The Clonal Relationship Between the Ductal and Lobular Components of Mixed Ductal-Lobular Carcinomas Suggested a Ductal Origin in Most Tumors

Abstract

The relationship between the ductal and lobular components of invasive ductolobular carcinomas (IDLC) has not been fully elucidated. In this study, the molecular alterations of both components were analyzed in a series of 20 IDLC that were selected, not only by morphologic criteria, but also by the loss of E-cadherin expression in the lobular component. We found that 80% of tumors shared alterations of driver genes in both components, being PIK3CA the most common alteration. In addition, 45% of IDLC carried CDH1 mutations in their lobular component that were absent in the ductal component. Fluorescent in situ hybridization analysis of the CDH1 gene excluded homozygous CDH1 loss as a frequent cause of E-cadherin loss in tumors without CDH1 mutations. In addition, no pathogenic mutations of catenin genes were detected in this series of tumors. In 25% of tumors, actionable mutations in PIK3CA, AKT1, and ERBB2 were found in only 1 component. Altogether, our results confirm that most IDLC derive from invasive carcinoma of no special type, in which a population of cells lose E-cadherin and acquire a lobular phenotype. The frequency of CDH1 mutations in IDLC appears to be lower than in conventional invasive lobular carcinomas, suggesting the implication of alternative mechanisms of E-cadherin loss. Moreover, molecular heterogeneity between ductal and lobular areas suggests the need for molecular characterization of both components to guide targeted therapies.

Spatial molecular profiling of mixed invasive ductal-lobular breast cancers reveals heterogeneity in intrinsic molecular subtypes, oncogenic signatures, and mutations

“…However, in lobular regions of MDLC-2, CDH1 promoter methylation was observed, indicating an alternative but less studied route of lobular tumor formation via epigenetic inactivation. This is an intriguing observation, suggesting that the pathogenesis of lobular regions within mDLC maybe more complex and diverse than previously thought 6,68,[78][79][80] . Our expression analysis of various previously reported 81 epithelial to mesenchymal (EMT) markers (Supplementary Fig.…”

“…Assessment of H&E and E- cadherin/p120 dual staining confirmed that each case exhibited histomorphic features in line with the latest mDLC definition i.e., admix of E-cadherin negative lobular tumor regions with at least 10-90% of E-cadherin positive ductal tumor regions (Supplementary Table S1B). Importantly, overall, these cases exhibited collision of spatially distinct ductal and lobular tumor regions 68,78 along with some regions of intermixing and hence could be broadly defined as mDLC of “collision” type. These cases were particularly amenable for downstream multi-omic profiling compared to those that exhibited more intermingling or intermixing with close proximity of histologic tumor regions.…”

“…Although our study presents a unique and novel analysis of mDLC of “collision” type, it has some limitations, including small sample size and a lack of analysis of other subtypes (such as lobular-like IDC-NST 83 and intermixed/intermingled mDLC 68 ) and tumor microenvironment of individual tumor regions within mDLC. Future studies will be necessary to validate our observations in larger and more diverse cohorts of mDLC.…”

“…Importantly, overall, these cases exhibited collision of spatially distinct ductal and lobular tumor regions 68,78 along with some regions of intermixing and hence could be broadly defined as mDLC of "collision" type. These cases were particularly amenable for downstream multi-omic profiling compared to those that exhibited more intermingling or intermixing with close proximity of histologic tumor regions.…”

“…Importantly, this current WHO definition of mixed invasive breast cancers MDLC differs considerably from its previous definition i.e., tumors presenting with areas of 10-49% of the special subtype and at least 50% IBC-NST 22 , indicating the fluid interpretation of this disease. Mixed tumors comprising of both ILC and IBC-NST are the most common (~5-10% of all breast cancer cases [23][24][25][26][27][28] ) and have different terminologies in the literature including mixed invasive ductal and lobular breast carcinoma (MDLC) 29 (used throughout this study), mixed invasive ductolobular breast cancer (MIDLC) 30 ), invasive ductolobular carcinomas (IDLC) 31 , and more. Despite increasing appreciation of MDLC disease 32,33 , it remains understudied, leading to diagnostic and prognostic uncertainty and clinical management challenges for the patients with this elusive disease.…”