Mutation and immune profiling of metaplastic breast cancer: Correlation with survival

Abstract

The goal of this study is to characterize the genomic and immune profiles of metaplastic breast cancer (MpBC) and identify the association with survival through an analysis of archived tumor tissue. A next-generation sequencing-based mutational assay (Onco-48) was performed for 21 MpBC patients. Clinicopathologic characteristics were captured, including relapse free survival (RFS) and overall survival (OS). Immunohistochemistry (IHC) for CD3, CD4, CD8, and programmed death-ligand 1 (PD-L1) was also performed. Recurrence free survival (RFS) at 5 years was 57% (95% CI 0.34–0.75) and overall survival (OS) at 5 years was 66% (95% CI 0.41–0.82). The most commonly altered genes were TP53 (68.4%, 13/19), PIK3CA (42.1%, 8/19), and PTEN (15.8%, 3/19. For patients with PIK3CA mutations, RFS and OS were significantly worse than for those without (HR 5.6, 95% CI 1.33–23.1 and HR 8.0, 95% CI 1.53–41.7, respectively). Cox regression estimated that PD-L1 expression was associated with worse RFS and OS (HR 1.08, 95% CI 1.01–1.16 and HR 1.05, 95% CI 1.00–1.11, respectively, for an absolute increase in PD-L1 expression of 1%). In conclusion, PIK3CA mutation and PD-L1 expression confer poor prognosis in this cohort of patients with MpBC.

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

“…Recent studies have identified mutations in the TP53, PI3K MAPK, RB1, and Wnt pathways as the most frequent somatic mutations in MBCs. [2][3][4][5][6][7][8][9][10][11] Our data confirm that spindle cell MBC shares similar molecular features with other morphologic subtypes of MBCs. 6,[9][10][11]23 PIK3CA mutations are particularly relevant because the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) classified them as strong predictors of response to PIK3CA inhibitors (level IA) (see Supplemental Table 2 in the online version).…”

“…[2][3][4][5][6][7][8][9][10][11] Our data confirm that spindle cell MBC shares similar molecular features with other morphologic subtypes of MBCs. 6,[9][10][11]23 PIK3CA mutations are particularly relevant because the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) classified them as strong predictors of response to PIK3CA inhibitors (level IA) (see Supplemental Table 2 in the online version). 24,25 Furthermore, the United States Food and Drug Administration (FDA) recently approved the PIK3CA inhibitor b Both cases were further tested by immunohistochemistry (CD117 and panTRK antibodies) and were negative.…”

“…1 Somatic mutations in TP53, PI3K MAPK, RB1, and Wnt pathways genes have been frequently described in MBCs. [2][3][4][5][6][7][8][9][10][11] MBCs are basallike and claudin-low breast cancers with a triple-negative phenotype: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu)-negative. 7,9,[12][13][14] With rare exceptions (low-grade adenosquamous and fibromatosislike metaplastic variants), MBCs are associated with a high recurrence/metastasis risk, chemotherapy resistance, and poor outcome.…”

“…7,9,[12][13][14] With rare exceptions (low-grade adenosquamous and fibromatosislike metaplastic variants), MBCs are associated with a high recurrence/metastasis risk, chemotherapy resistance, and poor outcome. 15 Mutational diversity is reflected in the morphologic heterogeneity of MBCs; PIK3CA mutations were detected in all morphologic variants of MBCs, excluding the chondroid variant, 5,6,11 whereas TERT mutations were more prevalent in spindle cell and squamous variants. 5 Microarray expression-based studies also revealed differences between the morphologic subtypes of MBC in regards to epithelial-mesenchymal transition (EMT)-related genes such as CDH1 and EPCAM.…”

“…7 Programmed death-ligand 1 (PD-L1) expression in cancer and/or immune cells, as a predictor of response to immune checkpoint inhibitors, has also been described in a subset of MBCs. 3,9,11,16,17 Pure spindle cell variants of MBC constitute < 10% of all MBCs; the spindle cell pattern is usually seen within a mixed MBC that constitutes w70% of all MBC morphologies. In the present study, we explored a cohort of pure (> 90% of invasive tumor) spindle cell MBC for the biomarkers of response to immunooncology (I-O) and targeted therapies.…”