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Clinical Trial
. 2012 Mar 14;14(2):R46.
doi: 10.1186/bcr3145.

ER and HER2 expression are positively correlated in HER2 non-overexpressing breast cancer

Isabel Pinhel  1 , Margaret Hills, Suzanne Drury, Janine Salter, Georges Sumo, Roger A'Hern, Judith M Bliss, Ivana Sestak, Jack Cuzick, Peter Barrett-Lee, Adrian Harris, Mitch Dowsett; NCRI Adjuvant Breast Cancer Trial Management Group
Affiliations
Clinical Trial

ER and HER2 expression are positively correlated in HER2 non-overexpressing breast cancer

Isabel Pinhel et al. Breast Cancer Res. .

Abstract

Introduction: Estrogen receptor-α (ER) and human epidermal growth factor receptor 2 (HER2) positivity are inversely correlated by standard criteria. However, we investigated the quantitative relation between ER and HER2 expression at both RNA and protein levels in HER2+ve and HER2-ve breast carcinomas.

Methods: ER and HER2 levels were assessed with immunohistochemistry (IHC) and (for HER2) fluorescent in situ hybridization (FISH) and by quantitative reverse transcription-polymerase chain reaction (q-RT-PCR) in formalin-fixed primary breast cancers from 448 patients in the National Cancer Research Institute (NCRI) Adjuvant Breast Cancer Trial (ABC) tamoxifen-only arm. Relations at the RNA level were assessed in 1,139 TransATAC tumors.

Results: ER and HER2 RNA levels were negatively correlated as expected in HER2+ve (IHC 3+ and/or FISH-amplified) tumors (r = -0.45; P = 0.0028). However, in HER2-ve tumors (ER+ve and ER-ve combined), a significant positive correlation was found (r = 0.43; P < 0.0001), HER2 RNA levels being 1.74-fold higher in ER+ve versus ER-ve tumors. This correlation was maintained in the ER+veHER2-ve subgroup (r = 0.24; P = 0.0023) and confirmed in this subgroup in 1,139 TransATAC tumours (r = 0.25; P < 0.0001). The positive relation extended to IHC-detected ER in ABC: mean ± 95% confidence interval (CI) H-scores were 90 ± 19 and 134 ± 19 for 0 and 1+ HER2 IHC categories, respectively (P = 0.0013). A trend toward lower relapse-free survival (RFS) was observed in patients with the lowest levels of ER and HER2 RNA levels within the ER+veHER2-ve subgroup both for ABC and TransATAC cohorts.

Conclusions: ER and HER2 expression is positively correlated in HER2-ve tumors. The distinction between HER2+ve and HER2-ve is greater in ER-ve than in ER+ve tumors. These findings are important to consider in clinical trials of anti-HER2 and anti-endocrine therapy in HER2-ve disease.

Trial registration: Clinical trial identifier: ISRCTN31514446.

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Figures

Figure 1
Figure 1
CONSORT flow chart of the ABC Tamoxifen Late Relapse Study in which the number of samples with data available for ER and HER2 by qRT-PCR, IHC, and FISH (for HER2 only) are shown. ER, estrogen receptor; FISH, fluorescence in situ hybridization; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; qRT-PCR, quantitative reverse-transcription polymerase chain reaction.
Figure 2
Figure 2
Relation of RNA levels. (a) Relation of ER RNA levels (qRT-PCR) with protein expression assessed with IHC (H score). (b) ER RNA levels according to IHC status. ER-ve (IHC H score ≤ 1); n = 84; and ER+ve (IHC H score > 1); n = 173. (c) Relation of HER2 RNA levels (qRT-PCR) with HER2 amplification levels (FISH). HER2+ve, n = 34; HER2-ve, n = 199; and HER2 equivocal, n = 3. (d) HER2 RNA levels according to IHC HercepTest categories. IHC 0, n = 96; IHC 1+, n = 101; IHC 2+, n = 19; and IHC 3+, n = 37. Means with 95%CI are shown. CI, confidence interval; ER, estrogen receptor; FISH, fluorescence in situ hybridization; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; qRT-PCR, quantitative reverse-transcription polymerase chain reaction.
Figure 3
Figure 3
Correlation of ER and HER2 transcript levels (qRT-PCR). HER2-ve is defined as HER2 FISH-ve and IHC 0/1+/2+; n = 211. HER2+ve is defined as HER2 FISH+ve and/or IHC 3+; n = 42. ER, estrogen receptor; FISH, fluorescence in situ hybridization; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; qRT-PCR, quantitative reverse-transcription polymerase chain reaction.
Figure 4
Figure 4
RNA and protein levels. (a) ER RNA levels and (b) ER protein levels according to HER2 protein and gene-amplification levels (IHC HercepTest and FISH, respectively); IHC 0, n = 96; IHC 1+, n = 101; IHC 2+ FISH-ve, n = 13; IHC 2+ FISH+ve, n = 2; IHC 3+ FISH-ve, n = 5; IHC 3+ FISH+ve, n = 29; IHC 3+, n = 37. Means with 95% CI are shown (95% confidence intervals for IHC2+ FISH+ve subgroup are 4a, -5.1 to 5.8, and 4b, -892.2 to 1045; these were omitted for ease of visualization). CI, confidence interval; ER, estrogen receptor; FISH, fluorescence in situ hybridization; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; qRT-PCR, quantitative reverse-transcription polymerase chain reaction.
Figure 5
Figure 5
Kaplan-Meier plots for relapse-free survival in HER2-ve cases. (a, b) Relapse-free survival by ER and HER2 RNA quartiles (qRT-PCR), respectively, in the HER2-ve population of the ABC study, irrespective of ER status. (c, d) Relapse-free survival by ER and HER2 RNA quartiles, respectively, in the subgroup of ER+ve HER2-ve cases of the ABC study. (e, f) Relapse-free survival by ER and HER2 RNA quartiles, respectively, in the ER+ve HER2-ve cohort of the TransATAC study. First quartile defined as the lowest RNA levels for ER and HER2. N.B.: The y-axis scale in the ABC study is different from that in the TransATAC study. ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; qRT-PCR, quantitative reverse-transcription polymerase chain reaction.
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