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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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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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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.

Mentions: In a parallel approach, odds ratios for pCR for the three quantitative markers, ESR1 mRNA, HER2 mRNA and SISH ratio, were determined in different subgroups. The predictive effect of HER2 mRNA levels was particularly strong in the group of cHER2-positive/ESR1-positive tumors; in this group ESR1 mRNA level was also significant (Figure 5). In contrast, HER2 as well as ESR1 mRNA levels were not significant in cHER2-positive/ESR1-negative tumors, similar to the results of the STEPP analysis. If the analysis was restricted to cHER2-positive cases, ESR1 mRNA was a significant predictive marker only in the groups of ESR1-positive tumors. Neither SISH ratio (Figure 5) nor SISH copy number (Figure 5), was significant in the group of cHER2-positive cases.


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)

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

License
Show All Figures
getmorefigures.php?uid=PMC3672694&req=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.
Mentions: In a parallel approach, odds ratios for pCR for the three quantitative markers, ESR1 mRNA, HER2 mRNA and SISH ratio, were determined in different subgroups. The predictive effect of HER2 mRNA levels was particularly strong in the group of cHER2-positive/ESR1-positive tumors; in this group ESR1 mRNA level was also significant (Figure 5). In contrast, HER2 as well as ESR1 mRNA levels were not significant in cHER2-positive/ESR1-negative tumors, similar to the results of the STEPP analysis. If the analysis was restricted to cHER2-positive cases, ESR1 mRNA was a significant predictive marker only in the groups of ESR1-positive tumors. Neither SISH ratio (Figure 5) nor SISH copy number (Figure 5), was significant in the group of cHER2-positive cases.

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