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- Title
HER2-Low Luminal Breast Carcinoma Is Not a Homogenous Clinicopathological and Molecular Entity.
- Authors
André, Céline; Bertaut, Aurélie; Ladoire, Sylvain; Desmoulins, Isabelle; Jankowski, Clémentine; Beltjens, Françoise; Charon-Barra, Céline; Bergeron, Anthony; Richard, Corentin; Boidot, Romain; Arnould, Laurent
- Abstract
Simple Summary: The new HER2-low category, comprising HER2 IHC 1+ and 2+ carcinomas, expressing predominantly hormone receptors, has been added to the HER2 classification of breast carcinoma. With the advent of antibody–drug conjugates, these carcinomas need to be better characterized at the clinicopathological, molecular, and transcriptomic levels. We analyzed 62 HER2-low luminal carcinomas, comparing them with 43 HER2-positive and 20 HER2-negative carcinomas. The transcriptomic activities of three HER2 effector pathways (PI3K-AKT, MAPK, and JAK-STAT) were investigated using RNA sequencing, and the mutational status of key breast cancer-associated genes was determined using DNA sequencing. The impact of the presence of a PIK3CA mutation appears to be essential in the activation of the PI3K-AKT signaling pathway. PIK3CA mutations could be a lead in variable responses to conventional anti-HER2 therapies. Background: With the development of some new antibody–drug conjugates, the HER2 classification of breast carcinomas now includes the HER2-low (H2L) category: IHC 1+, 2+ non-amplified by ISH, and double-equivocal carcinomas, mostly luminal, expressing hormone receptors (HR+). Methods: We analyzed mutational status and transcriptomic activities of three HER2 effector pathways: PI3K-AKT, MAPK, and JAK-STAT, in association with clinicopathologic features, in 62 H2L carcinomas compared to 43 HER2-positive and 20 HER2-negative carcinomas, all HR+. Results: H2L carcinomas had significantly lower histoprognostic grades and mitotic and Ki67 proliferation indexes than HER2-positive carcinomas. Their PIK3CA mutation rates were close to those of HER2-negative and significantly higher than in HER2-positive carcinomas, contrary to TP53 mutations. At the transcriptomic level, we identified three distinct groups which did not reflect the new HER2 classification. H2L and HER2-negative carcinomas shared most of clinicopathological and molecular characteristics, except HER2 membrane expression (mRNA levels). The presence of a mutation in a signaling pathway had a strong pathway activation effect. PIK3CA mutations were more prevalent in H2L carcinomas, leading to a strong activation of the PI3K-AKT signaling pathway even in the absence of HER2 overexpression/amplification. Conclusion: PIK3CA mutations may explain the failure of conventional anti-HER2 treatments, suggesting that new antibody–drug conjugates may be more effective.
- Subjects
HORMONE receptor positive breast cancer; IMMUNOGLOBULINS; SYMPTOMS; RETROSPECTIVE studies; DESCRIPTIVE statistics; TUMOR markers; GENE expression; MESSENGER RNA; GENE expression profiling; MEDICAL records; ACQUISITION of data; GENETIC mutation; COMPARATIVE studies; MOLECULAR pathology
- Publication
Cancers, 2024, Vol 16, Issue 11, p2009
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers16112009