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Background: The aim of this study was to examine whether EndoPredict (EP), a novel genomic expression test, is effective in predicting local recurrence (LR)-free survival (LRFS) following surgery for breast cancer in postmenopausal women. In addition, we examined whether EP may help tailor local therapy in these patients. Methods: From January 1996 to June 2004, 3714 postmenopausal patients were randomly assigned to either tamoxifen or tamoxifen followed by anastrozole within the prospective ABCSG 8 trial. Using assay scores from EP, we classified breast tumour blocks as either low or high risk for recurrence. Results: Data were gathered from 1324 patients. The median follow-up was 72.3 months and the cumulative incidence of LR was 2.6% (0.4% per year). The risk of LR over a 10-year period among patients with high-risk lesions ( n =683) was significantly higher (LRFS=91%) when compared with patients with low-risk lesions ( n =641) (10-year LRFS=97.5%) (HR: 1.31 (1.16–1.48) P <0.005). The groups that received breast conservation surgery (BCT) and mastectomy (MX) had similar LR rates ( P =0.879). Radiotherapy (RT) after BCT significantly improved LRFS in the cohorts predicted by EP to be low-risk for LR (received RT: n =436, 10-year LRFS 99.8%; did not receive RT: n =63, 10-year LRFS 83.6%, P <0.005). Conclusions: EndoPredict is an effective prognostic tool for predicting LRFS. Among postmenopausal, low-risk patients, EP does not appear to be useful for tailoring local therapy.

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: We investigated whether body mass index (BMI) can be used as a predictive parameter indicating patients who benefit from extended aromatase inhibitor (AI) treatment. Methods: The ABCSG-6a trial re-randomised event-free postmenopausal hormone receptor-positive patients from the ABCSG-6 trial to receive either 3 additional years of endocrine therapy using anastrozole vs nil. In this retrospective analysis, we investigated the prognostic and predictive impact of BMI on disease outcome and safety. Results: In all, 634 patients (177 normal weight, 307 overweight, and 150 obese) patients were included in this analysis. Normal weight patients with additional 3 years of anastrozole halved their risk of disease recurrence (disease-free survival (DFS) HR 0.48; P =0.02) and death (HR 0.45; P =0.06) and had only a fifth of the risk of distant metastases (HR 0.22; P =0.05) compared with normal weight patients without any further treatment. In contrast, overweight+obese patients derived no benefit from additional 3 years of anastrozole (DFS HR 0.93; P =0.68; distant recurrence-free survival HR 0.91; P =0.78; and OS HR 0.9; P =0.68). The possible predictive impact of BMI on extended endocrine treatment could be strengthened by a Cox regression interaction model between BMI and treatment ( P =0.07). Conclusion: Body mass index may be used to predict outcome benefit of extended AI treatment in patients with receptor-positive breast cancer.

Objective To develop and assess a combined reading for contrast-enhanced magnetic resonance (CE-MRI) and diffusion weighted imaging (DWI) adapted to the BI-RADS for multiparametric MRI of the breast at 3 T. Methods A total of 247 patients with histopathologically verified breast lesions were included in this IRB-approved prospective study. All patients underwent CE-MR and DWI at 3 T. MRIs were classified according to BI-RADS and assessed for apparent diffusion coefficient (ADC) values. A reading method that adapted ADC thresholds to the assigned BI-RADS classification was developed. Sensitivity, specificity, diagnostic accuracy and the area under the curve were calculated. BI-RADS-adapted reading was compared with previously published reading methods in the same population. Inter- and intra-reader variability was assessed. Results Sensitivity of BI-RADS-adapted reading was not different from the high sensitivity of CE-MRI ( P  = 0.4). BI-RADS-adapted reading maximised specificity (89.4 %), which was significantly higher compared with CE-MRI ( P  < 0.001). Previous reading methods did not perform as well as the BI-RADS method except for a logistic regression model. BI-RADS-adapted reading was more sensitive in non-mass-like enhancements (NMLE) and was more robust to inter- and intra-reader variability. Conclusion Multiparametric 3-T MRI of the breast using a BI-RADS-adapted reading is fast, simple to use and significantly improves the diagnostic accuracy of breast MRI. Keypoints • Multiparametric breast 3-T MRI with BI-RADS-adapted reading improves diagnostic accuracy. • BI-RADS-adapted reading of CE-MRI and DWI is based on established reporting guidelines. • BI-RADS-adapted reading is fast and easy to use in routine clinical practice. • BI-RADS-adapted reading is robust to intra- and inter-reader variability.

Background: Body mass index (BMI) has an impact on survival outcome in patients treated with aromatase inhibitors (AIs). Obesity is associated with an increased body aromatisation and may be a cause of insufficient estradiol depletion. Methods: Sixty-eight postmenopausal oestrogen receptor-positive patients with early breast cancer were prospectively included in this study. Follicle stimulating hormone (FSH), luteinizing hormone (LH) and estradiol were analysed immediately in the clinical routine lab and in a dedicated central lab before (T1) and 3 months after start with aromatase inhibitors (T2). Results: A total of 40 patients were normal or overweight (non-obese: BMI 18.5–29.9 kg m −2 ) and 28 were obese (BMI⩾30 kg m −2 ). Aromatase inhibitors significantly suppressed estradiol serum levels (T1: 19.5 pg ml −1 , T2: 10.5 pg ml −1 , P <0.01) and increased FSH serum levels (T1: 70.2 mIU ml −1 , T2: 75.7 mIU ml −1 , P <0.05). However, after 3 months of AI treatment, estradiol levels of obese patients were nonsignificantly higher compared with non-obese patients (12.5 pg ml −1 vs 9.0 pg ml −1 , P =0.1). This difference was reflected by significantly lower FSH serum levels in obese compared with non-obese patients (65.5 mIU ml −1 vs 84.6 mIU ml −1 , P <0.01). The significant effects of BMI on FSH serum levels could be detected both in the routine as well as in the dedicated central lab. Conclusion: Aromatase inhibitors are less efficient at suppressing estradiol serum levels in obese when compared with non-obese women.

Background: Validated multigene signatures (MGS) provide additional prognostic information when evaluating clinical features of ER + , HER2 − early breast cancer. We have studied the quantitative and qualitative impact of MGS on multidisciplinary team (MDT) recommendations. Methods: We prospectively recruited 75 ER + , HER2 − breast cancer patients. Inclusion was based on biopsy assessment of grade, hormone receptor status, HER2, clinical tumour and nodal status. A fresh tissue sample was sent for MammaPrint (MP), TargetPrint analysis at surgery. Clinical risk was decided by the MDT in the absence of MP results and repeated following the collection of MP results. Decision changes were recorded and a health technology assessment was undertaken to compare cost effectiveness. Results: The majority of patients were assigned low to intermediate clinical risk by the MDT. According to MP, 76% were low risk. A very high correlation between local IHC and the TargetPrint assessment was shown. In over a third of patients, discordance between clinical and molecular risk was observed. Decision changes were recorded in half of these cases (18.6%) and resulted in two out of three patients not requiring chemotherapy. The use of MP was also found to be more cost effective. Conclusions: The multigene signature MP revealed clinical and molecular risk discordance in a third of patients. The impact of this on MDT recommendations was most profound in cases where few clinical risk factors were observed and enabled some women to forgo chemotherapy. The use of MGS is unlikely to have an impact in either clinically low-risk women or in patients with more than one relative indication for chemotherapy.

Background: Data regarding the safety and effectiveness of aromatase inhibitors (AIs) as monotherapy or combined with gonadotropin-releasing hormone (GnRH) analogue in male breast cancer are scarce. Methods: In this retrospective chart review, cases of male breast cancer patients treated with AIs with or without a GnRH analogue were evaluated. Results: Twenty-three men were included into this case series. Aromatase inhibitors in combination with or without a GnRH analogue were given as first-line therapy in 60.9% and as second-line therapy in 39.1% of patients, respectively. All patients had visceral metastases, whereas in five of them bone lesions coexisted. In all cases AIs were tolerated well, and no case of grade 3 and 4 adverse events was reported. A partial response was observed in 26.1% of patients and stable disease in 56.5%. Median overall survival (OS) was 39 months and median progression-free survival (PFS) was 13 months. Regarding OS and PFS, no significant effects of GnRH analogue co-administration or type of AI were noted. Conclusion: Our study shows that AIs with or without GnRH analogues may represent an effective and safe treatment option for hormone-receptor positive, pretreated, metastatic, male breast cancer patients.

Background: Brain metastases (BM) are frequently diagnosed in patients with HER-2-positive metastatic breast cancer; in addition, an increasing incidence was reported for triple-negative tumours. We aimed to compare brain metastases free survival (BMFS) of breast cancer subtypes in patients treated between 1996 until 2010. Methods: Brain metastases free survival was measured as the interval from diagnosis of extracranial breast cancer metastases until diagnosis of BM. HER-2 status was analysed by immunohistochemistry and reanalysed by fluorescent in situ hybridisation if a score of 2+ was gained. Oestrogen-receptor (ER) and progesterone-receptor (PgR) status was analysed by immunohistochemistry. Brain metastases free survival curves were estimated with the Kaplan–Meier method and compared with the log-rank test. Results: Data of 213 patients (46 luminal/124 HER-2/43 triple-negative subtype) with BM from breast cancer were available for the analysis. Brain metastases free survival differed significantly between breast cancer subtypes. Median BMFS in triple-negative tumours was 14 months (95% CI: 11.34–16.66) compared with 18 months (95% CI: 14.46–21.54) in HER-2-positive tumours ( P =0.001) and 34 months (95% CI: 23.71–44.29) in luminal tumours ( P =0.001), respectively. In HER-2-positive patients, co-positivity for ER and HER-2 prolonged BMFS (26 vs 15 m; P =0.033); in luminal tumours, co-expression of ER and PgR was not significantly associated with BMFS. Brain metastases free survival in patients with lung metastases was significantly shorter (17 vs 21 months; P =0.014). Conclusion: Brain metastases free survival in triple-negative breast cancer, as well as in HER-2-positive/ER-negative, is significantly shorter compared with HER-2/ER co-positive or luminal tumours, mirroring the aggressiveness of these breast cancer subtypes.

Background: Trastuzumab-based therapy after diagnosis of brain metastases (BM) may improve survival due to prolonged systemic disease control. We investigated whether lapatinib may yield additional survival benefit. Methods: Eighty patients with BM from HER2-positive breast cancer were identified. Karnofsky Performance Score (KPS) of at least 70 was required. We included a control group of 37 patients treated before 2003, when continuation of trastuzumab after diagnosis of BM was not yet recommended. Remainders received either trastuzumab or lapatinib and trastuzumab (either concomitantly or sequentially) with or without chemotherapy. Results: Median overall survival (OS) in patients receiving trastuzumab after diagnosis of BM was 13 months; corresponding numbers were 9 months in patients treated with chemotherapy, and 3 months with radiotherapy alone. Median OS was not reached in the lapatinib group. Addition of lapatinib prolonged OS over trastuzumab alone ( P =0.002). After correction for potential confounders, lapatinib therapy remained an independent positive predictor for survival (HR 0.279; P =0.012). Interpretation: This retrospective single-centre study suggests that the introduction of lapatinib improved survival in patients with BM from HER2-positive breast cancer. Patients with KPS ⩾70 may benefit when treated with lapatinib in addition to trastuzumab after completion of local therapy.

Objective The objective of our study was to evaluate the clinical application of bilateral high spatial and temporal resolution dynamic contrast-enhanced magnetic resonance imaging (HR DCE-MRI) of the breast at 7 T. Methods Following institutional review board approval 23 patients with a breast lesion (BIRADS 0, 4–5) were included in our prospective study. All patients underwent bilateral HR DCE-MRI of the breast at 7 T (spatial resolution of 0.7 mm 3 voxel size, temporal resolution of 14 s). Two experienced readers (r1, r2) and one less experienced reader (r3) independently assessed lesions according to BI-RADS®. Image quality, lesion conspicuity and artefacts were graded from 1 to 5. Sensitivity, specificity and diagnostic accuracy were assessed using histopathology as the standard of reference. Results HR DCE-MRI at 7 T revealed 29 lesions in 23 patients (sensitivity 100 % (19/19); specificity of 90 % (9/10)) resulting in a diagnostic accuracy of 96.6 % (28/29) with an AUC of 0.95. Overall image quality was excellent in the majority of cases (27/29) and examinations were not hampered by artefacts. There was excellent inter-reader agreement for diagnosis and image quality parameters (κ = 0.89–1). Conclusion Bilateral HR DCE-MRI of the breast at 7 T is feasible with excellent image quality in clinical practice and allows accurate breast cancer diagnosis. Key points • Dynamic contrast-enhanced 7-T MRI is being developed in several centres. • Bilateral high resolution DCE-MRI of the breast at 7 T is clinically applicable. • 7-T HR DCE-MRI of the breast provides excellent image quality. • 7-T HR DCE-MRI should detect breast cancer with high diagnostic accuracy.