Introduction: Cytokeratin (CK) 14, one of several markers expressed in normal myoepithelial/basal cells, is also expressed in a proportion of breast carcinomas. Previous studies have suggested that expression of such 'basal' markers predicts different biological behaviour, with more frequent lung and brain metastases and poorer prognosis than other carcinomas. Methods: We performed CK14 immunohistochemistry on 443 grade III invasive ductal carcinomas with extended clinical follow-up (mean 116 months), and we correlated CK14 immunopositivity (basal-like phenotype) with clinicopathological criteria. Results: Eighty-eight of 443 (20%) tumours showed CK14 expression. CK14-positive tumours were more likely to be oestrogen receptor-negative (p < 0.0001) and axillary node-negative (p = 0.001) than were CK14-negative cases. CK14-positive cases developed less bone and liver metastases (hazard ratio [HR] 0.49, p = 0.01, and HR 0.53, p = 0.035, respectively) but more frequent brain metastases (HR 1.92, p = 0.051). In patients without metastatic disease, disease-free survival in CK14-positive cases was significantly better than in CK14-negative cases (HR 0.65, p = 0.005). In patients with metastatic disease, however, CK14 positivity was associated with a poorer prognosis (HR 1.84, p = 0.001). The overall survival in CK14-positive and -negative patients was similar at 5 years (60% and 59%, respectively), but the long-term survival was better in CK14-positive patients (HR 0.69, p = 0.02). Conclusion: These results demonstrate that basal-like tumours differ in their biological behaviour from other tumours, with a distinct pattern of metastatic spread. Compared to other grade III tumours, basal-like tumours appear to have a relatively good long-term survival but survival after metastases is poor.

Male breast carcinoma is a rare condition. Few male breast cancer-specific epidemiological or clinical trial data are available - our understanding of male breast cancer thus comes from studies of female breast cancer, painting an inaccurate picture when it comes to determining contributing factors. Clinicians report an increase in diagnoses of male breast cancer but this has not been formally reported. We therefore undertook a review of data obtained from four western nations: England, Scotland, Canada and Australia. When adjusted for age, this review clearly showed an increase in the incidence of male breast cancer over a 15-year period. Reasons for the increased incidence are discussed in the context of suggested risk factors such as BRCA2 and lifestyle changes over the past few decades. The clinical management of male breast carcinoma is considered, in particular the potential role of aromatase inhibitors and fulvestrant and targeting pathways involving prolactin and androgen receptor.

Lobular neoplasia of the breast represents a group of related malignancies with clinical implications ranging from risk lesions [atypical lobular hyperplasia and lobular carcinoma in situ (LCIS)] through to aggressive invasive lesions, notably invasive pleomorphic lobular carcinoma. The diversity in lobular carcinoma is evident at the morphological level, at the molecular marker level and in cytogenetic profiles. Research in these areas is already changing the face of the disease group, for example suggesting that some lobular and ductal carcinomas are closely related and even that one of the lobular group, the tubulo‐lobular carcinomas, should, in fact, be regarded as a ductal cancer. More research is required to understand the long‐term pathogenic implications of a diagnosis of in situ lobular neoplasia, particularly pleomorphic LCIS, and to understand the genetics behind the well‐recognized high risk of bilateral disease. For invasive carcinoma, molecular studies will allow refinement of therapy and the possibility of novel targeted therapies, for example directed against fibroblast growth factor receptor 1.

Management of screen-detected ductal carcinoma in situ (DCIS) remains controversial. A prospective cohort of patients with DCIS diagnosed through the UK National Health Service Breast Screening Programme (1st April 2003 to 31st March 2012) was linked to national databases and case note review to analyse patterns of care, recurrence and mortality. Screen-detected DCIS in 9938 women, with mean age of 60 years (range 46-87), was treated by mastectomy (2931) or breast conserving surgery (BCS) (7007; 70%). At 64 months median follow-up, 697 (6.8%) had further DCIS or invasive breast cancer after BCS (7.8%) or mastectomy (4.5%) (p < 0.001). Breast radiotherapy (RT) after BCS (4363/7007; 62.3%) was associated with a 3.1% absolute reduction in ipsilateral recurrent DCIS or invasive breast cancer (no RT: 7.2% versus RT: 4.1% [p < 0.001]) and a 1.9% absolute reduction for ipsilateral invasive breast recurrence (no RT: 3.8% versus RT: 1.9% [p < 0.001]), independent of the excision margin width or size of DCIS. Women without RT after BCS had more ipsilateral breast recurrences (p < 0.001) when the radial excision margin was <2 mm. Adjuvant endocrine therapy (1208/9938; 12%) was associated with a reduction in any ipsilateral recurrence, whether RT was received (hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.41-0.80) or not (HR 0.68; 95% CI 0.51-0.91) after BCS. Women who developed invasive breast recurrence had a worse survival than those with recurrent DCIS (p < 0.001). Among 321 (3.2%) who died, only 46 deaths were attributed to invasive breast cancer. Recurrent DCIS or invasive cancer is uncommon after screen-detected DCIS. Both RT and endocrine therapy were associated with a reduction in further events but not with breast cancer mortality within 5 years of diagnosis. Further research to identify biomarkers of recurrence risk, particularly as invasive disease, is indicated.

Multi-drug Resistance associated Protein-1 (MRP1) can export chemotherapeutics from cancer cells and is implicated in chemoresistance, particularly as is it known to be up-regulated by chemotherapeutics. Our aims in this study were to determine whether activation of Notch signalling is responsible for chemotherapy-induced MRP1 expression Notch in breast cancers, and whether this pathway can be manipulated with an inhibitor of Notch activity. MRP1 and Notch1 were investigated in 29 patients treated with neoadjuvant chemotherapy (NAC) for breast cancer, using immunohistochemistry on matched biopsy (pre-NAC) and surgical samples (post-NAC). Breast epithelial cell cultures (T47D, HB2) were treated with doxorubicin in the presence and absence of functional Notch1, and qPCR, siRNA, Western blots, ELISAs and flow-cytometry were used to establish interactions. In clinical samples, Notch1 was activated by neoadjuvant chemotherapy (Wilcoxon signed-rank p < 0.0001) and this correlated with induction of MRP1 expression (rho = 0.6 p = 0.0008). In breast cell lines, doxorubicin induced MRP1 expression and function (non-linear regression p < 0.004). In the breast cancer line T47D, doxorubicin activated Notch1 and, critically, inhibition of Notch1 activation with the γ-secretase inhibitor DAPT abolished the doxorubicin-induced increase in MRP1 expression and function (t-test p < 0.05), resulting in enhanced cellular retention of doxorubicin and increased doxorubicin-induced apoptosis (t-test p = 0.0002). In HB2 cells, an immortal but non-cancer derived breast cell line, Notch1-independent MRP1 induction was noted and DAPT did not enhance doxorubicin-induced apoptosis. Notch inhibitors may have potential in sensitizing breast cancer cells to chemotherapeutics and therefore in tackling chemoresistance.