Mitotic counts in breast cancer after neoadjuvant systemic chemotherapy and development of metastatic disease.

Although pathologic complete response after neoadjuvant systemic chemotherapy (NST) is associated with an excellent prognosis, the prognosis for patients with residual disease is variable. The mitotic count (MC) is commonly used in the evaluation of histologic tumor grade, but its prognostic value relative to other factors when determined after NST has not been studied. We evaluated MC in the residual tumor after NST in order to determine whether it provided prognostic information independent of other factors, including the residual cancer burden (RCB). We retrospectively reviewed pathologic specimens from 80 patients with localized breast cancer who received standard NST, of whom 61 had residual disease evaluable for MC analysis and RCB score. The exact number of mitotic figures was counted in 10 high power (40×) fields (hpf). We classified tumors as having high (≥13 per 10 hpf) and low (<13 per 10 hpf) MC because this threshold fell at the midpoint for an intermediate MC score in the Nottingham combined histologic grade. Distant metastases developed in 2 of 32 (6.3 %) patients with a low MC compared with 18 of 29 (62.1 %) with a high MC (log-rank test, p < 0.001). When adjusted for other covariates, including age, estrogen receptor, HER2/neu expressions, and RCB score, a high MC was associated with a significantly higher risk of developing distant metastases (hazard ratio 11.21, 95 % CI [2.19, 57.37]; p = 0.004). Our findings indicated that evaluation of MC after NST warrants validation and further evaluation as a prognostic marker in breast cancer.

High expression of class III ß-tubulin predicts good response to neoadjuvant taxane and doxorubicin/cyclophosphamide-based chemotherapy in estrogen receptor-negative breast cancer.

BACKGROUND: Expression of class ΙΙΙ ß-tubulin (ßΙΙΙ-tubulin) correlates with tumor progression and resistance to taxane-based therapies for several human malignancies including breast cancer. However its predictive value in a neoadjuvant setting in breast cancer remains unexplored. The objective of this explorative study was to determine whether ßΙΙΙ-tubulin expression in breast cancer correlated with pathologic characteristics and whether its expression was predictive of response to neoadjuvant chemotherapy. PATIENTS AND METHODS: We determined ßΙΙΙ-tubulin expression in 85 breast cancers, including 41 localized breast cancers treated with primary surgery and 44 treated with neoadjuvant chemotherapy before surgery. ßΙΙΙ-tubulin expression was evaluated by immunohistochemical methods and was correlated with pathologic characteristics and response to neoadjuvant chemotherapy using residual cancer burden (RCB) score. RESULTS: High ßΙΙΙ-tubulin expression was significantly associated with poorly differentiated high-grade breast cancers (P = .003) but not with tumor size, estrogen receptor (ER) status, or human epidermal growth factor receptor 2 (HER2)/neu overexpression. In ER(-) tumors treated with neoadjuvant chemotherapy, high ßΙΙΙ-tubulin expression was associated with a significantly greater likelihood of achieving a good pathologic response to chemotherapy as reflected by lower RCB scores (P = .021). CONCLUSION: This study reveals differential ßΙΙΙ-tubulin expression in breast cancers of different histologic grades, hormone receptors, and HER2/neu status. It also suggests a potential role for ßΙΙΙ-tubulin as a predictive biomarker for response in neoadjuvant chemotherapy for ER(-) breast cancer, which has not been previously reported. These data provide a strong rationale for considering ßΙΙΙ-tubulin status and further validation of this marker in a large study.

Hsa-miR-375 is differentially expressed during breast lobular neoplasia and promotes loss of mammary acinar polarity.

Invasive lobular carcinoma (ILC) of the breast, characterized by loss of E-cadherin expression, accounts for 5-15% of invasive breast cancers and it is believed to arise via a linear histological progression. Genomic studies have identified a clonal relationship between ILC and concurrent lobular carcinoma in situ (LCIS) lesions, suggesting that LCIS may be a precursor lesion. It has been shown that an LCIS diagnosis confers a 15-20% risk of progression to ILC over a lifetime. Currently no molecular test or markers can identify LCIS lesions likely to progress to ILC. Since microRNA (miRNA) expression changes have been detected in a number of other cancer types, we explored whether their dysregulation might be detected during progression from LCIS to ILC. Using the Illumina miRNA profiling platform, designed for simultaneous analysis of 470 mature miRNAs, we analysed the profiles of archived normal breast epithelium, LCIS lesions found alone, LCIS lesions concurrent with ILC, and the concurrent ILCs as a model of linear histological progression towards ILC. We identified two sets of differentially expressed miRNAs, the first set highly expressed in normal epithelium, including hsa-miR-224, -139, -10b, -450, 140, and -365, and the second set up-regulated during lobular neoplasia progression, including hsa-miR-375, -203, -425-5p, -183, -565, and -182. Using quantitative RT-PCR, we validated a trend of increasing expression for hsa-miR-375, hsa-miR-182, and hsa-miR-183 correlating with ILC progression. As we detected increased expression of hsa-miR-375 in LCIS lesions synchronous with ILC, we sought to determine whether hsa-miR-375 might induce phenotypes reminiscent of lobular neoplasia by expressing it in the MCF-10A 3D culture model of mammary acinar morphogenesis. Increased expression of hsa-miR-375 resulted in loss of cellular organization and acquisition of a hyperplastic phenotype. These data suggest that dysregulated miRNA expression contributes to lobular neoplastic progression.

Triple-negative breast cancers are increased in black women regardless of age or body mass index.

INTRODUCTION: We investigated clinical and pathologic features of breast cancers (BC) in an unselected series of patients diagnosed in a tertiary care hospital serving a diverse population. We focused on triple-negative (Tneg) tumours (oestrogen receptor (ER), progesterone receptor (PR) and HER2 negative), which are associated with poor prognosis. METHODS: We identified female patients with invasive BC diagnosed between 1998 and 2006, with data available on tumor grade, stage, ER, PR and HER2 status, and patient age, body mass index (BMI) and self-identified racial/ethnic group. We determined associations between patient and tumour characteristics using contingency tables and multivariate logistic regression. RESULTS: 415 cases were identified. Patients were racially and ethnically diverse (born in 44 countries, 36% white, 43% black, 10% Hispanic and 11% other). 47% were obese (BMI > 30 kg/m2). 72% of tumours were ER+ and/or PR+, 20% were Tneg and 13% were HER2+. The odds of having a Tneg tumour were 3-fold higher (95% CI 1.6, 5.5; p = 0.0001) in black compared with white women. Tneg tumours were equally common in black women diagnosed before and after age 50 (31% vs 29%; p = NS), and who were obese and non-obese (29% vs 31%; p = NS). Considering all patients, as BMI increased, the proportion of Tneg tumours decreased (p = 0.08). CONCLUSIONS: Black women of diverse background have 3-fold more Tneg tumours than non-black women, regardless of age and BMI. Other factors must determine tumour subtype. The higher prevalence of Tneg tumours in black women in all age and weight categories likely contributes to black women's unfavorable breast cancer prognosis.