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Abstract: GABG-IV B-93 is a prospective, randomised study comparing goserelin (n =384) with no further treatment (n =392) in hormone receptor (HR)-negative breast cancer patients (n =465) after 3 cycles cyclophosphamide, methotrexate, 5-fluorouracil (CMF) for patients with 0–3 positive lymph nodes (LN) or 4 cycles epirubicin, cyclophosphamide (EC) followed by 3 cycles CMF for patients with 4–9 positive LN. After completion of the ZEBRA trial the study was amended to enrol also HR-positive patients with 1–9+LN (n =311). After a median follow-up of 4.7 years neither HR-negative nor HR-positive patients showed a benefit for goserelin. The adjusted estimated hazard ratio for event-free survival in HR-negative patients was 1.01 (goserelin versus control, 95% confidence interval [CI] 0.72–1.42, P =0.97) and 0.77 in HR-positive patients (95% CI 0.47–1.24, P =0.27). These results do not support the general use of goserelin after adjuvant chemotherapy in this group of premenopausal patients. [Copyright &y& Elsevier]

Abstract: Background: Molecular markers displaying bimodal expression distribution can reveal distinct disease subsets and may serve as prognostic or predictive markers or represent therapeutic targets. Oestrogen (ER) and human epidermal growth factor receptor 2 (HER2) receptors are strongly bimodally expressed genes in breast cancer. Material and methods: We applied a novel method to identify bimodally expressed genes in 394 triple negative breast cancers (TNBC). We identified 133 bimodally expressed probe sets (128 unique genes), 69 of these correlated to previously reported metagenes that define molecular subtypes within TNBC including basal-like, molecular-apocrine, claudin-low and immune cell rich subgroups but 64 probe sets showed no correlation with these features. Results: The single most prominent functional group among these uncorrelated genes was the X chromosome derived Cancer/Testis Antigens (CT-X) including melanoma antigen family A (MAGE-A) and Cancer/Testis Antigens (CTAG). High expression of CT-X genes correlated with worse survival in multivariate analysis (HR 2.02, 95% CI 1.27–3.20; P =0.003). The only other significant variable was lymph node status. The poor prognosis of patients with high MAGE-A expression was ameliorated by the concomitant high expression of immune cell metagenes (HR 1.87, 95% CI 0.96–3.64; P =0.060), whereas the same immune metagene had lesser prognostic value in TNBC with low MAGE-A expression. Conclusions: MAGE-A antigen defines a very aggressive subgroup of TNBC; particularly in the absence of immune infiltration in the tumour microenvironment. These observations suggest a therapeutic hypothesis; TNBC with MAGE-A expression may benefit the most from further augmentation of the immune response. Novel immune stimulatory drugs such as (anti-cytotoxic T-lymphocyte antigen-4 CTLA-4) directed therapies provide a realistic opportunity to directly test this hypothesis in the clinic. [Copyright &y& Elsevier]

Abstract: To compare dose-intensified epirubicin monotherapy with a standard sequential regimen, patients with primary breast cancer and ⩾10 involved axillary nodes were randomised to either four 21-day cycles of epirubicin 120mg/m2 (E120; n =202) or four 21-day cycles of epirubicin 90mg/m2 plus cyclophosphamide 600mg/m2 (EC) followed by three 28-day cycles of cyclophosphamide, methotrexate and 5-fluorouracil (CMF; n =209). Simultaneous hormonal treatment was applied in both arms. At 5years’ median follow-up, the 5-year event-free survival (EFS) rates were 47.7% (95% confidence interval [CI], 40.2–55.2%) for E120 and 45.9% (38.5–53.3%) for EC-CMF. E120 was as effective as EC-CMF with regard to EFS (hazard ratio [HR] for E120 versus EC-CMF 1.04; 95% CI, 0.79–1.36; p =0.79) and overall survival (HR 1.06; 95% CI 0.77–1.46; p =0.72). The data demonstrate that 4 cycles of dose-intensified epirubicin monotherapy can be as effective as 7 cycles of standard sequential polychemotherapy in high-risk breast cancer patients with ⩾10 positive lymph nodes, despite treatment with a single agent and a shorter treatment duration. [Copyright &y& Elsevier]

Abstract: Plexins, cell-surface receptors for semaphorins, are involved in cell adhesion and migration. In the previous work, we demonstrated that the loss of Plexin B1 expression is associated with poor outcome in breast cancer patients. The goal of the present study was a validation of Plexin B1 expression in a large scale microarray dataset from n =1086 breast cancer patients. Plexin B1 correlates with ER status (p <0.001) and is of prognostic significance only in ER positive (p =0.024) but not in ER negative samples (p =0.85). Among ER positive tumours, the loss of Plexin B1 expression is associated with a positive ErbB2 status (p =0.05) and a high Ki67 expression (p =0.016) in univariate analysis. Multivariate Cox regression including all standard parameters among ER positive tumours revealed that Plexin B1 (HR 1.59, 95% confidence interval (CI) 1.03–2.47, p =0.036) remains a significant prognostic marker besides tumour size (HR 2.27, 95% CI 1.33–3.89, p =0.0028) and Ki67 (HR 1.78, 95% CI 1.12–2.84, p =0.0149). Interestingly, the prognostic value of Plexin B1 was pronounced in low proliferating ER positive tumours otherwise characterised by a low risk of recurrence. In conclusion, this study confirms our previous observations suggesting Plexin B1 as a new prognostic marker in ER positive breast cancers. [Copyright &y& Elsevier]

Abstract: Primary systemic therapy (PST) allows the observation of tumour response under treatment, but little is known regarding the typical course of clinical response during such therapy. The aim of this study is to support decision making in case of insufficient clinical response. Tumour response was assessed by palpation at different times in 436 patients with operable breast cancer from the dose-dense biweekly therapy arm of the GEPARDUO phase III trial. The predictive value of clinical response for pathologic complete response (pCR), prognostic models to assess the prognosis and individual courses of clinical response were investigated. Sensitivity and positive predictive value were low, but comparatively highest after the 3rd cycle. The predictive value of clinical response by palpation for pCR was subsequently limited. The majority of patients (68.1%) experienced a consistent decrease in tumour size during PST. The results indicate that decisions about further treatment should take place at the earliest after the 3rd cycle or 6 weeks of dose-dense PST. [Copyright &y& Elsevier]

Abstract: Gonadotrophin-releasing hormone analogues were investigated as adjuvant treatment for patients with node-negative, hormone-sensitive, premenopausal breast cancer. Patients were randomised to either three cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) chemotherapy (n =378) or goserelin every 28d for 2years (n =393). During a median follow-up of 4.9 years, 123 events were observed. The first-failure event of CMF versus goserelin, respectively, was ipsilateral locoregional recurrence (18 versus 20), contralateral breast cancer (7 versus 6), distant failure (35 versus 24) and death without recurrence (2 versus 2). Forty-two (23 versus 19) deaths of any cause occurred. The estimated adjusted hazard ratio for goserelin versus CMF (intention-to-treat analysis) was 0.79 (95% CI=0.54–1.14; P =0.19). It is concluded that medical ovarian ablation with goserelin represents a valid option for premenopausal patients with node-negative breast cancer. [Copyright &y& Elsevier]

Abstract: Nitric oxide synthases are expressed in breast cancer. To elucidate the clinical role of the inducible NOS (i-NOS) in human breast cancer, 161 primary breast cancer tissues were stained immunohistochemically. Staining patterns for i-NOS were correlated with classical prognostic factors such as lymph node status, age, hormonal receptor status, tumour size and tumour differentiation. With classical prognostic factors such as lymph node status, age, hormonal receptor status, tumour size and tumour differentiation. Patients survival was also analysed. Sixty-one percent of the tumours stained positively for i-NOS. Detection of i-NOS was positively correlated with increasing tumour size and decreasing tumour differentiation (P=0.018 and P=0.039, respectively). However, in the ⩽50 year age group, i-NOS staining also correlated with lymph node status. Patients with i-NOS-positive breast carcinomas had a significantly worse overall survival rate versus those with negative stains (5-year survival rate 84.8% versus 67.1%; P=0.049; log-rank test). To date, this is the largest analysis of i-NOS expression in breast cancer patients and the only study to assess survival. [Copyright &y& Elsevier]