Biological and clinical features of early triple-negative invasive lobular carcinomas of the breast.

Abstract

e12570 Background: Hormone receptors and HER2 negative (triple negative, TN) invasive lobular carcinomas (ILCs) are very rare, accounting for 1-2% of all TN breast cancers (BCs). Methods: We extracted data from our prospectively collected institutional database on all consecutive patients (pts) with early stage TN ILC operated at the European Institute of Oncology (IEO) between June 1994 and December 2012. Invasive disease-free survival (iDFS) and cumulative incidence of distant metastases (CI-DM) were calculated. Biological features of these tumors, including molecular intrinsic subtypes based on PAM50 assay, expression of androgen receptor (AR) and mutational status of c-erbB2 gene were also evaluated. Additionally, NGS data of 45 TN ILCs were obtained from 3 large public databases, to confirm mutations in c-erbB2 gene and to identify other recurrently mutated genes. Results: Among 2952 ILCs treated at IEO, 44 (1.5%) were TN and were included in the analysis. All pts received adjuvant chemotherapy. The iDFS rates at 5 and 10 years of follow-up were 47.4% (95% CI, 31.1-62.0) and 29.5% (95% CI, 14.8-45.8), respectively. The corresponding CI-DM percentages were 17.6% (95% CI, 7.6-31.2) and 20.8% (95% CI, 9.5-35.1). The molecular intrinsic subtype was defined through PAM50 for 31 out of 44 TN ILCs: 48% were classified as luminal A, 3% luminal B, 32% HER2-enriched, and only 16% basal-like. The group of pts with luminal A or B tumors had a significantly better CI-DM as compared with pts with non-luminal tumors (i.e. HER2-enriched and basal-like; p=0.003). Luminal tumors expressed AR more frequently than non-luminal tumors (AR≥1% in 96% of luminal tumors versus 53% in non-luminal tumors; p=0.001), and at significantly higher levels (median percentage of AR-positive cells was 80% in luminal tumors versus 15% in non-luminal tumors; p=0.01). Higher AR expression was associated with significantly better iDFS in the whole cohort of TN ILCs (p=0.01), as well as in the group of luminal tumors (p=0.05). 27 TN ILCs of the IEO cohort were analyzed for mutations in c-erbB2 gene, and 9 (33%) harbored mutations. Analysis of the 3 public databases, confirmed c-erbB2 mutations in 9 out of 45 (20%) TN ILCs. All the c-erbB2 mutations found were previously reported to be pathogenetic in BCs and to predict response to neratinib. ErbB signaling and DNA damage response were among the top 10 pathways significantly enriched for mutated genes in TN ILCs. Conclusions: TN ILCs are rare tumors with dire prognosis. Their specific biological features require newly defined targeted therapeutic strategies.