AimsContemporary adjuvant treatment for early breast cancer is associated with improved survival but at the cost of increased risk of cardiotoxicity and cardiac dysfunction. We tested the hypothesis that concomitant therapy with the angiotensin receptor blocker candesartan or the β-blocker metoprolol will alleviate the decline in left ventricular ejection fraction (LVEF) associated with adjuvant, anthracycline-containing regimens with or without trastuzumab and radiation.Methods and resultsIn a 2 × 2 factorial, randomized, placebo-controlled, double-blind trial, we assigned 130 adult women with early breast cancer and no serious co-morbidity to the angiotensin receptor blocker candesartan cilexetil, the β-blocker metoprolol succinate, or matching placebos in parallel with adjuvant anticancer therapy. The primary outcome measure was change in LVEF by cardiac magnetic resonance imaging. A priori, a change of 5 percentage points was considered clinically important. There was no interaction between candesartan and metoprolol treatments (P = 0.530). The overall decline in LVEF was 2.6 (95% CI 1.5, 3.8) percentage points in the placebo group and 0.8 (95% CI −0.4, 1.9) in the candesartan group in the intention-to-treat analysis (P-value for between-group difference: 0.026). No effect of metoprolol on the overall decline in LVEF was observed.ConclusionIn patients treated for early breast cancer with adjuvant anthracycline-containing regimens with or without trastuzumab and radiation, concomitant treatment with candesartan provides protection against early decline in global left ventricular function.

Purpose: The incidence of malignant melanoma is increasing worldwide in fair-skinned populations. Melanomas respond poorly to systemic therapy, and metastatic melanomas inevitably become fatal. Although spontaneous regression, likely due to immune defense activation, rarely occurs, we lack a biological rationale and predictive markers in selecting patients for immune therapy.Experimental Design: We performed unsupervised hierarchical clustering of global gene expression data from stage IV melanomas in 57 patients. For further characterization, we used immunohistochemistry of selected markers, genome-wide DNA copy number analysis, genetic and epigenetic analysis of the CDKN2A locus, and NRAS/BRAF mutation screening.Results: The analysis revealed four distinct subtypes with gene signatures characterized by expression of immune response, pigmentation differentiation, proliferation, or stromal composition genes. Although all subtypes harbored NRAS and BRAF mutations, there was a significant difference between subtypes (P < 0.01), with no BRAF/NRAS wild-type samples in the proliferative subtype. Additionally, the proliferative subtype was characterized by a high frequency of CDKN2A homozygous deletions (P < 0.01). We observed a different prognosis between the subtypes (P = 0.01), with a particularly poor survival for patients harboring tumors of the proliferative subtype compared with the others (P = 0.003). Importantly, the clinical relevance of the subtypes was validated in an independent cohort of 44 stage III and IV melanomas. Moreover, low expression of an a priori defined gene set associated with immune response signaling was significantly associated with poor outcome (P = 0.001).Conclusions: Our data reveal a biologically based taxonomy of malignant melanomas with prognostic effect and support an influence of the antitumoral immune response on outcome. Clin Cancer Res; 16(13); 3356-67. ©2010 AACR.Malignant melanoma is an aggressive form of skin cancer with a rapidly increasing incidence in the western world (1). Approximately 15% of patients diagnosed with primary melanoma develop distant metastases (2), and current treatment regimens for metastatic melanoma have little effect on long-term survival. Single agent dacarbazine (DTIC) has been standard treatment for many years with response rates of 7% to 13%; however, long-lasting responses are few (3). Importantly, several novel treatment approaches, systemic and targeted, are emerging (4). The concept and arguments for immunotherapy in melanoma include reports on spontaneous remissions and lymphocytic infiltration in tumors (5). However, a rationale for selecting patients eligible for immunotherapy is still lacking.Although there have been several reports on gene expression signatures in malignant melanomas (6-8), only few studies have indicated molecular subtypes of clinical relevance in metastatic melanoma (7, 9). In primary melanoma, genetic profiles are correlated to anatomic site

This study revealed letrozole (2.5 mg once daily) to be a more potent suppressor of total-body aromatization and plasma estrogen levels compared with anastrozole (1 mg once daily) in postmenopausal women with metastatic breast cancer.

Sununary The effect of anastrozole ('Arimidex', ZD1033), a new, selective, non-steroidal aromatase inhibitor on in vivo aromatisation and plasma oestrogen levels was evaluated in post-menopausal women with breast cancer. Twelve patients progressing after treatment with tamoxifen were randomised to receive anastrozole 1 mg or 10 mg once daily for a 28 day period in a double-blinded crossover design. In vivo aromatisation and plasma oestrogen levels were determined before commencing treatment and at the end of each 4-week period. Breast cancer is the most common malignancy among women in the western hemisphere. Many of these patients develop metastatic disease, for which no cure is currently available. Because endocrine treatment causes fewer side-effects than chemotherapy, such therapy is first-line treatment in patients with metastatic disease and hormone receptor-positive tumours. While the anti-oestrogen tamoxifen is first choice of therapy in post-menopausal patients with metastatic breast cancer. increasing use of tamoxifen as adjuvant therapy focuses on the need for alternative endocrine treatment options on relapse in breast cancer patients.While ovarian oestrogen synthesis ceases at the menopause, oestrogens are synthesised in peripheral tissue from circulating androgens by the process called aromatisation (Grodin et al., 1973). The main pathway is conversion of androstenedione (A) into oestrone (El), with a minor contribution from conversion of testosterone into oestradiol (E2) (L0nning et al., 1990).Aromatase inhibitors are drugs that inhibit the peripheral conversion of androgens to oestrogens (Santen et al., 1982a), thereby suppressing plasma oestrogen levels in postmenopausal women. The first-generation aromatase inhibitor, aminoglutethimide, was implemented in breast cancer treatment more than 20 years ago (Cash et al., 1967). While the drug is effective in hormone-sensitive breast cancer, lack of specificity (inhibition of adrenal steroid-synthesising enzymes) and side-effects (such as skin rash and lethargy) provoked the development of new aromatase inhibitors (Coombes et al., 1984;Evans et al., 1992;Johnston et al., 1994;Lipton et al., 1995; Santen et al., 1989).Anastrozole (Arimidex; 2,2'[5-(1H-1 ,2,4-triazol-1-ylmethyl) -1,3-phenylene]bis-(2-methylpropiononitrile, Figure 1) is a new, potent and selective aromatase inhibitor belonging to the triazole class. Pilot studies in post-menopausal women have shown the drug to suppress plasma E2 by > 80% (Plourde et al., 1994), and preclinical studies as well as observations in women suggest the drug to be highly specific with no influence on adrenal steroid synthesis (Plourde et al., 1995). A major problem in evaluating the biochemical efficacy of aromatase inhibitors has been the lack of internal consistency between the percentage aromatase inhibition and degree of plasma oestrogen suppression. While aminoglutethimide as well as the second-generation aromatase inhibitor formestane and the third-generation inhibitor fadrozole (L0nning et al., 1991) ...

Exemestane modestly enhanced bone loss from the femoral neck without significant influence on lumbar bone loss. Except for a 6% to 9% drop in plasma high-density lipoprotein cholesterol, no major effects on serum lipids, coagulation factors, or homocysteine were recorded. Bone mineral density should be assessed according to the US Preventive Services Task Force guidelines.

Breast cancers exhibit genome-wide aberrant DNA methylation patterns. To investigate how these affect the transcriptome and which changes are linked to transformation or progression, we apply genome-wide expression–methylation quantitative trait loci (emQTL) analysis between DNA methylation and gene expression. On a whole genome scale, in cis and in trans, DNA methylation and gene expression have remarkably and reproducibly conserved patterns of association in three breast cancer cohorts (n = 104, n = 253 and n = 277). The expression–methylation quantitative trait loci associations form two main clusters; one relates to tumor infiltrating immune cell signatures and the other to estrogen receptor signaling. In the estrogen related cluster, using ChromHMM segmentation and transcription factor chromatin immunoprecipitation sequencing data, we identify transcriptional networks regulated in a cell lineage-specific manner by DNA methylation at enhancers. These networks are strongly dominated by ERα, FOXA1 or GATA3 and their targets were functionally validated using knockdown by small interfering RNA or GRO-seq analysis after transcriptional stimulation with estrogen.

Purpose For primary melanomas, tumor thickness, mitotic rate, and ulceration are well-laid cornerstones of prognostication. However, a molecular exposition of melanoma aggressiveness is critically missing. We recently uncovered a four-class structure in metastatic melanoma, which predicts outcome and informs biology. This raises the possibility that a molecular structure exists even in the early stages of melanoma and that molecular determinants could underlie histophenotype and eventual patient outcome. Experimental Design We subjected 223 archival primary melanomas to a horizontally integrated analysis of RNA expression, oncogenic mutations at 238 lesions, histomorphometry, and survival data. Results Our previously described four-class structure that was elucidated in metastatic lesions was evident within the expression space of primary melanomas. Because these subclasses converged into two larger prognostic and phenotypic groups, we used the metastatic lesions to develop a binary subtype-based signature capable of distinguishing between "high" and "low" grade forms of the disease. The two-grade signature was subsequently applied to the primary melanomas. Compared with low-grade tumors, high-grade primary melanomas were significantly associated with increased tumor thickness, mitotic rate, ulceration (all P < 0.01), and poorer relapse-free (HR = 4.94; 95% CI, 2.84–8.59), and overall (HR = 3.66; 95% CI, 2.40–5.58) survival. High-grade melanomas exhibited elevated levels of proliferation and BRCA1/DNA damage signaling genes, whereas low-grade lesions harbored higher expression of immune genes. Importantly, the molecular-grade signature was validated in two external gene expression data sets. Conclusions We provide evidence for a molecular organization within melanomas, which is preserved across all stages of disease.

Purpose: To evaluate the influence of the third-generation aromatase inhibitor letrozole (Femara) on breast cancer tissue levels of estrone (E 1 ), estradiol (E 2 ), and estrone sulfate (E 1 S) in postmenopausal women undergoing primary treatment for locally advanced estrogen receptor/progesterone receptor^positive breast cancers. Experimental Design: Breast cancer tissue samples were collected before and following 4 months of neoadjuvant therapy with letrozole (2.5 mg o.d.), and tissue estrogen levels measured using a highly sensitive RIA after high-pressure liquid chromatography purification. Results: Letrozole suppressed pretreatment tumor levels of E 2 , E 1 , and E 1 S by 97.6%, 90.7%, and 90.1%, respectively.These data reveal that letrozole suppresses tissue estrogen levels significantly below what has previously been recorded with anastrozole (89.0%, 83.4%, and 72.9% suppression, respectively) using the same methods. To confirm the differential effect of letrozole and anastrozole on each plasma estrogen fraction, we re-analyzed plasma samples obtained from a previous intrapatient cross-over study comparing letrozole and anastrozole using an improved RIA (detection limits of 0.67, 1.14, and 0.55 pmol/L for E 2 , E 1 , and E 1 S, respectively). Letrozole consistently suppressed each plasma estrogen fraction below the levels recorded for anastrozole: E 2 (average suppression by 95.2% versus 92.8%; P = 0.018), E 1 (98.8% suppression versus 96.3%; P = 0.003), and E 1 S (98.9% suppression versus 95.3%; P = 0.003). Conclusion: Our data reveals that letrozole (2.5 mg o.d.) is more effective compared with anastrozole (1.0 mg o.d.) with respect to tissue as well as plasma estrogen suppression in patients with postmenopausal breast cancer.Contemporary clinical studies have shown that three thirdgeneration aromatase inhibitors (anastrozole, letrozole, and exemestane) improve time to progression in metastatic disease (1 -3) and relapse-free as well as overall survival compared with tamoxifen for adjuvant therapy of patients with postmenopausal breast cancer (4 -6). These results are most likely related to their improved potency. The third-generation compounds inhibit total body aromatization by z98% in vivo (7 -10). In contrast, compounds belonging to the first and second generation of inhibitors cause 80% to 90% (11 -14) aromatase inhibition and do not improve clinical outcome compared with tamoxifen or megestrol acetate (see ref. 15).An ongoing controversy relates to potential differences between the three third-generation aromatase inhibitors with respect to mechanism of action (16) and resistance (17), as well as clinical efficacy and safety. Thus, studies in metastatic breast cancer have revealed a lack of complete cross-resistance between nonsteroidal aromatase inhibitors and the steroidal aromatase inactivators (18 -22). However, except for a single study comparing anastrozole and letrozole as second-line therapy in metastatic disease (23), we lack results from direct head-to-head comparisons.Alth...