Impact of HER2 copy number in IHC2+/FISH-amplified breast cancer on outcome of adjuvant trastuzumab treatment in a large UK cancer network

Abstract

Background:Adjuvant trastuzumab with chemotherapy is standard treatment for HER2-positive breast cancer, defined as either HER2 IHC3+ or IHC2+ and FISH amplified. The aim of this study was to investigate the degree to which HER2 amplification in terms of HER2 gene copy numbers in HER2+IHC2+ cancers affected the outcome in a community setting.Methods:Case records of 311 consecutive patients with early breast cancer presenting between 1st January 2005 and 31st December 2008 were reviewed. Progression-free survival and overall survival were calculated with the Kaplan–Meier method using STATA 13.Results:Among 3+ cases (n=230) 163 received T vs 67 no-T. Among 2+ cases (n=81) 59 received T vs 22 no-T. Among 59 IHC2+-treated cases n=28 had an average of >12, n=13 had >6 to <12, and n=18 had >2 to <6 HER2 gene copies, respectively. The time of progression and overall survival of high and low copy number patients was similar and better than the intermediate copy number and the untreated cohorts.Conclusions:High HER2 copy number (>12) appears to be associated with consistently better response compared with patients with intermediate HER2 copy numbers (6–12). In light of emerging data of patients showing insensivity to trastuzumab therapy, we propose that the HER2 gene copy number value should be included as an additional indicator for stratifying both the management and the follow-up of breast cancer patients.

HER2 immunohistochemical scores provide prognostic information for patients with HER2‐type invasive breast cancer

“…Compared with the present study including 886 cases, one smaller-scale study conducted in patients presenting between 2005 and 2008 did not reveal a significant survival difference between 163 HER2 IHC 3+ patients and 59 IHC 2+/ISH+ patients receiving adjuvant trastuzumab therapy. 8 However, similar to our results, IHC 2+/ISH+ patients with high HER2 copy numbers (>12) had better survival rates than did those with intermediate HER2 copy numbers (6-12) (it was not possible to analyse P-values). 8 As the study cohorts were different, the cut-off value of HER2 signals to define a high HER2 copy number for the other study was different from that used in our study (≥8).…”

“…8 However, similar to our results, IHC 2+/ISH+ patients with high HER2 copy numbers (>12) had better survival rates than did those with intermediate HER2 copy numbers (6-12) (it was not possible to analyse P-values). 8 As the study cohorts were different, the cut-off value of HER2 signals to define a high HER2 copy number for the other study was different from that used in our study (≥8). In a study of metastatic breast cancer, high HER2 copy numbers (>13) were associated with a short time-to-metastasis; however, patients responded well to trastuzumab-based therapy.…”

“…As the protein expression of HER2 IHC 3+ is higher than that of HER2 IHC 2+, we predicted that patients with HER2 IHC 3+ tumours would have a better response to anti‐HER2 therapy, and their prognosis would be better than those with HER2 IHC 2+ tumours. Other prognostic factors that may have impacts on the survival of breast cancer patients, such as age, cancer stage, hormone receptor status, intermediate HER2 copy number (6–12), HER2 low ISH ratio (≥2 to <5) and dual blockade of anti‐HER2 therapy, are all included in the analysis.…”

Clinical Overestimation of HER2 Positivity in Early Estrogen and Progesterone Receptor–Positive Breast Cancer and the Value of Molecular Subtyping Using BluePrint

“…From our data analysis, it was clear that the current ASCO guidelines for HER2/CEP17 ratio and copy number has a poor PPV. It is possible that using higher cut-off values might reduce the number of luminal tumors selected; some authors have reported a better response to trastuzumab with copy number > 12 28 and higher HER2/CEP17 ratio, 29 although the HER2E tumors in this series have copy numbers ranging from 6.55 to 19.05 and HER2/CEP17 ratios from 3.17 to 6.68.…”

Reclassification of early stage breast cancer into treatment groups by combining the use of immunohistochemistry and microarray analysis

“…Some tumours reported as HER2 positive are subtyped as Luminal B and retain some responsiveness to endocrine treatment in addition to chemotherapy and HER2 targeted treatments. 4 Borley et al 5 demonstrated that the HER2 gene copy number provides additional information for stratifying breast cancer patients into different treatment groups, because HER2-positive patients with a low degree of HER amplification were shown to derive less benefit from trastuzumab (the chemotherapy agent more commonly known as Herceptin ® ).…”