Metaplastic breast cancers frequently express immune checkpoint markers FOXP3 and PD-L1.

BACKGROUND: Metaplastic breast carcinoma encompasses a heterogeneous group of tumours with differentiation into squamous and/or spindle, chondroid, osseous or rhabdoid mesenchymal-looking elements. Emerging immunotherapies targeting Programmed Death Ligand 1 (PD-L1) and immune-suppressing T cells (Tregs) may benefit metaplastic breast cancer patients, which are typically chemo-resistant and do not express hormone therapy targets. METHODS: We evaluated the immunohistochemical expression of PD-L1 and FOXP3, and the extent of tumour infiltrating lymphocytes (TILs) in a large cohort of metaplastic breast cancers, with survival data. RESULTS: Metaplastic breast cancers were significantly enriched for PD-L1 positive tumour cells, compared to triple-negative ductal breast cancers (P < 0.0001), while there was no significant difference in PD-L1 positive TILs. Metaplastic breast cancers were also significantly enriched for TILs expressing FOXP3, with FOXP3 positive intra-tumoural TILs (iTILs) associated with an adverse prognostic outcome (P = 0.0226). Multivariate analysis identified FOXP3 iTILs expression status as an important independent prognostic factor for patient survival. CONCLUSIONS: Our findings indicate the clinical significance and prognostic value of FOXP3, PD-1/PD-L1 checkpoint and TILs in metaplastic breast cancer and confirm that a subset of metaplastics may benefit from immune-based therapies.

Pediatric Acral Angioleiomyoma: Report of an Unusual Case and Review of the Literature.

BACKGROUND: Angioleiomyoma is a classic painful cutaneous tumor of the limbs of middle aged adults. They are usually a straight-forward histologic diagnosis, being well-circumscribed or encapsulated lesions with both smooth muscle and vascular components. CASE REPORT: We report the case of an angioleiomyoma on the toe of an 8-year-old girl which displayed an unusual plexiform growth pattern. It was treated successfully with surgical excision, with no recurrence at one month. CONCLUSIONS: Angioleiomyoma is uncommon in children, particularly at acral sites. We describe the first such lesion to display a plexiform growth pattern.

Tradeoff between metabolic i-proteasome addiction and immune evasion in triple-negative breast cancer.

In vitro studies have suggested proteasome inhibitors could be effective in triple-negative breast cancer (TNBC). We found that bortezomib and carfilzomib induce proteotoxic stress and apoptosis via the unfolded protein response (UPR) in TNBC cell lines, with sensitivity correlated with expression of immuno-(PSMB8/9/10) but not constitutive-(PSMB5/6/7) proteasome subunits. Equally, the transcriptomes of i-proteasome-high human TNBCs are enriched with UPR gene sets, and the genomic copy number landscape reflects positive selection pressure favoring i-proteasome activity, but in the setting of adjuvant treatment, this is actually associated with favorable prognosis. Tumor expression of PSMB8 protein (ß5i) is associated with levels of MHC-I, interferon-γ-inducible proteasome activator PA28ß, and the densities of stromal antigen-presenting cells and lymphocytes (TILs). Crucially, TILs were protective among TNBCs that maintain high ß5i but did not stratify survival amongst ß5i-low TNBCs. Moreover, ß5i expression was lower in brain metastases than in patient-matched primary breast tumors (n = 34; P = 0.007), suggesting that suppression contributes to immune evasion and metastatic progression. Hence, inhibiting proteasome activity could be counterproductive in the adjuvant treatment setting because it potentiates anti-TNBC immunity.