Clinicopathologic and Whole Exome Sequencing Analyzes of High-Grade Serous Carcinoma-Like Carcinoma of the Breast Reveal Unique Genetic Profile and Poor Clinical Outcome.

Abstract

We identified 9 cases of primary high-grade serous-like carcinoma (HG-SL-Ca) of the breast that displayed the morphology of high-grade serous carcinoma of Müllerian origin. These cases could represent a new entity of breast carcinoma. This study included 9 cases of HG-SL-Ca of the breast. Extensive clinicopathologic features and outcome data were available and evaluated in 8 cases. We, for the first time, performed whole exome sequencing (WES) on 6 of these cases to identify pathogenic germline and somatic genetic mutations and conducted gene pathway enrichment analyses. Six cases were triple negative; 2 were HER2 positive, and 1 was ER+/PR+/HER2-. Eight of the 9 cases had high nuclear grade and the other 1 had intermediate nuclear grade. Six patients received chemotherapy; the patient with ER+/PR+/HER2-cancer received hormonal therapy only, and 1 patient with dementia did not receive any systemic therapy. Follow-up data showed 2 patients had distant metastasis and 1 had chest wall recurrence. Two patients died of disease, including 1 patient receiving palliative care and 1 with lung and pleural metastasis. Most of the cases were positive for GATA3 immunohistochemistry (IHC) staining and all were negative for PAX8. All except for 1 case (focally positive) were negative for WT1 nuclear stain. Aberrant p53 IHC staining patterns were observed in 6 cases. WES analyses showed 26 genes with pathogenic germline mutations and 28 genes with pathogenic somatic mutations in these cases that were in the ACR GENIE mutated gene list. Pathway analyses showed that these genes with pathogenic germline or somatic mutations were enriched in the PI3K-AKT-mTOR pathway, WNT pathways, and death receptor pathway. TP53 was recurrently mutated, containing somatic variants in 4 cases, and all these 4 cases had aberrant p53 IHC staining patterns. We, for the first time, performed WES analyses on HG-SL-Ca of the breast. The majority of HG-SL-Ca were triple negative or HER2 positive with high nuclear grade. Patients with HG-SL-Ca of the breast had a poor prognosis. Our pathway analyses showed that genes containing pathogenic germline or somatic mutations were enriched in the PI3K-AKT-mTOR pathway, WNT pathways, and death receptor pathway, which could provide potential targeted treatment options. TP53 was recurrently mutated in 4 cases and all these 4 cases had aberrant p53 IHC staining patterns.