Related Experiment Video
Updated: Jul 1, 2025
Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers
Published on: December 5, 2017
Molecular and Clinical Portrait of HER2-low Invasive Lobular Carcinomas
Lounes Djerroudi1, Ahmad El Sabeh-Ayoun2, Camille Benoist3
1Institut Curie, PSL University, Department of Diagnostic and Theranostic Medicine, Paris, France; Institut Curie, Stress and Cancer laboratory, Inserm U830, PSL University, Paris, France.
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.
Insights
HER2-low invasive lobular carcinomas (ILCs) have distinct clinical and molecular features compared to HER2-negative invasive breast carcinoma of no special type. Understanding these HER2-low ILC characteristics is crucial for developing targeted therapies.
Area of Science:
- Oncology
- Breast Cancer Research
- Molecular Pathology
Background:
- Invasive lobular carcinomas (ILCs) rarely amplify ERBB2, limiting conventional anti-HER2 therapies.
- Emerging antibody drug conjugates targeting HER2 show promise for HER2-low breast cancers, including ILCs.
- Limited data exists on HER2-low ILCs, necessitating research into their unique characteristics.
Purpose of the Study:
- To investigate the clinicopathological and molecular features of HER2-low ILCs.
- To compare HER2-low prevalence in ILCs versus invasive breast carcinoma of no special type (IBC-NST).
- To identify potential therapeutic targets within HER2-low ILCs.
Main Methods:
- Retrospective analysis of 7970 patients (1103 ILC, 6867 IBC-NST) for HER2-low prevalence.
- Clinicopathological and molecular analysis of 251 ILC patients (HER2-zero, HER2-low, HER2-positive).
- RNA sequencing for mutational profiling of ILC subgroups.
Main Results:
- HER2-negative ILCs showed higher HER2-zero (59.4%) and lower HER2-low (40.6%) rates than HER2-negative IBC-NSTs.
- HER2-low ILCs associated with older age, postmenopausal status, nonclassic histology, higher grade, proliferation, and ER expression.
- ERBB3 mutations were exclusively found in HER2-low ILCs (7.1%), with no significant impact on survival outcomes.
Conclusions:
- HER2-low ILCs possess distinct clinical-pathological and molecular profiles.
- These findings suggest HER2-low ILCs may benefit from specific therapeutic strategies.
- Further multicenter validation studies are warranted to confirm these observations.
