA level initially decreased to 4.8 ng/mL, but he developed castration-resistant prostate cancer 7 months after starting ADT. He died 21 months after the initial prostate biopsy from disseminated intravascular coagulation. CONCLUSION: CUP remains a considerable challenge in clinical oncology. Biopsies of metastatic lesions and multimodal approaches were helpful in this case.

CYP19 genetic polymorphism haplotype AASA is associated with a poor prognosis in premenopausal women with lymph node-negative, hormone receptor-positive breast cancer.

Given the critical role of CYP19 in estrogen synthesis, we investigated the influence of CYP19 gene polymorphisms on the clinical outcome of lymph node- (LN-) negative, hormone receptor- (HR-) positive early breast cancers. Genotyping for the CYP19 polymorphisms rs4646 (A/C), rs1065779 (A/C), CYP19 (TTTA)n (short allele/long (S/L) allele using the 7 TTTA repeat polymorphism as the cut-off), and rs1870050 (A/C) was performed on 296 patients with LN-negative, HR-positive breast cancers. All patients received adjuvant hormonal therapy. Associations were examined between these 4 genotypes and 6 common haplotypes of CYP19 and distant disease-free survival (DDFS), disease-free survival (DFS), and overall survival (OS). Patients were divided into the 6 subhaplotypes of CCLA (41.1%), AASA (17.1%), CASA (11.9%), CCLC (8.9%), CCSA (7.5%), AASC (8.9%), and others (4.6%). In premenopausal patients, haplotype AASA was significantly associated with a poor DDFS (adjusted hazard ratio (aHR), 3.3; P = 0.001), DFS (aHR, 2.5; P = 0.0008), and OS (aHR, 2.9; P = 0.0004) after adjusting for age, tumor size, tumor grade, estrogen receptor status, progesterone receptor status, chemotherapy, pathology, adjuvant hormone therapy, menopausal status, and radiotherapy. Furthermore, haplotype AASA remained a negative prognostic factor for premenopausal patients receiving adjuvant chemotherapy in terms of DDFS (aHR, 4.5; P = 0.0005), DFS (HR, 3.2; P = 0.003), and OS (HR, 6.4; P = 0.0009). However, in postmenopausal patients, haplotype AASA was not associated with a poor prognosis, whereas the AASC haplotype was significantly associated with a poor DFS (aHR, 3.1; P = 0.03) and OS (aHR, 4.4; P = 0.01). Our results indicate that, in patients with LN-negative, HR-positive breast cancers, genetic polymorphism haplotype AASA is associated with poor survival of premenopausal women but does not affect survival of postmenopausal women.

Soy and its isoflavones: the truth behind the science in breast cancer.

Epidemiological and migratory evidence suggests that dietary soy consumption can lower the risk for breast cancer. The role of soy isoflavones in cancer prevention and promotion is somewhat unclear. There are two views in terms of soy isoflavones and breast cancer. One line of evidence suggests that soy and its isoflavones have exhibited cancer-preventive properties including lengthening the menstrual cycle, altering estrogen metabolism away from cancerous compounds, and demonstrating anti-proliferative properties in vivo. On the contrary, isoflavones found in soy products are suggested to behave as weak estrogens and as such, much speculation surrounds the influence of soy and/or its isoflavones on hormone-receptor-positive cancers. The objective of this review is to present the latest knowledge regarding the role of soy and its isoflavones with the development and advancement of breast cancer, the safety of soy isoflavones for breast cancer survivors, and a comparison of the carcinogenic effects in animal models following soy isoflavone and estrogen administration. This review compares and contrasts literature in terms of the anti-cancer and cancer-promoting effects of soy isoflavones and estrogen in humans and animal models. In conclusion, current human and animal data provide evidence for several anticancer properties of soy and/or its isoflavones. Although the specific quantities and constituents responsible for the observed anti-cancer effects have not been elucidated, it appears that soy isoflavones do not function as an estrogen, but rather exhibit anti-estrogenic properties. However, their metabolism differs between humans and animals and therefore the outcomes of animal studies may not be applicable to humans. The majority of breast cancer cases are hormone-receptor-positive; therefore, soy isoflavones should be considered a potential anti-cancer therapeutic agent and warrant further investigation.

Letrozole combined with gonadotropin-releasing hormone analog for metastatic male breast cancer.

The role of aromatase inhibitors combined with gonadotropin-releasing hormone analog in metastatic male breast cancer patients remains unknown. In this retrospective study we evaluated the activity of letrozole combined with a gonadotropin-releasing hormone analog as a first- or second-line therapy for metastatic male breast cancer patients. 19 men entered the study. We did not observe any grade 3 or 4 adverse events. 2 patients (10.5 %) had complete response, 7 patients (36.8 %) experienced a partial response, 7 patients (36.8 %) had stable disease lasting ≥ 6 months, and 3 patients (15.8 %) had progressive disease. Overall, the disease control rate was 84.2 %. Median progression-free survival was 12.5 months (95 % CI 8.2-16.9), median overall survival was 35.8 months (95 % CI 24.4-49.2), 1- and 2-year survival rates were 89.5 and 67 %, respectively. Interestingly, 3 out of 4 patients treated with the combination following disease progression while on aromatase inhibitor monotherapy confirmed or improved the best overall response observed in the first-line setting. The combination of letrozole and gonadotropin-releasing hormone analog is effective and safe in hormone-receptor positive, metastatic male breast cancer patients.

[Pregnancy and breast cancer]. / Embarazo y cáncer de mama.

INTRODUCTION: association of breast cancer and pregnancy is not common. The objective of this investigation was to evaluate the pregnancy, young age, stage, treatment, prognosis and mortality of women with breast cancer during pregnancy. METHODS: retrospective analysis from March 1992 to February 2009, 16 patients were included with breast cancer and pregnancy. They were analized: histological characteristic of tumor, therapeutic response of the oncological treatment, evolution of the pregnancy. From of baby born: Apgar and weight. The woman's mortality with breast cancer during pregnancy was evaluated for age group and for interval of time between late pregnancy and diagnosis posterior of breast cancer and pregnancy. RESULTS: characteristic predominant clinicohistological: stage III (81.2%), T3-T4 (75%), N+ 93.7%, invasive ductal carcinoma (87.5%), histological grade 2-3 (93.7%), receptor estrogeno positive (43.7%); RPpositive (25%); HER-2/neu positive (31.2%). 27 chemotherapy cycles were applied with 5-fluorouracil, epirubicin and cyclophosphamide during the second or third trimester of the pregnancy, there were not severe adverse effects for the mothers and the baby born exposed to chemotherapy. The mean time to disease recurrence was 18.8 months (range, 6-62 months). The rate of mortality for specific age (< 35 years) was of 31.3% (p = 0.358). From the 16 patients, 7 have died and 9 were live without evidence of disease. CONCLUSIONS: the advanced stage and the number of affected axillary lymph node more than the age was predictors of worse pronostic influencing the relapse and mortality of the young patients with breast cancer and pregnancy.