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.
Keywords: breast cancer, HER2, FISH, 21-gene expression assay, MammaPrint plus BluePrint