Elucidating MDLC’s molecular features

A collaborative group of researchers, from the University of Pittsburgh, the University of Michigan and the Memorial Sloan Kettering Cancer Center analysed collision-type MDLC tumours, finding particular molecular features and highlighting the complexity of these cancers. Their findings indicate that alternative treatment approaches may be superior.

In breast cancer biopsies, most cancerous cells form circular groups, known as invasive ductal carcinoma (IDC). Fewer patients have invasive lobular carcinomas (ILC), in which the abnormal cells are more dispersed throughout the breast tissue. Very rarely, IDC and ILC occur together as a collision type called mixed ductal-lobular breast cancer (MDLC).

Dr Steffi Oesterreich, co-leader of the Cancer Biology Program at UMPC Hillman Cancer Center and professor in the Department of Pharmacology and Chemical Biology at Pitt, explained that MDLC tumours are complex, difficult to define and have not been well researched, so there is little understanding of the molecular features and best approaches for treatment.

Dr Oesterreich and her team, which included researchers from the University of Michigan and Memorial Sloan Kettering Cancer Center, discovered that IDC and ILC regions had distinct molecular features. Dr Oesterreich explained: “We found that the different regions of mixed tumours had very different underlying biology…These patients essentially have two independent diseases that may respond differently to different treatments.”

Transcriptomes

In the study, the three breast cancer cases that three pathologists agreed were MDLC were identified. Novel spatial sequencing technology was used to compare gene expression in different areas of the tumour, as well as a mutation analysis to locate alterations in the DNA sequences of tumour cells across the tumour. IDC and ILC regions of the tumours had very different transcriptomes.

Dr Oesterreich stated: “In one of the cases, we found very different molecular subtypes in different regions of the tumour…One is what we call luminal, and the other was triple-negative. These molecular subtypes are treated very differently. Our findings suggest that spatial sequencing of mixed-type breast cancers could inform different therapies for patients.”

Importantly, all three cases had distinct molecular features. Dr Oesterreich added: “Our study reveals tremendous variation within this already highly variable disease.”

Although genetic sequencing is a routine part of cancer care, existing approaches do not account for variation across the tumour. Moving forwards, spatial sequencing could be combined with other technology like single cell sequencing to provide an enhanced picture of mixed tumours to guide personalised treatments.

This study was published in Proceedings of the National Academy of Sciences (PNAS).