Invasive Breast Cancer with HER2 ≥4.0 and <6.0: Risk Classification and Molecular Typing by a 21-Gene Expression Assay and MammaPrint Plus BluePrint Testing

Abstract

Purpose

To investigate the HER2 status and clinicopathological features in invasive breast cancer with HER2 ≥4.0 and <6.0, which has always been controversial.

Methods

Forty breast cancer cases with HER2 ≥4.0 and <6.0 by fluorescence in situ hybridization (FISH) were collected and classified into two groups based on the HRE2/CEP17 ratio (Group A: ≥2.0, n=22; Group B: <2.0, n=18). Clinicopathological characteristics, HER2 status, risk classification, and molecular typing were further analyzed and compared by 21-Gene expression assay and MammaPrint plus BluePrint test.

Results

The majority of cases in both groups were invasive carcinoma (NOS), with histological grade II, HR+, Ki-67 ≥20%, HER2 2+, and a high risk of recurrence, although younger patients and lymph node metastases were more common in Group A. Surprisingly, all HR+ breast cancers in both groups were classified as luminal-type, HR− cases were all basal-type or unknown, and the index of HER2 in all cases was <0.000 using the BluePrint test, which indicated that HER2 status should be negative. Furthermore, the level of HER2 mRNA expression in all cases of both groups was <10.7, which was defined as HER2 negative by the 21-Gene expression assay. In addition, 10 patients of Group A received anti-HER2 neoadjuvant therapy; only one patient with HR- achieved Grade 5 based on the Miller-Payne system, whereas none of the patients achieved pathological complete response (pCR) based on the Residual Cancer Burden system.

Conclusion

Group A breast cancer, which has always been unquestionably diagnosed as HER2 amplification, was more likely to be HER2 negative and derived less benefit from anti-HER2 neoadjuvant chemotherapy. Group A breast cancer should be distinguished from classical HER2-positive breast cancers when assessing HER2 FISH, and a larger cohort of Group A patients should be included in further studies.

Graphical Abstract

Keywords:

• breast cancer
• HER2
• FISH
• 21-gene expression assay
• MammaPrint plus BluePrint

Data Sharing Statement

The dataset used and analyzed during the current study is available from the corresponding author upon reasonable request.

Acknowledgments

This research was funded by the Science and Technology Commission of Shanghai Municipality (No.19441904900), Shanghai Science and Technology Development Fund (19MC1911000), Shanghai Municipal Key Clinical Specialty (shslczdzk01301), Innovation Program of Shanghai Science and Technology Committee (20Z11900300), and Innovation Group Project of Shanghai Municipal Health Commission Grant (2019CXJQ03).

Disclosure

The authors declare no conflicts of interest in this work.