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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.

SUBMITTER: Rye IH

PROVIDER: S-EPMC6210052 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Intratumor heterogeneity defines treatment-resistant HER2+ breast tumors.

Rye Inga H IH Trinh Anne A Saetersdal Anna B AB Nebdal Daniel D Lingjaerde Ole Christian OC Almendro Vanessa V Polyak Kornelia K Børresen-Dale Anne-Lise AL Helland Åslaug Å Markowetz Florian F Russnes Hege G HG

Molecular oncology 20180921 11

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 express ...[more]

PMID: 30133130

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Project description:ObjectiveHER2 status in breast cancer is an essential parameter in individual therapeutic decision-making and is routinely assessed in primary tumors in accordance with international recommendations. Reports of HER2 heterogeneity raise the question of basing treatment decisions on HER2 status in metastases, if present. We investigated the degree and clinical implications of HER2 heterogeneity in lymph node-positive breast cancer. Because of recent recognition of therapeutic opportunities in this group of tumors, we especially focused on cases involving low-level HER2 expression.MethodsThe HER2 status of primary tumors and of corresponding lymph node metastases was determined in archived material at the protein and gene levels using the gene- protein assay and interpreted in accordance with 2018 ASCO/CAP criteria. HER2-low status was defined as protein expression levels 1+ or 2+ with negative amplification status.ResultsWe analyzed a series of 43 cases of primary infiltrating breast cancer, each with at least two axillary nodes harboring macrometastases (>2 mm), in total 206 such nodes. In 7% of cases, we detected intertumoral HER2 heterogeneity. Three of nine HER2-positive primary tumors were associated with HER2-negative metastases. No cases with HER2-negative primary tumors had HER2-positive metastases, but 55% (6/11) of HER2 0 primary tumors had HER2 1+ and/or 2+ metastases, and 19% (3/16) HER2 1+ cases had exclusively HER2 0 metastases. All metastases in HER2 2+ cases showed HER2-low protein expression levels. Internodal HER2 heterogeneity at low protein expression levels (presence of HER2 0, HER2 1+, and/or HER2 2+ metastatic deposits within the same axilla) was seen in 40% (17/43) of cases. We found no statistically significant association between HER2 heterogeneity and other tumor-related parameters. Survival data indicated worse outcomes in the HER2-low group compared with the rest of the cohort.ConclusionOur results indicate a substantial instability of HER2 protein expression, leading to considerable intertumoral and internodal HER2 heterogeneity in lymph node-positive breast carcinomas. This heterogeneity is particularly relevant in HER2-low tumors in which the corrective effects of HER2 gene copy number analysis definitionally is absent. Our findings suggest that determining HER2 status in metastatic lymph nodes may generate relevant information for therapeutic decision-making.

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Intratumor heterogeneity defines treatment-resistant HER2+ breast tumors.

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Intratumor heterogeneity defines treatment-resistant HER2+ breast tumors.

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