Molecular and Clinical Portrait of HER2-low Invasive Lobular Carcinomas

Lounes Djerroudi; Ahmad El Sabeh-Ayoun; Camille Benoist; Gaelle Pierron; Julien Masliah-Planchon; Laetitia Fuhrmann; Yann Kieffer; Matthieu Carton; Toulsie Ramtohul; Celine Callens; Victor Renault; François-Clément Bidard; Fatima Mechta-Grigoriou; Anne Vincent-Salomon

doi:10.1016/j.modpat.2024.100463

Molecular and Clinical Portrait of HER2-low Invasive Lobular Carcinomas

Mod Pathol. 2024 Feb 28;37(5):100463. doi: 10.1016/j.modpat.2024.100463. Online ahead of print.

Authors

Affiliations

¹ Institut Curie, PSL University, Department of Diagnostic and Theranostic Medicine, Paris, France; Institut Curie, Stress and Cancer laboratory, Inserm U830, PSL University, Paris, France. Electronic address: lounes.djerroudi@curie.fr.
² Institut Curie, PSL University, Department of Diagnostic and Theranostic Medicine, Paris, France.
³ Institut Curie, PSL University, Clinical Bioinformatics, Paris, France.
⁴ Institut Curie, Stress and Cancer laboratory, Inserm U830, PSL University, Paris, France.
⁵ Department of Statistics, Institut Curie, PSL University, Paris, France.
⁶ Department of Radiology, Institut Curie, PSL University, Paris, France.
⁷ Department of Medical Oncology, Institut Curie, Université Versailles Saint Quentin, Saint Cloud, France.

PMID: 38428737
DOI: 10.1016/j.modpat.2024.100463

Abstract

Invasive lobular carcinomas (ILCs) have a low frequency of ERBB2 amplification, therefore restricting the use of conventional anti-HER2 therapies for this histologic special type. Conversely, ILCs with low HER2 overexpression may represent a broader target for the use of emerging antibody 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 histomolecular specificities compared with invasive breast carcinoma of no special type (IBC-NST). Our aims in that context were to decipher the clinicopathological 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 7970 patients from Institut Curie, with either primary invasive lobular (N = 1103) or no special type (N = 6867) invasive carcinoma. Clinicopathological 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 a lower frequency of HER2-low (40.6% vs 46.3%) (P < .001). Clinicopathological features associated with HER2-low status (vs HER2-zero) in ILC were older age, postmenopausal status, nonclassic ILC histological types, higher grade, proliferation, and estrogen receptor 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%) (false discovery rate < 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.

Keywords: ERBB3 mutation; HER2-low; breast cancer; human epidermal growth factor receptor 2 (HER2) status; invasive lobular carcinoma.