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Background A meta-analysis of the effects of HER2 status, specifically within the first 2–3 years of adjuvant endocrine therapy, has the potential to inform patient selection for upfront aromatase inhibitor (AI) therapy or switching strategy tamoxifen followed by AI. The pre-existing standardisation of methodology for HER2 (immunohistochemistry/fluorescence in situ hybridization) facilitates analysis of existing data for this key marker. Methods Following a prospectively designed statistical analysis plan, patient data from 3 phase III trials Arimidex, Tamoxifen, Alone or in Combination Trial (ATAC), Breast International Group (BIG) 1-98 and Tamoxifen Exemestane Adjuvant Multicentre Trial (TEAM)] comparing an AI to tamoxifen during the first 2–3 years of adjuvant endocrine treatment were collected and a treatment-by-marker analysis of distant recurrence-free interval-censored at 2–3 years treatment – for HER2 status × AI versus tamoxifen treatment was performed to address the clinical question relating to efficacy of ‘upfront’ versus ‘switch’ strategies for AIs. Results A prospectively planned, patient-level data meta-analysis across 3 trials demonstrated a significant treatment (AI versus tamoxifen) by marker (HER2) interaction in a multivariate analysis; (interaction hazard ratio [HR] = 1.61, 95% CI 1.01–2.57; p < 0.05). Heterogeneity between trials did not reach statistical significance. The HER2 negative (HER2−ve) group gained greater benefit from AI versus tamoxifen (HR = 0.70, 95% CI 0.56–0.87) than the HER2-positive (HER2+ve) group (HR = 1.13, 95% CI 0.75–1.71). However, the small number of HER2+ve cases (n = 1092 across the 3 trials) and distant recurrences (n = 111) may explain heterogeneity between trials. Conclusions A patient-level data meta-analysis demonstrated a significant interaction between HER2 status and treatment with AI versus tamoxifen in the first 2–3 years of adjuvant endocrine therapy. Patients with HER2−ve cancers experienced improved outcomes (distant relapse) when treated with upfront AI rather than tamoxifen, whilst patients with HER2+ve cancers fared no better or slightly worse in the first 2–3 years. However, the small number of HER2+ve cancers/events may explain a large degree of heterogeneity in the HER2+ve groups across all 3 trials. Other causes, perhaps related to subtle differences between AIs, cannot be excluded and warrant further exploration. [ABSTRACT FROM AUTHOR]

In breast cancer the human epidermal growth factor receptor 2 (HER2) is an important target for a number of different HER2 inhibitors. Different slide-based assays are available for assessment of treatment eligibility, which include fluorescence in situ hybridization (FISH) or other in situ hybridization (ISH) methods for assessment of the HER2 gene status. Here we report a summary of the validation data on HER2 IQFISH pharmDx™ (Dako Omnis), a newly developed assay for the automated staining platform Dako Omnis. The assay uses a non-toxic buffer that significantly reduces the hybridization time, which results in a total turnaround time of 3½ to 4 h from deparaffinization to counting of the gene and centromere signals. The data reported in the current summary covers method comparison, assessment of staining quality, observer-to-observer reproducibility as well as reproducibility within and between laboratories. Based on data from the different studies it was concluded that HER2 IQFISH pharmDx (Dako Omnis) is a reliable and robust assay with a high precision that is at least comparable to the manual HER2 IQFISH pharmDx™ assay and the PathVysion ® HER-2 DNA Probe Kit. [ABSTRACT FROM AUTHOR]

Summary: Background: The Breast International Group (BIG) 1-98 trial (a randomised double-blind phase III trial) has shown that letrozole significantly improves disease-free survival (DFS) compared with tamoxifen in postmenopausal women with endocrine-responsive early breast cancer. Our aim was to establish whether the benefit of letrozole versus tamoxifen differs according to the ERBB2 status of tumours. Methods: The BIG 1-98 trial consists of four treatment groups that compare 5 years of monotherapy with letrozole or tamoxifen, and sequential administration of one drug for 2 years followed by the other drug for 3 years. Our study includes data from the 4922 patients randomly assigned to the two monotherapy treatment groups (letrozole or tamoxifen for 5 years; 51 months median follow-up [range <1 to 90 months]). A central assessment of oestrogen receptor (ER), progesterone receptor (PgR) and ERBB2 status using paraffin-embedded primary tumour material was possible for 3650 (74%) patients. ER, PgR, and ERBB2 expression were measured by immunohistochemistry (IHC) and ERBB2-positivity was confirmed by fluorescence in-situ hybridisation (FISH). Positive staining in at least 1% of cells was considered to show presence of ER or PgR expression. Tumours were deemed ERBB2-positive if amplified by FISH, or, for the few tumours with unassessable or unavailable FISH results, if they were IHC 3+. Hazard ratios (HR) estimated by Cox modelling were used to compare letrozole with tamoxifen for DFS, which was the primary endpoint, and to assess treatment-by-covariate interactions. The BIG 1-98 trial is registered on the clinical trials site of the US National Cancer Institute website http://www.clinicaltrials.gov/ct/show/NCT00004205. Findings: By central assessment 7% (257 of 3650) of tumours were classified as ERBB2-positive. In 3533 patients with tumours confirmed to express ER, DFS was poorer in patients with ERBB2-positive tumours (n=239) than in those with ERBB2-negative tumours (n=3294; HR 2·09 [95% CI 1·59–2·76]; p<0·0001). There was no statistical evidence of heterogeneity in the treatment effect according to ERBB2 status of the tumour (p=0·60 for interaction), thus, letrozole improves DFS compared with tamoxifen regardless of ERBB2 status. The observed HRs were 0·62 (95% CI 0·37–1·03) for ERBB2-positive tumours and 0·72 (0·59–0·87) for ERBB2-negative tumours. Interpretation: A benefit of letrozole over tamoxifen was noted, irrespective of ERBB2 status of the tumour, and, therefore, ERBB2 status does not seem to be a selection criterion for treatment with letrozole versus tamoxifen in postmenopausal women with endocrine-responsive early breast cancer. [Copyright &y& Elsevier]

Abstract: The prevalence of HER2 amplification according to the percentage of positively stained cells, of polysomy 17 and their correlation with clinical and pathologic characteristics were retrospectively evaluated in a population of 415 breast cancers where fluorescence in situ hybridisation (FISH) was performed to clarify HER2 status previously determined by immunohistochemistry. Forty-two tumours with intense and complete staining in >50% of cells were selected from the same database as internal controls. Among the 415 cases, 233 tumours were IHC 1+, 168 tumours were 2+ and 14 tumours showed an intense and complete immunostaining in ⩽50% of neoplastic cells. HER2 was amplified in 3/14 (21.4%) tumours with ⩽50% and in 36/42 (85.7%) tumours with >50% of intense stained cells, (p <0.001). Polysomy 17 was detected in 77 tumours (16.85%). It was inversely correlated with the percentage of positively stained cells, but not with amplification. Patients with polysomy 17 and no amplification were significantly more likely to have tumours with favourable biological features when compared with patients with HER2 amplification. Our results suggest that FISH testing should be considered for tumours with ⩽50% positive stained cells and that polysomy 17 without amplification is not associated with poor prognostic features. [Copyright &y& Elsevier]