Intratumor heterogeneity defines treatment‐resistant HER2+ breast tumors

Abstract

Targeted therapy for patients with HER2‐positive (HER2+) breast cancer has improved overall survival, but many patients still suffer relapse and death from the disease. Intratumor heterogeneity of both estrogen receptor (ER) and HER2 expression has been proposed to play a key role in treatment failure, but little work has been done to comprehensively study this heterogeneity at the single‐cell level. In this study, we explored the clinical impact of intratumor heterogeneity of ER protein expression, HER2 protein expression, and HER2 gene copy number alterations. Using combined immunofluorescence and in situ hybridization on tissue sections followed by a validated computational approach, we analyzed more than 13 000 single tumor cells across 37 HER2+ breast tumors. The samples were taken both before and after neoadjuvant chemotherapy plus HER2‐targeted treatment, enabling us to study tumor evolution as well. We found that intratumor heterogeneity for HER2 copy number varied substantially between patient samples. Highly heterogeneous tumors were associated with significantly shorter disease‐free survival and fewer long‐term survivors. Patients for which HER2 characteristics did not change during treatment had a significantly worse outcome. This work shows the impact of intratumor heterogeneity in molecular diagnostics for treatment selection in HER2+ breast cancer patients and the power of computational scoring methods to evaluate in situ molecular markers in tissue biopsies.

Functional and genomic characterization of three novel cell lines derived from a metastatic gallbladder cancer tumor

“…ERBB2 was particularly highly expressed in PUC-GBC1 and PUC-GBC2, and showed a somewhat lower expression in PUC-GBC3. This is not an unexpected finding considering that intratumor heterogeneity is a common event in cancer, and genetic heterogeneity of HER2 has been reported for other tumors [82][83][84][85][86][87][88]. For instance, focal or patchy positivity of HER2 is a pattern encountered in primary gastric tumors, which is consequence of the intratumor heterogeneity and could explain discordances observed in HER2 status between the primary tumor and metastatic sites [82,85].…”

A spatial cell culture model for predicting chemotherapy dosing strategies

“…During later cycles of chemotherapy in patients, intratumor heterogeneity is common and sensitive and resistant cells often co-exist (25). Hence, we hypothesized that our model system could be used to test the overall tumor response to chemotherapy.…”

Impact of Surgical Margins in Breast Cancer After Preoperative Systemic Chemotherapy on Local Recurrence and Survival

“…Intratumoural heterogeneity causes heterogeneous response to NAC that further leads to unpredictable tumour shrinkage. 11,12 While concentric tumour shrinkage during NAC leads to a solitary residual tumour, other patterns of shrinkage can result in multifocal or patch-like lesions, or CI confidence interval, y years, m months, HR hormone receptor, HER2 human epidermal growth factor receptor 2, RT radiotherapy, ?positive, -negative, nd not done even a residual tumour with satellite lesions. 9 Residual patchy lesions after NAC impede the assessment of the required resection extent.…”