Comprehensive clinical and molecular analyses of neuroendocrine carcinomas of the breast

Abstract

Neuroendocrine breast carcinomas represent a rare subtype of breast cancer. Their definition, prevalence, and prognosis remain controversial in the literature. The 2012 WHO classification of breast cancer categorizes neuroendocrine carcinomas into three morphologically distinct subtypes: well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinomas, and invasive breast carcinomas with neuroendocrine differentiation. We aimed to gain insight into the clinical, morphologic, phenotypic, and molecular features of 47 neuroendocrine breast carcinomas. Targeted next-generation sequencing by an AmpliSeq 22 cancer gene hotspot panel and the Prosigna assay were performed on 42/47 and 35/47 cases, respectively. Average age at diagnosis was 69 years. All tumors were estrogen receptor-positive and the large majority expressed progesterone receptor (89%), GATA3 (98%), FOXA1 (96%), and CK8/18 (98%). There was an almost equal distribution of luminal A (52%) and B (48%) carcinomas. Almost half of the cohort (49%) displayed a high risk of recurrence score with the Prosigna test. Patients with a neuroendocrine carcinoma had a shorter disease-free survival compared with those affected by carcinomas of no special type matched for age, size, grade, and estrogen receptor status. No significant differences were observed in terms of overall survival. Stratification of neuroendocrine carcinomas using the 2012 WHO criteria did not reveal statistically significant differences among the distinct categories (well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinomas, and invasive breast carcinomas with neuroendocrine differentiation), in terms of either progression-free or overall survival. Our targeted sequencing analysis found three cases (7%) harboring a PIK3CA mutation, and in three other cases (7%) TP53 mutations were detected. This study showed that neuroendocrine breast carcinoma is a distinct subtype of luminal carcinoma with a low rate of PIK3CA mutations and with an aggressive clinical behavior. An accurate identification of neuroendocrine differentiation may be useful to better tailor patient adjuvant therapy within luminal carcinomas.

Potential Novel Therapy Targets in Neuroendocrine Carcinomas of the Breast

“…Observed genomic alterations of NECs in our series are comparable with the data from previous studies on NEC. 4,8,9,46,47 The molecular alterations (PIK3CA, TP53, RB1, CCND1) in breast NEC are common in invasive ER þ (luminal) ductal carcinomas of no-special-type suggesting potential relevance of cell cycle (CDK4/6 inhibitors) in isolated cases of this rare cancer. 48,49 There are also ongoing clinical trials with cell cycle inhibitors aimed to treat patients with lung and head/neck cancers harboring CCND1 amplification (trials: NCT03356223 and NCT02785939).…”

“…These results are in line with previous data that revealed the luminal A/B (ER þ ) phenotype of the vast majority of NECs. 4,9,20 Given the positivity for ER and/or PR, most patients with NEC are eligible for endocrine therapy against ER. AR expression has been extensively studied in breast cancer, as a diagnostic (eg, apocrine breast cancer), 21 prognostic (favorable in ER þ /AR-positive [AR þ ] breast cancers), 22 and predictive biomarker (eg, clinical trials with antiandrogens in patients with advanced/metastatic triple-negative breast cancer).…”

“…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][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. 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).…”

“…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.…”