Molecular Profiling of the Metaplastic Spindle Cell Carcinoma of the Breast Reveals Potentially Targetable Biomarkers

Abstract

Spindle cell carcinoma is a rare subtype of metaplastic breast cancer, with triple-negative phenotype. Twenty-three spindle cell carcinomas were comprehensively explored for biomarkers of immuno-oncology and targeted therapies using immunohistochemistry and DNA/RNA sequencing. Spindle cell carcinomas are characterized by targetable molecular alterations in the majority of cases, but, owing to the lack of uniform findings, individual patient profiling is necessary. Introduction: Spindle cell carcinoma is a rare subtype of metaplastic breast cancer, with triple-negative (TNBC: estrogen receptor-negative/progesterone receptor-negative/human epidermal growth factor receptor 2-negative) phenotype. It is associated with a marked resistance to conventional chemotherapy and has an overall poor outcome. Materials and Methods: Twenty-three pure spindle cell carcinomas of the breast (18 primary and 5 recurrent/metastatic) were comprehensively explored for biomarkers of immuno-oncology and targeted therapies using immunohistochemistry and DNA/RNA sequencing. Results: The majority (21/23) of spindle cell carcinomas were TNBC. Estrogen and androgen receptor expression above the therapeutic thresholds were detected in 2 cases each. Pathogenic gene mutations were identified in 21 of 23 cases, including PIK3CA, TP53, HRAS, NF1, and PTEN. One case with matched pre-and postchemotherapy samples exhibited a consistent mutational profile (PIK3CA and HRAS mutations) in both samples. Gene amplifications were present in 5 cases, including 1 case without detectable mutations. The spindle cell carcinomas cohort had consistently low total mutational burden (all below the 80th percentile for the entire TNBC cohort). All tumors were microsatellite stable. Programmed death-ligand 1 expression was observed on both tumor cells (in 7/21 cases), and in tumor-infiltrating immune cells (2/21 cases). Conclusions: Spindle cell carcinomas are characterized by targetable molecular alterations in the majority of cases, but owing to the lack of uniform findings, individual patient profiling is necessary. Detection of individual combinations of biomarkers should improve treatment options for this rare but aggressive disease.

Molecular Features of Metaplastic Breast Carcinoma: An Infrequent Subtype of Triple Negative Breast Carcinoma

“…In one series, important age differences among histological subtypes were observed, MBC with chondroid differentiation occurring at a mean age of 71 years, whereas spindle and squamous cell carcinomas presented at mean ages of 56 and 48 years old, respectively [ 5 ]. MBC are usually large tumors with a mean size of 3.9 cm, among the series reviewed [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. Most tumors present in stage II.…”

“…In this study, we reviewed 14 series [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 28 , 29 ] including a total of 539 molecularly characterized tumors. Eight series [ 5 , 6 , 9 , 10 , 11 , 15 , 29 , 30 ] included copy number variations (CNVs) data. The most frequent alterations are presented in Table S1 , which includes the specific results of all the studies.…”

“…TP53 was the most frequently mutated gene in the 13 series that sequenced it, and it was found altered in all histological subtypes [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 29 , 31 ]. The frequency of mutations ranged from 26% to 70%, (median 58.7%).…”

“…PIK3CA was the second gene with the highest mutation frequency. This gene was sequenced in 13 of the 14 series reviewed [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 29 , 31 ], and the frequency of mutations ranged from 12% to 48%, (median 32.8%). Nineteen different mutations were observed in the 224 cases of the 8 series in which the mutations were detailed [ 5 , 7 , 8 , 10 , 11 , 12 , 13 , 15 ], being 17 of the mutations missense substitutions and only 2 frameshift mutations.…”

Author Reply to: “A case of HRAS Q61‐mutated metaplastic breast carcinoma associated with squamous metaplasia: Which came first, metaplasia or neoplasia?”

“…4 However, HRAS mutations are not exclusive of adenomyoepitheliomas and have been reported in other breast tumors, including MBCs without a contiguous adenomyoepithelioma. 5 Krings et al 6 reported a HRAS mutation in a paired analysis of MBC and its associated ductal carcinoma in situ (DCIS). Therefore, the detection of HRAS mutations has no diagnostic implications in the absence of a morphological context.…”