Phenotypic and molecular dissection of Metaplastic Breast Cancer and the prognostic implications.

McCart Reed AE1, Kalaw E1, Nones K2, Bettington M1, Lim M1, Bennett J1,3, Johnstone K1,3, Kutasovic JR1, Saunus JM1, Kazakoff S2, Xu Q2, Wood S2, Holmes O2, Leonard C2, Reid LE1, Black D1, Niland C1, Ferguson K1, Gresshoff I1, Raghavendra A1, Harvey K4, Cooper C4, Liu C1,3, Kalinowski L1,3, Reid AS1,3, Davidson M1,3, Pearson JV2, Pathmanathan N5, Tse G6, Papadimos D7, Pathmanathan R8, Harris G9, Yamaguchi R10, Tan PH11, Fox S12, O'Toole SA4, Simpson PT1, Waddell N2, Lakhani SR1,3.

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Abstract

Metaplastic Breast Carcinoma (MBC) is relatively rare but accounts for a significant proportion of global breast cancer mortality. This group is extremely heterogeneous and by definition exhibits metaplastic change to squamous and/or mesenchymal elements, including spindle, squamous, chondroid, osseous and rhabdomyoid features. Clinically, patients are more likely to present with large primary tumours (higher stage), distant metastases and overall, have shorter 5-year survival compared to Invasive Carcinomas of no special type. The current World Health Organisation (WHO) diagnostic classification for this cancer type is based purely on morphology - the biological basis and clinical relevance of its seven sub-categories are currently unclear. By establishing the Asia-Pacific MBC (AP-MBC) consortium, we amassed a large series of MBC (n=347) and analysed the mutation profile of a subset, expression of 14 breast cancer biomarkers and clinicopathologic correlates, contextualizing our findings within the WHO guidelines. The most significant indicators of poor prognosis were: large tumour size (T3; p=0.004), loss of cytokeratin expression (lack of staining with pan-Cytokeratin AE1/3 antibody; p=0.007), EGFR overexpression (p=0.01) and for 'mixed' MBC, the presence of more than three distinct morphological entities (p=0.007). Conversely, fewer morphological components and EGFR negativity were favourable indicators. Exome sequencing of 30 cases confirmed enrichment of TP53 and PTEN mutations, and intriguingly, concurrent mutations of TP53, PTEN and PIK3CA. Mutations in neurofibromatosis-1 (NF1) were also over-represented (16.7% MBC compared to ~5% of breast cancers overall; enrichment p=0.028; mutation significance p=0.006 (OncodriveFM)), consistent with published case reports implicating germline NF1 mutations in MBC risk. Taken together, we propose a practically minor but clinically significant modification to the guidelines: all WHO_1 mixed type tumours should have the number of morphologies present recorded, as a mechanism for refining prognosis, and that EGFR and pan-cytokeratin expression are important prognostic markers.