Analysis of circulating tumor DNA to monitor metastatic breast cancer.

BACKGROUND: The management of metastatic breast cancer requires monitoring of the tumor burden to determine the response to treatment, and improved biomarkers are needed. Biomarkers such as cancer antigen 15-3 (CA 15-3) and circulating tumor cells have been widely studied. However, circulating cell-free DNA carrying tumor-specific alterations (circulating tumor DNA) has not been extensively investigated or compared with other circulating biomarkers in breast cancer. METHODS: We compared the radiographic imaging of tumors with the assay of circulating tumor DNA, CA 15-3, and circulating tumor cells in 30 women with metastatic breast cancer who were receiving systemic therapy. We used targeted or whole-genome sequencing to identify somatic genomic alterations and designed personalized assays to quantify circulating tumor DNA in serially collected plasma specimens. CA 15-3 levels and numbers of circulating tumor cells were measured at identical time points. RESULTS: Circulating tumor DNA was successfully detected in 29 of the 30 women (97%) in whom somatic genomic alterations were identified; CA 15-3 and circulating tumor cells were detected in 21 of 27 women (78%) and 26 of 30 women (87%), respectively. Circulating tumor DNA levels showed a greater dynamic range, and greater correlation with changes in tumor burden, than did CA 15-3 or circulating tumor cells. Among the measures tested, circulating tumor DNA provided the earliest measure of treatment response in 10 of 19 women (53%). CONCLUSIONS: This proof-of-concept analysis showed that circulating tumor DNA is an informative, inherently specific, and highly sensitive biomarker of metastatic breast cancer. (Funded by Cancer Research UK and others.).

Conservative management of screen-detected radial scars: role of mammotome excision.

AIMS: Traditionally, a core biopsy diagnosis of radial scar will prompt diagnostic surgery because of the risk of associated malignancy. However, in the absence of atypia, the risk of malignancy is low. The recent introduction of the mammotome device facilitates vacuum-assisted large-volume sampling of a lesion, such that a benign diagnosis may be accepted more confidently, and if the lesion has been entirely removed, it effectively becomes a therapeutic procedure. The aim of this study was to review the role of mammotome excision in the management of non-atypical radial scars in the screening population. METHODS: Screen-detected radial scars diagnosed on core biopsy between July 2004 and September 2008 were identified from pathology records. From January 2006, the mammotome device was used to excise non-atypical radial scars on core biopsy, as an alternative to surgery. RESULTS: 22 core biopsy samples containing radial scars without atypia were included in the study; 14 were planned for mammotome excision and eight for diagnostic surgical excision. In the mammotome group, 78% (11/14) of patients had confirmation of non-atypical radial scars and thus avoided an operation. Three of the 14 cases planned for mammotome excision required surgery; in one case, the mammotome cores contained lobular in situ neoplasia, and, in two cases, attempts to sample the lesion with the mammotome were unsuccessful. Only one of the 22 cases ultimately proved malignant. This was a case of ductal carcinoma in situ arising within a radial scar, where the patient proceeded straight to surgery in view of discordance between radiological and pathological features. CONCLUSION: Utilisation of mammotome excision in the management of non-atypical radial scars successfully avoided surgery in 78% of eligible patients. Pathologists have an important role in selecting patients for mammotome excision by excluding the presence of atypia.

What is the significance of flat epithelial atypia and what are the management implications?

AIMS: To assess the significance of flat epithelial atypia (FEA) on core biopsy by evaluating the proportion of cases upgraded to in-situ and invasive carcinoma on further sampling with vacuum-assisted biopsy (VAB) or diagnostic surgical biopsy. METHODS: A retrospective analysis was performed of all core biopsies containing FEA and/or atypical intraductal proliferation (AIDP) in the pathology database from April 2008 to April 2010 (n=90). Before April 2009, the majority of core biopsies containing FEA and/or AIDP proceeded to surgical biopsy. From April 2009 onwards, a new patient management pathway was introduced incorporating VAB to sample core biopsies containing FEA and/or AIDP as an alternative to surgical biopsy. RESULTS: Of 90 core biopsies, the following were identified: FEA only in 42%; FEA with concomitant AIDP in 21% and AIDP only in 37%. There was a stepwise increase in the proportion of cases upgraded to in-situ or invasive carcinoma: 19% in the FEA group; 29% in the FEA and AIDP group and 53% in the AIDP group. In the FEA-only group, one invasive tumour (grade 1 tubular carcinoma) and six cases of ductal carcinoma in situ were found. CONCLUSION: The presence of FEA on core biopsy warrants further tissue sampling to ensure concomitant malignancy is not missed. Sampling with VAB provides sufficient tissue for histopathological evaluation, reducing the need for surgical biopsy. It is important that the utilisation of VAB is incorporated into a safe patient management pathway with careful multidisciplinary team discussion to ensure radiological-pathological concordance.