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Background: ER+/HER2− breast cancers have a proclivity for late recurrence. A personalised estimate of relapse risk after 5 years of endocrine treatment can improve patient selection for extended hormonal therapy. Methods: A total of 1702 postmenopausal ER+/HER2− breast cancer patients from two adjuvant phase III trials (ABCSG6, ABCSG8) treated with 5 years of endocrine therapy participated in this study. The multigene test EndoPredict (EP) and the EPclin score (which combines EP with tumour size and nodal status) were predefined in independent training cohorts. All patients were retrospectively assigned to risk categories based on gene expression and on clinical parameters. The primary end point was distant metastasis (DM). Kaplan–Meier method and Cox regression analysis were used in an early (0–5 years) and late time interval (>5 years post diagnosis). Results: EP is a significant, independent, prognostic parameter in the early and late time interval. The expression levels of proliferative and ER signalling genes contribute differentially to the underlying biology of early and late DM. The EPclin stratified 64% of patients at risk after 5 years into a low-risk subgroup with an absolute 1.8% of late DM at 10 years of follow-up. Conclusion: The EP test provides additional prognostic information for the identification of early and late DM beyond what can be achieved by combining the commonly used clinical parameters. The EPclin reliably identified a subgroup of patients who have an excellent long-term prognosis after 5 years of endocrine therapy. The side effects of extended therapy should be weighed against this projected outcome.

Background: Germline mutations in BRCA1 and BRCA2 predispose to pancreatic cancer. We estimated the incidence of pancreatic cancer in a cohort of female carriers of BRCA1 and BRCA2 mutation. We also estimated survival rates in pancreatic cancer cases from families with a BRCA mutation. Methods: We followed 5149 women with a mutation for new cases of pancreatic cancer. The standardised incidence ratios (SIR) for pancreatic cancer were calculated based on age group and country of residence. We also reviewed the pedigrees of 8140 pedigrees with a BRCA1 or a BRCA2 mutation for those with a case of pancreatic cancer. We recorded the year of diagnosis and the year of death for 351 identified cases. Results: Eight incident pancreatic cancer cases were identified among all mutation carriers. The SIR for BRCA1 carriers was 2.55 (95% CI=1.03–5.31, P =0.04) and for BRCA2 carriers was 2.13 (95% CI=0.36–7.03, P =0.3). The 5-year survival rate was 5% for cases from a BRCA1 family and 4% for cases from a BRCA2 family. Conclusion: The risk of pancreatic cancer is approximately doubled in female BRCA carriers. The poor survival in familial pancreatic cancer underscores the need for novel anti-tumoural strategies.

Background Ovarian cancer screening in BRCA1/2 mutation carriers utilizes assessment of carbohydrate antigen 125 (CA125) and transvaginal ultrasound (TVU), despite low sensitivity and specificity. We evaluated the association between CA125 levels, BRCA1/2 mutation status and menopausal status to provide more information on clinical conditions that may influence CA125 levels. Methods We retrospectively analyzed repeated measurements of CA125 levels and clinical data of 466 women at high risk for ovarian cancer. CA125 levels were compared between women with and without deleterious mutations in BRCA1/2. Pearson's correlation was used to determine the association between age and CA125 serum level. Differences in CA125 levels were assessed with the Mann–Whitney U test. The effect of BRCA1/2 mutation status and menopausal status on the change in CA125 levels was determined by Two-factor analysis of variance (ANOVA). Results The CA125 serum levels of premenopausal women (median, 13.8 kU/mL; range, 9.4 – 19.5 kU/mL) were significantly higher than in postmenopausal women (median, 10.4 kU/mL; range, 7.7 – 14.0 kU/mL; p  < .001). There was no significant difference in the CA125 levels of BRCA mutation carriers and non-mutation carriers across all age groups ( p  = .612). When investigating the combined effect of BRCA1/2 mutation and menopausal status, variance analysis revealed a significant interaction between BRCA1/2 mutation status and menopausal status on CA125 levels ( p  < .001). There was a significant difference between the CA125 levels of premenopausal and postmenopausal women, with a large effect in BRCA mutation carriers ( p  < .001, d = 1.05), whereas in non-mutation carriers there was only a small effect ( p  < .001, d = 0.32). Conclusion Our findings suggest that hereditary mutations in BRCA1/2 affect the decline of CA125 levels with increasing age. To prove a definite effect of this mutation on the CA125 level, prospective trials need to be conducted to define new cut-off levels of CA 125 in mutation carriers and optimize ovarian cancer screening.

Background The PALLAS trial investigated the addition of palbociclib to standard adjuvant endocrine therapy to reduce breast cancer recurrence. This pre-specified analysis was conducted to determine whether adjuvant palbociclib benefited patients diagnosed with lower risk stage IIA disease compared to those with higher stage disease. Methods PALLAS was an international, multicenter, randomized, open-label, phase III trial, representing a public–private partnership between Pfizer, the Austrian Breast Cancer Study Group, and the U.S. ALLIANCE Foundation. Patients diagnosed with stage II–III, hormone-receptor-positive, HER2/neu negative breast cancer within 12 months of diagnosis had completed all definitive therapy aside from endocrine therapy (started within 6 months prior to study entry) were eligible. All patients were required to submit a formalin-fixed paraffin-embedded (FFPE) tumor block. Patients were randomly assigned 1:1 to receive standard adjuvant endocrine therapy (of physicians’ choice) for at least 5 years with or without 2 years of palbociclib, administered orally at a starting dose of 125 mg daily, given for 21 days followed by a 7-day break. Results A total of 5,796 patients with HR + /HER2- early breast cancer (including 1,010 with stage IIA) were enrolled. Median follow-up was 50 months for stage IIA patients and 43.1 months overall. In the stage IIA cohort, 4-year iDFS in the palbociclib arm was 92.9% versus 92.1% for ET alone (HR 0.75, 95%CI 0.48–1.19, p  = 0.23). There was no differential benefit by histologic grade, chemotherapy receipt, age, or anatomic/clinical risk. Additionally, no benefit to palbociclib was seen in this cohort in invasive breast cancer-free survival (iBCFS), locoregional relapse-free survival (LRFS), distant relapse-free survival (DRFS), or overall survival (OS). For the stage IIB/III patients, 4-year iDFS was 85.3% for palbociclib + ET versus 83.6% for ET alone (HR 0.91, 95% CI 0.77–1.07, p  = 0.24). Conclusions and relevance While there were substantial differences in outcome for stage IIA versus IIB/III patients at 4 years of follow-up, the addition of 2 years of palbociclib did not improve outcomes for patients, regardless of stage. Trial Registration ClinicalTrials.gov number NCT02513394 Registered 30 Jul 2015.

Background: The BRCA1 and BRCA2 genes confer increased susceptibility to breast and ovarian cancer and to a spectrum of other cancers. There is controversy regarding the risk of colorectal cancer conferred by germline mutations in these two genes. Methods: We followed 7015 women with a BRCA mutation for new cases of colorectal cancer. Incidence rates in carriers were compared with population-specific incidence rates, and standardised incidence ratios (SIRs) were estimated. The expected numbers of cancers were computed by multiplying person–years at risk by the appropriate age-, sex- and country-specific incidence rates from the five countries. Results: Twenty-one incident colorectal cancer cases were observed among all mutation carriers, compared with 23.6 cases expected. The SIR for BRCA1 carriers was 0.92 (95% confidence interval (CI), 0.54–1.40, P =0.7) and for BRCA2 carriers was 0.82 (95% CI, 0.30–1.81, P =0.7). The SIR for colon cancer was 3.81 (95% CI 1.77–7.23) for women below the age of 50 years (both genes combined) and was 0.60 (95% CI 0.33–1.00) for women aged 50 years and above. Conclusion: The risk of colorectal cancer is increased in female carriers of BRCA1 mutations below the age of 50 years but not in women with BRCA2 mutations or in older women.

Proteolytic cleavage of the Her-2/ neu extracellular domain (ECD) has been shown to initiate receptor phosphorylation representing Her-2/ neu activation in vitro . The present investigation was performed to evaluate the clinical relevance of ECD cleavage for Her-2/ neu activation and the consequences of active intracellular Her-2/ neu signalling reflected by tyrosine kinase phosphorylation in patients treated with the anti-Her-2/ neu antibody trastuzumab. Sera from 62 patients receiving trastuzumab-based treatment for Her-2/ neu overexpressing metastatic breast cancer were assessed for pretreatment ECD levels using an enzyme-linked immunosorbent assay. In parallel, Her-2/ neu activation status of tumour specimens was assessed by immunohistochemistry using a Her-2/ neu phosphorylation state specific antibody (PN2A) and correlated with the patients’ ECD levels and clinical course of disease. Serum ECD levels were significantly higher in 15 (24%) patients with tumours exhibiting activated Her-2/ neu as compared to those without detectable Her-2/ neu phosphorylation (median 148.2 vs 28.5 ng ml −1 , P =0.010). Whereas response rate only showed a trend to be higher in patients with Her-2/ neu -phosphorylated breast cancer (47 vs 34%, P =0.197), both uni- and multivariate analyses revealed that the median progression-free survival under trastuzumab-based treatment was significantly longer in patients with Her-2/ neu -phosphorylated breast cancer–11.7 (95% CI 5.2–18.3) months–when compared to the progression-free survival of 4.5 (95% CI 3.4–5.6) months observed in patients with tumours lacking phosphorylated Her-2/ neu ( P =0.001). Proteolytic cleavage of the ECD represents a biologically relevant ligand-independent mechanism of Her-2/ neu activation in vivo . The influence of Her-2/ neu activation status upon the outcome of trastuzumab-based therapies merits further investigation in larger prospective trials.

Purpose Intratumoral estradiol levels in postmenopausal women with breast cancer are thought to be mainly regulated by the aromatase-mediated conversion from androgens and estrogen sulfotransferase (EST)-mediated reduction of bioavailability. While in invasive breast cancer (IBC) the role of both enzymes has been extensively studied and has led to the use of aromatase inhibitors as a key therapeutic strategy, comparably little is still known about their role in the local regulation of estradiol in ductal carcinoma in situ (DCIS). Methods We have performed immunohistochemistry to investigate the expression of aromatase and sulfotransferase in custom-made breast cancer tissue arrays containing 96 samples of pure DCIS and in 104 tumor biopsies which contain both, DCIS and invasive components. Results We found that aromatase was equally detectable in epithelial components of both, DCIS and IBC ( P  = 0.884, Chi square test). However, stromal aromatase expression was significantly higher in IBC compared to adjacent DCIS components ( P  = 0.034, Chi square test). Whereas no significant difference was observed for epithelial aromatase expression in high versus non-high grade DCIS ( P  = 0.735 Chi square test), epithelial EST levels were found to be significantly down-regulated in high-grade DCIS compared to non-high grade cases ( P  = 0.042). Conclusion We have demonstrated the presence of both aromatase and EST in malignant epithelium and adjacent stromal fibroblasts in DCIS. Lower stromal aromatase expression in preinvasive breast cancer and lower EST levels in high-grade DCIS suggest that the net effect of intratumoral estradiol (E2)-modulating enzymes results in lower local E2 levels in earlier stages of breast tumorigenesis.

Over-expression of members of the ErbB-receptor family has been associated with malignant transformation. The amplification of Her-2/neu in tumor tissue is now an established prognostic factor in breast cancer. In order to initiate signal transduction, ErbB-receptor monomers need to form homo- or heterodimers. The composition of these dimers is thought to influence both quality and quantity of downstream signaling pathways, and to determine the biological response. We have investigated the protein expression pattern of the four ErbB-receptors EGFR, Her-2/neu, Her-3 and Her-4, and correlated it with their putative ligands EGF, TGF-alpha and HRG in 74 women with invasive breast cancer. Using western blot-analysis on cell membrane isolates, we detected the co-expression of all four ErbB-family members in 79.7% of cases, and of all of the three investigated ligands in 82.4%. We did not observe a correlation between EGFR and Her-2/neu or Her-4 protein expression, EGFR and Her-3 (p = 0.005), and Her-3 and Her-4 (p = 0.05) were clearly co-expressed. The strongest overall correlation, was found between Her-2/neu and Her-3 (p < 0.001) and between Her-2/neu and Her-4 (p = 0.001). This was particularly true in nodal-positive tumors (p < 0.001 and p = 0.002) whereas in nodal-negative tumors the co-expression was either less significant (Her-2/neu and Her-3; p = 0.01) or not significant (Her-2/neu and Her-4). The co-expression of EGFR/Her-3 was associated with the expression of all ligands, whereas the Her-2/neu/Her-3 was correlated with HRG (p = 0.002), thereby indicating a functional relation between specific receptor-dimer combinations and putative ligands. Taken together, we have performed the first comprehensive survey of ErbB-system expression in breast cancer, and have demonstrated the presence of a co-regulated receptor/ligand system in vivo. We have further shown that Her-2/neu is the preferred co-expression partner in nodal-positive tumors and thus the most likely dimerization candidate in malignant breast tumors.

Our objective was to investigate the effects of age, weight, body mass index (BMI), sex steroid receptor status and serum parameters such as estradiol, testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS) and leptin on the size of a malignant breast tumor. A total of 62 premenopausal (median age 44.0 years) and 151 postmenopausal (median age 59.1 years) Caucasian women undergoing lumpectomy or mastectomy for invasive breast cancer were examined. Patient parameters (age, body weight, BMI), tumor parameters (tumor size, estrogen and progesterone receptor status) and serum parameters (estradiol, testosterone, androstenedione, DHEAS and leptin) were measured. An increase of BMI and DHEAS levels was associated with larger tumors by partial correlation (rp) analysis (rp=0.418, p=0.008; and rp=0.329, p=0.041, respectively), whereas higher androstenedione levels corresponded with smaller tumors. Furthermore, BMI, androstenedione and DHEAS levels were correlated: an increase in DHEAS was associated with higher androstenedione serum concentrations (rp=0.603, p<0.001), but was also associated with a lower BMI (rp=−0.378, p<001). BMI and androstenedione serum concentrations were also associated (rp=0.242, p=0.009), thus closing a circle of mutual interactions. We conclude that, although breast cancer progression is characterized by autonomous growth that has become independent of growth regulatory mechanisms, tumor size at the time of detection is influenced by a complex system of counterregulatory feedback mechanisms that might represent the body's physiological attempt to control the size of a malignant tumor.

In postmenopausal women with hormone receptor-positive, early-stage breast cancer, treatment with adjuvant aromatase inhibitors is the standard of care, but it increases risk for osteoporosis and fractures. Results from the ABCSG-18 trial showed that use of denosumab as an adjuvant to aromatase inhibitor therapy significantly reduced clinical fractures. Disease-free survival outcomes from ABCSG-18 have not yet been reported. Postmenopausal patients with early, hormone receptor-positive, non-metastatic adenocarcinoma of the breast, who had completed their initial adjuvant treatment pathway (surgery, radiotherapy, or chemotherapy, or a combination) and were receiving adjuvant aromatase inhibitors, were enrolled at 58 trial centres in Austria and Sweden into this prospective, double-blind, placebo-controlled, phase 3 trial. With permuted block randomisation (block sizes 2 and 4, stratified by previous aromatase inhibitor use, total lumbar spine bone mineral density score at baseline, and type of centre), patients were assigned (1:1) to receive subcutaneous denosumab (60 mg) or matching placebo every 6 months during aromatase inhibitor therapy. The primary endpoint (previously reported) was the time to first clinical fracture after randomisation. The secondary endpoint reported here is disease-free survival (defined as time from randomisation to first evidence of local or distant metastasis, contralateral breast cancer, secondary carcinoma, or death from any cause) in the intention-to-treat population. This study is registered with EudraCT (number 2005–005275–15) and ClinicalTrials.gov (number NCT00556374), and is ongoing for long-term follow-up. Between Dec 18, 2006, and July 22, 2013, 3425 eligible patients were enrolled and randomly assigned; 1711 to the denosumab group and 1709 to the placebo group (with five others withdrawing consent). After a median follow-up of 73 months (IQR 58–95), 240 (14·0%) patients in the denosumab and 287 (16·8%) in the placebo group had disease-free survival events. Disease-free survival was significantly improved in the denosumab group versus the placebo group (hazard ratio 0·82, 95% CI 0·69–0·98, Cox p=0·0260; descriptive analysis, without controlling for multiplicity). In the denosumab group, disease-free survival was 89·2% (95% CI 87·6–90·8) at 5 years and 80·6% (78·1–83·1) at 8 years of follow-up, compared with 87·3% (85·7–89·0) at 5 years and 77·5% (74·8–80·2) and 8 years in the placebo group. No independently adjudicated cases of osteonecrosis of the jaw or confirmed atypical femoral fractures were recorded. The total number of adverse events was similar in the denosumab group (1367 [including 521 serious] adverse events) and the placebo group (1339 [515 serious]). The most common serious adverse events were osteoarthritis (62 [3·6%] of 1709 in the denosumab group vs 58 [3·4%] of 1690 in the placebo group), meniscus injury (23 [1·3%] vs 24 [1·4%]), and cataract (16 [0·9%] vs 28 [1·7%]). One (<0·1%) treatment-related death (due to pneumonia, septic kidney failure, and cardiac decompensation) occurred in the denosumab group. Denosumab constitutes an effective and safe adjuvant treatment for patients with postmenopausal hormone receptor-positive early breast cancer receiving aromatase inhibitor therapy. Amgen.