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. 2013 Feb 7;15(1):R11.
doi: 10.1186/bcr3384.

HER2 and ESR1 mRNA expression levels and response to neoadjuvant trastuzumab plus chemotherapy in patients with primary breast cancer

Carsten Denkert, Jens Huober, Sibylle Loibl, Judith Prinzler, Ralf Kronenwett, Silvia Darb-Esfahani, Jan C Brase, Christine Solbach, Keyur Mehta, Peter A Fasching, Bruno V Sinn, Knut Engels, Mattea Reinisch, Martin-Leo Hansmann, Hans Tesch, Gunter von Minckwitz, Michael Untch

HER2 and ESR1 mRNA expression levels and response to neoadjuvant trastuzumab plus chemotherapy in patients with primary breast cancer

Carsten Denkert et al. Breast Cancer Res. .

Abstract

Introduction: Recent data suggest that benefit from trastuzumab and chemotherapy might be related to expression of HER2 and estrogen receptor (ESR1). Therefore, we investigated HER2 and ESR1 mRNA levels in core biopsies of HER2-positive breast carcinomas from patients treated within the neoadjuvant GeparQuattro trial.

Methods: HER2 levels were centrally analyzed by immunohistochemistry (IHC), silver in situ hybridization (SISH) and qRT-PCR in 217 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) core biopsies. All tumors had been HER2-positive by local pathology and had been treated with neoadjuvant trastuzumab/ chemotherapy in GeparQuattro.

Results: Only 73% of the tumors (158 of 217) were centrally HER2-positive (cHER2-positive) by IHC/SISH, with cHER2-positive tumors showing a significantly higher pCR rate (46.8% vs. 20.3%, P <0.0005). HER2 status by qRT-PCR showed a concordance of 88.5% with the central IHC/SISH status, with a low pCR rate in those tumors that were HER2-negative by mRNA analysis (21.1% vs. 49.6%, P <0.0005). The level of HER2 mRNA expression was linked to response rate in ESR1-positive tumors, but not in ESR1-negative tumors. HER2 mRNA expression was significantly associated with pCR in the HER2-positive/ESR1-positive tumors (P = 0.004), but not in HER2-positive/ESR1-negative tumors.

Conclusions: Only patients with cHER2-positive tumors - irrespective of the method used - have an increased pCR rate with trastuzumab plus chemotherapy. In patients with cHER2-negative tumors the pCR rate is comparable to the pCR rate in the non-trastuzumab treated HER-negative population. Response to trastuzumab is correlated to HER2 mRNA levels only in ESR1-positive tumors. This study adds further evidence to the different biology of both subsets within the HER2-positive group.

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Figures

Figure 1
Figure 1
Consort statement indicating the flow of samples through the study. HER2, human epidermal growth factor receptor 2; FFPE, formalin-fixed paraffin-embedded; Ct, cycle threshold; ESR1, estrogen receptor 1; RT-PCR, real-time polymerase chain reaction.
Figure 2
Figure 2
Comparison of different methods for central assessment of human epidermal growth factor receptor 2 (HER2) overexpression. (A) Five different approaches were used: IHC 3+ or IHC2+/SISH >2.0 (gold standard), HER2 IHC, HER2 SISH ratio, HER2 SISH copy numbers as well as quantitative RT-PCR for evaluation of HER2 mRNA levels. In all approaches the pCR rate was significantly higher in the centrally HER2-positive cases. (P = 0.004, for IHC alone, P <0.0005 for all other comparisons, two-sided Fisher's exact test). (B) Comparison of quantitative HER2 mRNA levels and SISH ratio; pCR cases are marked as dark spots. A total of 11 cases were negative for HER2 mRNA despite an amplification of HER2 by SISH (lower right corner). These cases showed a pCR rate of only 27.3% (three pCRs out of eleven cases). IHC, immunohistochemistry; SISH, silver in situ hybridization; RT-PCR, real-time polymerase chain reaction; pCR, pathological complete response, ypT: tumor stage after neoadjuvant therapy.
Figure 3
Figure 3
mRNA-based combined quantitative determination of human epidermal growth factor receptor 2 (HER2) and estrogen receptor 1 (ESR1) mRNA. Cases with a pCR are marked as dark spots. (A) Total of 217 cases. (B) Centrally HER2-positive cases (n = 158). In this group a total of 21 cases (13.3%) were HER2-negative by mRNA analysis; the pCR rate of those 21 cases was only 23.8%. The pCR rate in those 137 cases that were HER2-positive by mRNA analysis was 50.4%, (P = 0.03, two-sided Fisher's exact test). (C, D, E) All 217 cases: different distribution patterns of HER2 mRNA with a continuous distribution in ESR1-positive tumors (D) and a more dichotomous distribution in ESR1-negative tumors (E). STEPP analysis for all 217 tumors (F), ESR1-positive tumors (G) and ESR1-negative tumors (H). HER2 mRNA levels were linked to pCR rate in the group of ESR1-positive tumors with a continuously increased pCR rate. pCR, pathological complete response; STEPP, subpopulation treatment effect pattern plot.
Figure 4
Figure 4
Subpopulation treatment effect pattern plot (STEPP) analysis using the classical parameters human epidermal growth factor receptor 2 (HER2) silver in situ hybridization (SISH) copy number and hormone receptor immunohistochemistry. Shown are analysis for all tumors (A), hormone receptor-positive tumors (B) and hormone receptor negative tumors (C). In contrast to the data shown ins the classical parameters were not linked to pCR rate. pCR, pathological complete response; IHC, immunohistochemistry; HR, hormone receptor.
Figure 5
Figure 5
Odds ratios for pathological complete response (pCR) for the quantitative markers estrogen receptor 1 (ESR1) mRNA (per dCT), human epidermal growth factor receptor 2 (HER2) mRNA (per dCT), silver in situ hybridization (SISH) ratio and SISH copy number in different subgroups. Results in the three columns (right) represent as odds ratios, 95% CI and P-values. ESR1 mRNA was significant only in the group of all 217 cases (which also contained the centrally evaluated HER2 (cHER2)-negative cases). If the analysis was restricted to the centrally evaluated HER2-positive cases, ESR1 mRNA was not significant. HER2 mRNA levels were only significant in the group of ESR1-positive tumors, similar to the subpopulation treatment effect pattern plot (STEPP) analysis. In contrast to the mRNA analysis, HER2 SISH ratio and copy number were not significant in centrally evaluated HER2-positive cases. ns, not signficant.
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