Bone marrow micrometastasis in breast cancer: review of detection methods, prognostic impact and biological issues

Immunocytochemical detection of disseminated tumour cells in the bone marrow of patients with primary breast cancer at surgery has been shown to be an independent prognostic factor in single institutional studies and in a large pooled analysis. However, bone marrow sampling and assessment of disseminated tumour cells is not a routine procedure in the clinical management of patients with breast cancer, but will certainly play a role in the near future for risk stratification and monitoring of therapeutic efficacy. Accurate identification of disseminated tumour cells in bone marrow must be based on standardised methodologies and procedures. This review describes these methodologies and the standardised morphological criteria used for disseminated tumour cell detection. The prognostic value of circulating tumour cells detection in peripheral blood is demonstrated in patients with metastatic disease but remains to be substantiated at early stage. The significance of disseminated tumour cells in bone marrow and in the blood for the prediction of response to therapy is briefly summarised. Finally, this review addresses the main biological questions raised by disseminated tumour cells, in particular understanding tumour dormancy and identifying metastatic stem cells

Low expression of bcl-2 in Brca1-associated breast cancers

Little data are available concerning the molecular mechanisms of action of Brca1 and Brca2 in breast oncogenesis. Recent experimental results suggest that Brca1 plays a role in the regulation of apoptosis. In order to determine whether the analysis of human tumours would provide data supporting this hypothesis, we have assessed the expression of the antiapoptotic bcl-2 and of the proapoptotic p53 genes in Brca1- and Brca2-associated breast carcinomas. The levels of expression of these genes were compared to those observed in controls and to the mitotic and the apoptotic indexes. Our series were composed of 16 cases of breast carcinoma in women with a germline Brca1 gene mutation, and of four cases with Brca2 mutation. A group of 39 patients aged under 36 years and for whom the search for Brca1 gene mutations was negative, and a group of 36 cases of sporadic cancers without data on their Brca status were used as controls. Immunohistochemistry was used to detect p53 and bcl-2 gene products. Mitotic and apoptotic indexes were higher in Brca1-associated tumours than in controls. No significant difference in p53 immunostaining was observed between the four groups of patients. In contrast, the rate of bcl-2-positive tumours was lower (31%) in Brca1-carcinomas than in carcinomas without Brca1 mutation (90%) (P< 10–3). A strong Bcl-2 expression was found in the four cases of Brca2-associated carcinomas. No significant correlation was observed between p53 and Bcl-2 immunostainings, either in cases or in controls. The association between Brca1 status and Bcl-2 expression remained significant after adjustment for the oestrogen receptor status. Our study shows that a low expression of bcl-2 characterises most Brca1-associated breast carcinomas, a biological trait which seems not to be shared by Brca2-associated tumours nor to be related to oestrogen receptor and/or p53 status.bcl-2 might thus be one of the target genes involved in the oncogenesis related to Brca1 and its down-regulation may account for the increased apoptosis and the high proliferative rate observed in Brca1-associated carcinomas. © 2000 Cancer Research Campaig

HRAS is a therapeutic target in malignant chemo-resistant adenomyoepithelioma of the breast

Abstract Malignant adenomyoepithelioma (AME) of the breast is an exceptionally rare form of breast cancer, with a significant metastatic potential. Chemotherapy has been used in the management of advanced AME patients, however the majority of treatments are not effective. Recent studies report recurrent mutations in the HRAS Q61 hotspot in small series of AMEs, but there are no preclinical or clinical data showing H-Ras protein as a potential therapeutic target in malignant AMEs. We performed targeted sequencing of tumours’ samples from new series of 13 AMEs, including 9 benign and 4 malignant forms. Samples from the breast tumour and the matched axillary metastasis of one malignant HRAS mutated AME were engrafted and two patient-derived xenografts (PDX) were established that reproduced the typical AME morphology. The metastasis-derived PDX was treated in vivo by different chemotherapies and a combination of MEK and BRAF inhibitors (trametinib and dabrafenib). All malignant AMEs presented a recurrent mutation in the HRAS G13R or G12S hotspot. Mutation of PIK3CA were found in both benign and malignant AMEs, while AKT1 mutations were restricted to benign AMEs. Treatment of the PDX by the MEK inhibitor trametinib, resulted in a marked anti-tumor activity, in contrast to the BRAF inhibitor and the different chemotherapies that were ineffective. Overall, these findings further expand on the genetic features of AMEs and suggest that patients carrying advanced HRAS-mutated AMEs could potentially be treated with MEK inhibitors

Interplay between telecommunications and face-to-face interactions - a study using mobile phone data

In this study we analyze one year of anonymized telecommunications data for over one million customers from a large European cellphone operator, and we investigate the relationship between people's calls and their physical location. We discover that more than 90% of users who have called each other have also shared the same space (cell tower), even if they live far apart. Moreover, we find that close to 70% of users who call each other frequently (at least once per month on average) have shared the same space at the same time - an instance that we call co-location. Co-locations appear indicative of coordination calls, which occur just before face-to-face meetings. Their number is highly predictable based on the amount of calls between two users and the distance between their home locations - suggesting a new way to quantify the interplay between telecommunications and face-to-face interactions