Abstract P1-07-08: Mixed ductal-lobular carcinomas of the breast: Abrogated cell adhesion in the clonal evolution from ductal to lobular morphology
Authors: AE McCart Reed, JR Kutasovic, K Nones, L da Silva, L Melville, J Jayanthan, AC Vargas, LE Reid, JM Saunus, MM Cummings, A Porter, E Evans, N Waddell, SR Lakhani, PT Simpson
Journal: Cancer Research (2017)

Abstract Mixed ductal-lobular carcinomas (MDL) display both ductal and lobular morphology, and are a clear example of intratumour morphological heterogeneity. The evolution of MDL carcinomas is not well understood. There is a paucity of data surrounding the genetic origin of the different morphological compartments and it remains to be seen whether the coincident presentation of these distinct morphological entities represents two independent tumours that have collided (so called 'collision tumours'), or whether they arise from a common clone. We propose that clonal progression during the evolution of these tumours is associated with a change in phenotype. To address this, a cohort of 82 MDLs was studied for clinical, morphological and molecular features. Key findings include: i) MDLs more frequently co-exist with ductal carcinoma in situ (DCIS) than lobular carcinoma in situ (LCIS); ii) the E-cadherin-catenin complex was recurrently normal in the ductal component but aberrantly localised in the lobular component of the same tumour; iii) E-cadherin deregulation in the lobular component was almost always aberrantly located to the cytoplasm, conversely classic ILCs are typically completely negative for this molecule; iv) epithelial to mesenchymal transition marker expression was not associated with E-cadherin deregulation. Comparative Genomic Hybridsation (CGH) and exome sequencing was performed to investigate clonal relationships between the different intratumour morphologies and identify mechanisms underlying the change in phenotype. Our analysis revealed that i) all morphological components within a case are clonally related; ii) divergence of the morphological components may occur early during tumour evolution (where both DCIS and LCIS are present) or later during tumour progression (cases with only DCIS detectible); and iii) mutations were identified in genes such as CDH1 and ESR1, and other breast cancer driver genes. Together, these data strongly support the concept that the disparate morphological components of these mixed tumours are clonally related, and are not the result of a collision event. Furthermore, we show that lobular morphology can arise via a 'ductal' pathway of tumour progression. The mechanisms driving the change in phenotype are yet to be fully elucidated, but there is significant intertumour heterogeneity and each case may utilise a unique molecular mechanism. Citation Format: McCart Reed AE, Kutasovic JR, Nones K, da Silva L, Melville L, Jayanthan J, Vargas AC, Reid LE, Saunus JM, Cummings MM, Porter A, Evans E, Waddell N, Lakhani SR, Simpson PT. Mixed ductal-lobular carcinomas of the breast: Abrogated cell adhesion in the clonal evolution from ductal to lobular morphology [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-07-08.