Genomic landscape of small cell carcinoma of the breast contrasted to small cell carcinoma of the lung

Abstract

Small cell carcinoma of the breast is a rare, aggressive form of breast cancer that is associated with extremely poor outcomes [1]. In an effort to identify possible targets for treatment, we utilized comprehensive genomic profiling in small cell carcinoma of the breast. Under an IRB approved protocol, we identified patients with small cell carcinoma of the breast and small cell carcinoma of the lung profiled by Caris Life Sciences between 2007 and 2015. Tumors were assessed with up to 25 immunohistochemical stains, in situ hybridization of cMET, EGFR, HER2, PIK3CA, and TOP2A, and next generation sequencing as well as Sanger sequencing of 47 genes. 19 patients with small cell carcinoma of the breast were identified, median age was 58 years (range 37-79) and 42 % had metastatic disease at presentation; for comparison, 58 patients with small cell carcinoma of the lung were identified (66 [36-86], 65 % metastatic). By immunohistochemistry, 31 % of small cell carcinoma of the breast patients expressed ER, 13 % expressed PR, and 16 % expressed AR; small cell carcinoma of the lung patients expressed ER 0 %, PR 2 %, and AR 6 %. Small cell carcinoma of the breast and small cell carcinoma of the lung patients had similar patterns of other immunohistochemical expression (0 v 0 % PDL1, 50 v 42 % PD1, and 77 v 95 % TOP2A, respectively). All small carcinoma of the breast and small cell carcinoma of the lung patients were negative for HER2 and cMET amplification by in situ hybridization. Next generation sequencing revealed TP53 mutations in 75 % of patients both with small cell carcinoma of the breast and small cell carcinoma of the lung and PIK3CA mutations in 33 % of small cell carcinoma of the breast patients but no small cell carcinoma of the lung patients (Fisher's exact test p = 0.005, OR 0.02 [0.00-0.52]). No other mutations were found in small cell carcinoma of the breast patients and no other mutation occurred in over 10 % of small cell carcinoma of the lung patients except RB1 in 19 % (p = 0.31). Small cell carcinoma of the breast is an aggressive tumor with few therapeutic options. Molecular profiling suggests many similarities between small cell carcinoma of the breast and small cell carcinoma of the lung with the exception an increased incidence of PIK3CA mutations in small cell carcinoma of the breast, which may have therapeutic implications.

Mechanism of immune evasion in breast cancer

“…It has frequently been found to be upregulated in various types of BCs, including inflammatory BCs, small-cell carcinomas of the breast, and basal tumors 37–39. Many researchers claim PD-L1 is overexpressed in TNBC,40–42 and that it is related to tumor grade,43 the local cytotoxic immune response, and prognosis 38,44.…”

Potential Novel Therapy Targets in Neuroendocrine Carcinomas of the Breast

“…1 Breast NECs are typically positive for estrogen (ER) and progesterone (PR) receptors and negative for ERBB2 (human epidermal growth factor receptor 2 [Her-2]/neu). [2][3][4] Despite its luminal (A or B) phenotype, 4,5 most studies have reported an aggressive clinical course and poor outcome for patients with NEC. 2,4,6,7 The mutational profile and molecular characteristics of breast NEC have been the focus of several recent studies.…”

“…2,4,6,7 The mutational profile and molecular characteristics of breast NEC have been the focus of several recent studies. 3,4,8,9 In contrast to gastroenterohepatic NECs, 10 these studies revealed inconsistent mutational profiles of NEC with limited targetable options (eg, PIK3CA mutations in 7%-33% of the cases). The role of programmed death-ligand 1 (PD-L1) as a predictor of the response to immune checkpoint inhibitors was explored in 2 studies involving only 6 cases of NEC.…”

“…The role of programmed death-ligand 1 (PD-L1) as a predictor of the response to immune checkpoint inhibitors was explored in 2 studies involving only 6 cases of NEC. 3,11 No systematic attempt to analyze breast NECs for biomarkers of therapy used in NECs of other…”

The Role of Immune Escape and Immune Cell Infiltration in Breast Cancer

“…PD-L1 could directly synergize with FOXP3+ regulatory T cells [62], but could also be affected by ubiquitination and N-glycosylation [63]. In different BC subtypes, heterogeneous expression of PD-1/PD-L1 was shown [64][65][66]. In particular in TNBC, PD-L1 was found to be overexpressed [67,68], which is related to tumor grade [69,70], local cytotoxic immune response, and prognosis [71].…”