Pre-surgical studies allow study of the relationship between mutations and response of oestrogen receptor-positive (ER+) breast cancer to aromatase inhibitors (AIs) but have been limited to small biopsies. Here in phase I of this study, we perform exome sequencing on baseline, surgical core-cuts and blood from 60 patients (40 AI treated, 20 controls). In poor responders (based on Ki67 change), we find significantly more somatic mutations than good responders. Subclones exclusive to baseline or surgical cores occur in ∼30% of tumours. In phase II, we combine targeted sequencing on another 28 treated patients with phase I. We find six genes frequently mutated: PIK3CA, TP53, CDH1, MLL3, ABCA13 and FLG with 71% concordance between paired cores. TP53 mutations are associated with poor response. We conclude that multiple biopsies are essential for confident mutational profiling of ER+ breast cancer and TP53 mutations are associated with resistance to oestrogen deprivation therapy.
Paget's disease of the nipple is an unusual epidermal presentation of underlying breast cancer. It presents as eczematous change or erythematous ulceration, but may also be an incidental histological finding in a mastectomy specimen. Approximately half of the underlying cancers are invasive, the remainder being ductal carcinoma in situ, and only rarely is there no associated malignancy. Routine clinical and mammographic assessment may significantly underestimate the extent of disease, but MRI may increase the sensitivity in detecting occult malignancy. Mastectomy maximizes local control; however, selected cases can be treated by nipple conisation with radiotherapy. Sentinel node biopsy is the standard of care for axillary staging in the clinically and ultrasonically node-negative case. Almost all invasive cases overexpress human EGF receptor-2 and, therefore, are likely to benefit from adjuvant chemotherapy and herceptin.
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