Molecular and clinical portrait of HER2-low invasive lobular carcinomas.

Invasive lobular carcinomas (ILCs) have a low frequency of ERBB2 amplification, therefore restricting the use of conventional anti-HER2 therapies for this histological special type. Conversely, ILCs with low HER2 overexpression may represent a broader target for the use of emerging anti-body drug conjugate therapies targeting HER2, since these treatments have proven effective in HER2-low breast cancers. Very scarce data about HER2-low ILCs have been so far published, although these tumors could have different prevalence and histo-molecular specificities compared to invasive breast carcinoma of no special type (IBC-NST). Our aims in that context were to decipher the clinico-pathological and molecular features of a large series of HER2-low ILCs. Comparative evaluation of HER2-low prevalence was done based on a retrospective series of 7,970 patients from Institut Curie, with either primary invasive lobular (N=1,103) or no special type (N=6,867) invasive carcinoma. Clinico-pathological and molecular analyses of HER2-zero, HER2-low, and HER2-positive ILCs were performed on a subgroup of 251 patients who underwent surgery for a primary ILC between 2005 and 2008. The mutational profile of these 251 cases was determined from RNAseq data. Compared with HER2-negative IBC-NSTs, the HER2-negative ILCs were found to display a higher frequency of HER2-zero cases (59.4% vs. 53.7%) and lower frequency of HER2-low (40.6% vs. 46.3%) (p <0.001). Clinicopathological features associated with HER2-low status (vs. HER2-zero) in ILC were older age, post-menopausal status, non-classic ILC histological types, higher grade, proliferation and ER expression levels. Survival curve analysis showed a significantly lower risk of local recurrence for HER2-low (vs HER2-zero) ILCs, but no association was found between HER2 status and either breast cancer-specific survival or distant metastasis-free interval. ERBB3 was the unique mutated gene exclusively associated with HER2-low ILCs yet being mutated at a low frequency (7.1%) (FDR <0.05). In conclusion, HER2-low ILCs exhibit their own particularities, both on clinical-pathological and molecular levels. Our findings call for larger multicenter validation studies.