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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. • Inflammatory breast cancer (IBC) is a rare understudied but aggressive type of breast cancer. • AURKA amplification appeared to be more common in patients with metastatic IBC as compared to non-IBC. • AURKA amplification is associated with AURKA expression. • AURKA protein expression is associated with worse prognosis in patients with IBC. [ABSTRACT FROM AUTHOR]

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. • Approximately 5 percent of primary breast cancer consist of a mixture of NST and ILC. • Mixed IBC-NST/ILC is understudied, especially in the metastatic setting. • We collected metastases of 2 patients with primary mixed IBC-NST/ILC via rapid autopsies. • All metastases of these patients displayed a lobular histology. • Awareness of symptoms related to ILC is needed in patients with mixed IBC-NST/ILC. [ABSTRACT FROM AUTHOR]

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. • Mammary adiposity is under-investigated in the context of breast cancer. • Digital pathology can measure adipocytes distant from the tumor as well as cancer-associated adipocytes (CAAs). • CAAs are smaller than distant adipocytes, reflecting the delipidation process undergone by CAAs. • The body mass index of the patient is associated with the size of distant adipocytes and CAAs. [ABSTRACT FROM AUTHOR]

Abstract: Background: The role of circulating tumor cells (CTCs) in HER2-positive breast cancer patients receiving neoadjuvant therapy is unclear. Patients & methods: We describe the CTC detection rate, HER2 phenotyping and pathological complete response (pCR) in patients enrolled in the NeoALTTO phase III trial. Participation in the CTC sub-study was optional. CTC evaluation was performed centrally using CellSearch® at baseline, week 2 and week 18 (prior to surgery) of neoadjuvant therapy. Results: Samples for CTC analysis were available for 51/455 patients randomized. At baseline, week 2 and week 18, we detected ≥1 CTC/22.5 ml in 5/46 (11%), 4/41 (10%), and 5/31 (16%) patients and ≥1 HER2-positive CTC/22.5 ml in 2/46 (4%), 2/41 (5%), and 3/31 (10%) patients with evaluable samples, respectively. 11/51 patients (21%) had ≥1 CTC/22.5 ml in at least one time point. pCR was observed in 3/11 (27.3%) versus 17/40 (42.5%) patients with detectable and no detectable CTCs, respectively (p = 0.36). No pCR was observed in the three patients with detectable HER2-positive CTCs prior to surgery. Conclusion: Numerically lower pCR rates were observed in patients with detectable CTCs, yet the study remains underpowered. A meta-analysis of CTC studies in this setting is warranted. [Copyright &y& Elsevier]

Anti-HER2 antibody-drug conjugates (ADCs) have shown important efficacy in HER2-low metastatic breast cancer (mBC). Criteria for receiving ADCs are based on a single assay on the primary tumour or a small metastatic biopsy. We assessed the intra-patient inter-metastasis heterogeneity of HER2-low status in HER2-negative mBC. We included samples of 10 patients (7 ER-positive and 3 ER-negative) donated in the context of our post-mortem tissue donation program UPTIDER. Excisional post-mortem biopsies of 257 metastases and 8 breast tumours underwent central HER2 immunohistochemistry (IHC), alongside 41 pre-mortem primary or metastatic samples. They were classified as HER2-zero, HER2-low (HER2-1+ or HER2-2+, in situ hybridisation [ISH] negative) or HER2-positive (HER2-3+ or HER2-2+, ISH-positive) following ASCO/CAP guidelines 2018. HER2-zero was further subdivided into HER2-undetected (no staining) and HER2-ultralow (faint staining in ≤10% of tumour cells). Median post-mortem interval was 2.5 h. In 8/10 patients, HER2-low and HER2-zero metastases co-existed, with the proportion of HER2-low lesions ranging from 5% to 89%. A total of 32% of metastases currently classified as HER2-zero were HER2-ultralow. Intra-organ inter-metastasis heterogeneity of HER2-scores was observed in the liver in 3/6 patients. Patients with primary ER-positive disease had a higher proportion of HER2-low metastases as compared to ER-negative disease (46% versus 8%, respectively). At the metastasis level, higher percentages of ER-expressing cells were observed in HER2-low or -ultralow as compared to HER2-undetected metastases. Important intra-patient inter-metastasis heterogeneity of HER2-low status exists. This questions the validity of HER2-low in its current form as a theranostic marker. [Display omitted] • HER2-low metastatic breast cancer is now clinically actionable. • It's unknown how discordant HER2 status is between multiple metastases in a patient. • We assessed HER2 in 306 post- and pre-mortem samples from 10 HER2-negative patients. • In 8/10 patients, HER2-low and HER2-zero metastases co-existed. • This intra-patient heterogeneity of HER2 status complicates its theranostic value. [ABSTRACT FROM AUTHOR]

Invasive lobular carcinoma (ILC) represents up to 15% of all breast carcinomas. While the proportion of women with overweight and obesity increases globally, the impact of body mass index (BMI) at primary diagnosis on clinicopathological features of ILC and the prognosis of the patients has not been investigated yet. We performed a multicentric retrospective study including patients diagnosed with non-metastatic pure ILC. The association of BMI at diagnosis with clinicopathological variables was assessed using linear or multinomial logistic regression. Univariable and multivariable survival analyses were performed to evaluate the association of BMI with disease-free survival (DFS), distant recurrence-free survival (DRFS), and overall survival (OS). The data of 2856 patients with ILC and available BMI at diagnosis were collected, of which 2570/2856 (90.0%) had oestrogen receptor (ER)-positive and human epidermal growth factor receptor (HER2) not amplified/overexpressed (ER+/HER2−) ILC. Of these 2570 patients, 80 were underweight (3.1%), 1410 were lean (54.9%), 712 were overweight (27.7%), and 368 were obese (14.3%). Older age at diagnosis, a higher tumour grade, a larger tumour size, a nodal involvement, and multifocality were associated with a higher BMI. In univariable models, higher BMI was associated with worse outcomes for all end-points (DFS: hazard ratio (HR) 1.21, 95CI 1.12–1.31, p value < 0.01; DRFS: HR 1.25, 95CI 1.12–1.40, p value < 0.01; OS: HR 1.25, 95CI 1.13–1.37, p value < 0.01). This association was not statistically significant in multivariable analyses (DFS: HR 1.09, 95CI 0.99–1.20, p value 0.08; DRFS: HR 1.03, 95CI 0.89–1.20, p value 0.67; OS: HR 1.11, 95CI 0.99–1.24, p value 0.08), whereas grade, tumour size, and nodal involvement were still prognostic for all end-points. Worse prognostic factors such as higher grade, larger tumour size, and nodal involvement are associated with higher BMI in ER+/HER2− ILC, while there was no statistical evidence for an independent prognostic role for BMI. Therefore, we hypothesise that the effect of BMI on survival could be mediated through its association with these clinicopathological variables. [Display omitted] • Higher BMI at diagnosis is associated with worse features for ER+/HER2− ILC. • Higher BMI is not an independent prognostic factor for patients with ER+/HER2− ILC. • The role of BMI might be mediated through other variables. • HER2+ and ER−/HER2− ILC might be impacted differently by BMI. [ABSTRACT FROM AUTHOR]