Intrinsic molecular signature of breast cancer in a population-based cohort of 412 patients

BACKGROUND: Molecular markers and the rich biological information they contain have great potential for cancer diagnosis, prognostication and therapy prediction. So far, however, they have not superseded routine histopathology and staging criteria, partly because the few studies performed on molecular subtyping have had little validation and limited clinical characterization. METHODS: We obtained gene expression and clinical data for 412 breast cancers obtained from population-based cohorts of patients from Stockholm and Uppsala, Sweden. Using the intrinsic set of approximately 500 genes derived in the Norway/Stanford breast cancer data, we validated the existence of five molecular subtypes – basal-like, ERBB2, luminal A/B and normal-like – and characterized these subtypes extensively with the use of conventional clinical variables. RESULTS: We found an overall 77.5% concordance between the centroid prediction of the Swedish cohort by using the Norway/Stanford signature and the k-means clustering performed internally within the Swedish cohort. The highest rate of discordant assignments occurred between the luminal A and luminal B subtypes and between the luminal B and ERBB2 subtypes. The subtypes varied significantly in terms of grade (p < 0.001), p53 mutation (p < 0.001) and genomic instability (p = 0.01), but surprisingly there was little difference in lymph-node metastasis (p = 0.31). Furthermore, current users of hormone-replacement therapy were strikingly over-represented in the normal-like subgroup (p < 0.001). Separate analyses of the patients who received endocrine therapy and those who did not receive any adjuvant therapy supported the previous hypothesis that the basal-like subtype responded to adjuvant treatment, whereas the ERBB2 and luminal B subtypes were poor responders. CONCLUSION: We found that the intrinsic molecular subtypes of breast cancer are broadly present in a diverse collection of patients from a population-based cohort in Sweden. The intrinsic gene set, originally selected to reveal stable tumor characteristics, was shown to have a strong correlation with progression-related properties such as grade, p53 mutation and genomic instability

Skin toxicity as a risk factor for major infections in breast cancer patients treated with docetaxel

To access publisher full text version of this article. Please click on the hyperlink in Additional Link fieldDocetaxel-related skin toxicity, oral and gastrointestinal mucosal toxicity, and changes in blood cell counts were investigated as predictive factors for major infections in 143 women treated with 3-weekly docetaxel (100 mg/m2) as second-line therapy for metastatic breast cancer in a randomized trial. Each patient with a major infection (n = 37) was compared with two controls. Skin toxicity (odds ratio 2.97, 95% CI 1.37-6.47), oral mucositis (1.98, CI 1.30-3.04), and the leukocyte nadir (0.12, CI 0.02-0.51) were significantly associated with a major infection in a univariate logistic regression analysis. In a multivariate analysis, skin toxicity was the only independent factor predictive for grade 3 to 4 infection (2.75, CI 1.00-7.58). A major infection was diagnosed in 62% (8 out of 13) of the docetaxel cycles in severely (grade 4) leukopenic patients who had grade 2 to 4 skin toxicity. Major infections are common in leukopenic patients who develop docetaxel-associated skin toxicity, and leukopenic patients presenting with docetaxel-induced skin toxicity may be candidates for prophylactic anti-infection measures such as prophylactic therapy with hematopoietic growth factors