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Background: The adipose tissue may serve as a source of energy supporting cancer growth and metastasis. Our understanding of the adipocytes which compose the adipose tissue in different anatomical locations of the body as well as potential microscopic tumor infiltration in patients with metastatic breast cancer remains limited. This study therefore investigates regional variations in adipocyte size and adipose tissue tumor infiltration in patients with metastatic breast cancer. Methods: Within the UPTIDER rapid autopsy program, (NCT04531696), 94 adipose tissue samples from subcutaneous, visceral, retroperitoneal, and mammary depots of 22 patients with metastatic breast cancer were collected and analyzed. Distant adipocyte size was quantified using digital pathology, and tumor infiltration was assessed histologically. Linear mixed quantile regression analyzed the associations between adipocyte size, fat depot type and major histological subtypes. Results: Distant adipocyte size did not significantly differ across fat depots. A trend towards smaller adipocytes in mammary fat at autopsy versus diagnosis was observed, suggesting potential age and/or treatment effects. Adipocyte size correlated positively with BMI at death, especially in subcutaneous and visceral fat. Visceral fat exhibited higher tumor infiltration, notably in patients with invasive lobular carcinoma (ILC). Conclusion: This study highlights the relatively uniform adipocyte size across fat depots in patients with metastatic breast cancer, with potential changes in mammary adipocytes over the disease course. The microscopic tumor cell infiltration observed in the visceral fat, mainly for ILC, underscores the need to undertake additional research to understanding the contribution of the adipose tissue in breast cancer metastasis.

Primary tumors with a mixed invasive breast carcinoma of no-special type (IBC-NST) and invasive lobular cancer (ILC) histology are present in approximately five percent of all patients with breast cancer and are understudied at the metastatic level. Here, we characterized the histology of metastases from two patients with primary mixed IBC-NST/ILC from the postmortem tissue donation program UPTIDER (NCT04531696). The 14 and 43 metastatic lesions collected at autopsy had morphological features and E-cadherin staining patterns consistent with pure ILC. While our findings still require further validation, they may challenge current clinical practice and imaging modalities used in these patients.

Inflammatory breast cancer (IBC) is a rare but aggressive subtype of breast cancer, mainly characterized using primary tumor samples. Here, using public datasets, we compared the genomic alterations in primary and metastatic samples from patients with metastatic IBC versus patients with metastatic non-IBC. We observed a higher frequency of AURKA amplification in IBC. We further showed that AURKA amplification was associated with increased AURKA mRNA expression, which we demonstrated was higher in IBC. Finally, higher protein expression of AURKA was associated with worse prognosis in patients with IBC. These findings deserve further investigation given the existence of AURKA-inhibitors.

Adipocytes and cancer-associated adipocytes (CAAs) are poorly investigated cells in the tumor microenvironment. Different image analysis software exist for identifying and measuring these cells using scanned hematoxylin and eosin (H&E)-stained slides. It is however unclear which one is the most appropriate for breast cancer (BC) samples. Here, we compared three software (AdipoCount, Adiposoft, and HALO®). HALO® outperformed the other methods with regard to adipocyte identification, (> 96% sensitivity and specificity). All software performed equally good with regard to area and diameter measurement (concordance correlation coefficients > 0.97 and > 0.96, respectively). We then analyzed a series of 10 BCE samples (n = 51 H&E slides) with HALO®. Distant adipocytes were defined >2 mm away from cancer cells or fibrotic region, whereas CAAs as the first three lines of adipocytes close to the invasive front. Intra-mammary heterogeneity was limited, implying that measuring a single region of ∼500 adipocytes provides a reliable estimation of the distribution of their size features. CAAs had smaller areas (median fold-change: 2.62) and diameters (median fold-change: 1.64) as compared to distant adipocytes in the same breast (both p = 0.002). The size of CAAs and distant adipocytes was associated with the body mass index (BMI) of the patient (area: rho = 0.89, p = 0.001; rho = 0.71, p = 0.027, diameter: rho = 0.87 p = 0.002; rho = 0.65 p = 0.049, respectively). To conclude, we demonstrate that quantifying adipocytes in BC sections is feasible by digital pathology using H&E sections, setting the basis for a standardized analysis of mammary adiposity in larger series of patients.