Resistance to HER2 targeted therapy in early breast cancer (EBC): The clinical management of intratumoral heterogeneity (ITH) in HER2 overexpressing EBC

Introduction A case report presenting the diagnostic and therapeutic challenges of ITH in EBC, highlighting the need for multilayer testing to allow appropriate treatment.

Methodology A 49-year-old female presented with cT₂N₀ EBC confined to the left breast. The core needle biopsy (CNB) revealed an invasive HER2 enriched carcinoma (clone #1: ER 0/12, PR 0/12, HER2 Score 3+, Ki67 50%) and she was assigned to NACT with dual HER2 blockade, resulting in a non-pathologic complete response (non-pCR). The excisional biopsy (EB) revealed an ypT₂N₀ luminal B HER2 negative residual tumor (clone #2: ER 12/12, PR 2/12, HER2 Score 0, Ki67 25%). Fluorescent in-situ hybridization (FISH) and immunohistochemical staining was repeated in full depth of the CNB and EB. The analysis revealed a solitary, hormone receptor positive subclone in the deep sections of the CNB, confirming the clone #2.

Results Repeated testing identified a sensitive HER2 enriched clone #1 in pathologic complete response (pCR) and a resistant luminal B clone #2 in non-pCR after NACT. Interestingly comparing CNB and EB in clone #2 we observed a downregulation of the progesterone receptor level.

Conclusion The ITH in EBC introduces significant challenges in designing effective treatment strategies. Repeated testing and evaluation of the molecular mechanisms might offer a better understanding of clonal resistance and heterogeneity providing a clinical benefit, tailored to the patients needs. It would be interesting for future studies to identify biomarkers, which characterize the tumor’s evolutionary path, detect clonal shifts across treatment and establish new strategies to approach heterogenous tumors.

Publikationsverlauf

Artikel online veröffentlicht:
11. Oktober 2022