Invasive lobular carcinoma (ILC) is the second most common histological breast cancer (BC) subtype. Little is known regarding the tumor microenvironment (TME) that characterizes ILC. In this work, we aimed to study TME and uncover tumor and stroma cells interactions with potential clinical implication in ILC using spatial transcriptomics (ST).
We performed ST (Visium 10X Genomics®) on frozen tumor samples from 43 primary HR+, HER2- ILC patients. Nine samples were from patients who experienced disease relapse. Morphological annotation of the H&E slides relative to the ST samples was performed using QuPath software. METABRIC (HR+, HER2- ILC samples, n = 122) was used as external validation cohort.
Intriguingly, morphological annotations revealed a greater co-localization at the spot level between adipocytes and cancer cells in samples from patients with relapse (p = 0.04). This area was enriched in metabolism-related pathways (padj < 0.05). To assess the prognostic implication of this co-localization, we derived a 27 gene signature by performing differential gene expression analysis between patients with vs without relapse considering the ST spots laying on the tumor-adipocytes contact area. Interestingly, our adipocytes-related signature was significantly associated with poor survival in ILC patients in METABRIC. Of note, no correlation was found between the adipocytes-related and proliferation-related signatures (including genomic grade index – GGI), which were also found to be prognostic in ILC. By combining the adipocytes-related signature with the GGI, we built a robust prognostic index that outperformed the other prognostic-related signatures (computed with genefu R package) both at the univariable (HR = 1.8, p = 3.4x10-4) and at the multivariable analysis (HR 1.7, p = 0.0016) in predicting relapse free survival.
To our knowledge, the adipocytes-related signature is the first prognostic signature in ILC not related to proliferation, highlighting an important implication of adipocytes in the biology of ILC. The strong prognostic power of the integrated predictor has the potential to improve prognostication in ILC. Further validation is needed.
The authors.
FNRS, Fondation Jules Bordet, Breast Cancer Research Foundation, Fondation contre le Cancer.
F.P. Duhoux: Financial Interests, Institutional, Advisory Board: Roche, Pfizer, AstraZeneca, Lilly, Novartis, Amgen, Daiichi Sankyo, Pierre Fabre, Gilead, Seagen, MSD; Financial Interests, Institutional, Invited Speaker: Novartis, Pfizer, MSD, Roche, MSD, Boehringer Ingelheim, Pfizer, Novartis, Lilly, AbbVie, Seagen, Gilead, AstraZeneca, Menarini, Immutep; Financial Interests, Institutional, Expert Testimony: Seagen, Novartis, MSD. C. Sotiriou: Financial Interests, Institutional, Advisory Board: Astellas, Vertex, Seattle Genetics, AMGEN, INC, Merck & Co; Financial Interests, Personal, Advisory Board: Cepheid, Puma; Financial Interests, Personal, Invited Speaker: Eisai, Prime oncology, Teva; Financial Interests, Institutional, Other, Travel: Roche; Financial Interests, Institutional, Other, Internal speaker: Genentech; Financial Interests, Personal, Other, Regional speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: Exact Sciences. All other authors have declared no conflicts of interest.