Spindle cell carcinoma of the breast: Rare cancer with potentially targetable biomarkers.

Abstract

Background Spindle cell carcinoma is a rare, metaplastic breast cancer (<1% of all breast carcinomas), with reportedly triple-negative (TNBC: ER-/PR-/Her2-) phenotype, associated with a marked resistance to conventional chemotherapy and overall poor outcome. Methods Twenty pure spindle cell carcinomas of the breast (15 primary and 5 recurrent/metastatic) were comprehensively explored for biomarkers of immuno-oncology (I-O) and targeted therapies using immunohistochemistry and DNA (592 genes panel) and RNA (52 genes panel) sequencing. A cohort of 603 TNBC cases analyzed with NGS was used as a control for the total mutational burden (TMB). Results Majority (18/20) of spindle cell carcinomas were triple negative. Estrogen (2 cases) and androgen receptor (one case) expression above the therapeutic thresholds were rarely detected. Pathogenic mutations were detected in 80% including PIK3CA (30%), TP53 (25%), HRAS (20%), NF1 (20%), and PTEN (10%) as the most frequent. One case with matched pre- and post-chemotherapy samples analysis exhibited a consistent mutational profile (PIK3CA and HRAS mutations) in both samples. No gene fusions were identified in matched samples. No NTRK expression was detected in 4 tested cases. In comparison to the large (>600 patients) cohort of TNBC (11 mutations/Mb as 80th percentile cutoff value), the TMB in spindle cell carcinomas was low (below 80th percentile) in all cases (3-9 mutations/Mb). All tumors were microsatellite stable. Tumor cells (TC) PD-L1 expression was present in 6/18 cases. Conclusions Spindle cell carcinoma of the breast exhibits mutational profile similar to the published data in other types of metaplastic breast carcinomas. All spindle cell carcinomas have a low TMB and were microsatellite stable. PD-L1 expression was detected in one third of cases and may guide therapy trials with immune checkpoint inhibitors. Rare cases with ER and AR expression were detected and were candidates for respective hormonal therapies.