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

Denkert C, Huober J, Loibl S, Prinzler J, Kronenwett R, Darb-Esfahani S, Brase JC, Solbach C, Mehta K, Fasching PA, Sinn BV, Engels K, Reinisch M, Hansmann ML, Tesch H, von Minckwitz G, Untch M - Breast Cancer Res. (2013)

Bottom Line: Recent data suggest that benefit from trastuzumab and chemotherapy might be related to expression of HER2 and estrogen receptor (ESR1).Only patients with cHER2-positive tumors - irrespective of the method used - have an increased pCR rate with trastuzumab plus chemotherapy.This study adds further evidence to the different biology of both subsets within the HER2-positive group.

View Article: PubMed Central - HTML - PubMed

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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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.
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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.

Mentions: To evaluate the impact of different levels of HER2 mRNA on pCR in the groups of ESR1-positive and -negative tumors, we performed STEPP analysis. As shown in Figure 3G, HER2 mRNA levels were significantly linked to pCR rate in the group of ESR1 mRNA-positive tumors: in this group, the pCR rate continuously rose with increased HER2 mRNA levels. In contrast, for ESR1 mRNA-negative tumors an abrupt increase of the pCR rate occurred once the cutoff between HER2-positive and -negative tumors was crossed, while HER2 mRNA levels did not further influence the pCR rate once a tumor was in the HER2-positive group (Figure 3H). A similar assessment using the traditional factors, HR status by IHC and SISH copy number, did not show a rise of pCR rates with increased SISH ratios in HR-positive tumors (Figure 4).


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

Denkert C, Huober J, Loibl S, Prinzler J, Kronenwett R, Darb-Esfahani S, Brase JC, Solbach C, Mehta K, Fasching PA, Sinn BV, Engels K, Reinisch M, Hansmann ML, Tesch H, von Minckwitz G, Untch M - Breast Cancer Res. (2013)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3672694&req=5

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.
Mentions: To evaluate the impact of different levels of HER2 mRNA on pCR in the groups of ESR1-positive and -negative tumors, we performed STEPP analysis. As shown in Figure 3G, HER2 mRNA levels were significantly linked to pCR rate in the group of ESR1 mRNA-positive tumors: in this group, the pCR rate continuously rose with increased HER2 mRNA levels. In contrast, for ESR1 mRNA-negative tumors an abrupt increase of the pCR rate occurred once the cutoff between HER2-positive and -negative tumors was crossed, while HER2 mRNA levels did not further influence the pCR rate once a tumor was in the HER2-positive group (Figure 3H). A similar assessment using the traditional factors, HR status by IHC and SISH copy number, did not show a rise of pCR rates with increased SISH ratios in HR-positive tumors (Figure 4).

Bottom Line: Recent data suggest that benefit from trastuzumab and chemotherapy might be related to expression of HER2 and estrogen receptor (ESR1).Only patients with cHER2-positive tumors - irrespective of the method used - have an increased pCR rate with trastuzumab plus chemotherapy.This study adds further evidence to the different biology of both subsets within the HER2-positive group.

View Article: PubMed Central - HTML - PubMed

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.

Show MeSH
Related in: MedlinePlus