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Evaluation of the prognostic and predictive value of HER family mRNA expression in high-risk early breast cancer: a Hellenic Cooperative Oncology Group (HeCOG) study.

Koutras AK, Kalogeras KT, Dimopoulos MA, Wirtz RM, Dafni U, Briasoulis E, Pectasides D, Gogas H, Christodoulou C, Aravantinos G, Zografos G, Timotheadou E, Papakostas P, Linardou H, Razis E, Economopoulos T, Kalofonos HP, Fountzilas G, Hellenic Cooperative Oncology Group (HeCO - Br. J. Cancer (2008)

Bottom Line: At a median follow-up of 8 years, multivariate analysis showed that EGFR and HER2 mRNA expression was associated with reduced overall survival (OS).These data indicate that EGFR as well as HER2 are prognostic factors of worse clinical outcomes, whereas HER3 and HER4 gene transcription is associated with better prognosis in high-risk early breast cancer.However, HER2 mRNA expression did not predict clinical benefit from paclitaxel.

View Article: PubMed Central - PubMed

Affiliation: Division of Oncology, Department of Medicine, University Hospital of Patras, Rion, Greece. angkoutr@otenet.gr

ABSTRACT
The aim of the study was to evaluate the prognostic ability of the transcriptional profiling of the HER family genes in early breast cancer, as well as to investigate the predictive value of HER2 mRNA expression for adjuvant treatment with paclitaxel. RNA was extracted from 268 formalin-fixed paraffin-embedded (FFPE) tumour tissue samples of high-risk breast cancer patients enrolled in the randomised HE10/97 trial, evaluating the effect of dose-dense anthracycline-based sequential adjuvant chemotherapy with or without paclitaxel. The mRNA expression of all four HER family members was assessed by kinetic reverse transcription-polymerase chain reaction (kRT-PCR). The overall concordance between kRT-PCR and IHC/FISH for HER2 status determination was 74%. At a median follow-up of 8 years, multivariate analysis showed that EGFR and HER2 mRNA expression was associated with reduced overall survival (OS). HER3 and HER4 mRNA level had a favourable prognostic value in terms of OS and disease-free survival (DFS), respectively. Adjusting for HER2 mRNA expression, OS and DFS did not differ between treatment groups. These data indicate that EGFR as well as HER2 are prognostic factors of worse clinical outcomes, whereas HER3 and HER4 gene transcription is associated with better prognosis in high-risk early breast cancer. However, HER2 mRNA expression did not predict clinical benefit from paclitaxel. Kinetic RT-PCR represents an alternative method for evaluating the expression of HER family members in FFPE breast carcinomas.

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(A1) OS (P=0.022) and B1. DFS (P=0.076) for patients with EGFR mRNA expression <75th percentile (N=200, blue line) and ⩾75th percentile (N=67, red line). (A2) OS (P=0.024) and B2. DFS (P=0.026) for patients with HER2 mRNA expression <median (N=134, blue line) and ⩾median (N=134, red line). (A3) OS (P=0.026) and B3. DFS (P=0.135) for patients with HER3 mRNA expression <median (N=133, blue line) and ⩾median (N=134, red line). (A4) OS (P=0.010) and B4. DFS (P=0.001) for patients with HER4 mRNA expression <median (N=130, blue line) and ⩾median (N=130, red line).
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fig2: (A1) OS (P=0.022) and B1. DFS (P=0.076) for patients with EGFR mRNA expression <75th percentile (N=200, blue line) and ⩾75th percentile (N=67, red line). (A2) OS (P=0.024) and B2. DFS (P=0.026) for patients with HER2 mRNA expression <median (N=134, blue line) and ⩾median (N=134, red line). (A3) OS (P=0.026) and B3. DFS (P=0.135) for patients with HER3 mRNA expression <median (N=133, blue line) and ⩾median (N=134, red line). (A4) OS (P=0.010) and B4. DFS (P=0.001) for patients with HER4 mRNA expression <median (N=130, blue line) and ⩾median (N=130, red line).

Mentions: For each of the HER family receptors, three cutoff points (25th, 50th and 75th percentiles) were assessed for prognostic value. In the majority of cases, the median (50th percentile) was the optimal cutoff point. However, in the case of EGFR the 75th percentile was the best threshold, allowing us to distinguish two populations of significantly different prognosis. Using the 75th percentile, patients whose tumours had increased EGFR mRNA expression had significantly reduced OS (22 out of 67 deaths in EGFR-positive vs 38 out of 200 deaths in EGFR-negative patients, log-rank P=0.022) (Figure 2A1). The hazard ratio (HR) for death in EGFR-positive patients was 1.83 (95% CI: 1.08–3.09, P=0.024). The median value was used as a cutoff point for HER2, HER3 and HER4. A significant association between HER2 mRNA overexpression and reduced OS was demonstrated (39 out of 134 deaths in HER2-positive vs 22 out of 134 deaths in HER2-negative patients, log-rank P=0.024) (Figure 2A2). The HR for death in HER2-positive patients was 1.81 (95% CI: 1.07–3.05, P=0.027). In contrast, HER3 as well as HER4 mRNA expression had a favourable prognostic value in terms of OS (HR=0.56, 95% CI: 0.33–0.94, P=0.028 and HR=0.50, 95% CI: 0.29–0.86, P=0.011, respectively) (Figure 2A3 and A4). Among 134 HER3-positive patients 23 deaths were recorded, whereas among 133 HER3 negative patients 37 deaths were observed (log-rank P=0.026). Similarly, among 130 HER4-positive patients 21 deaths were observed vs 38 deaths among 130 HER4-negative patients (log-rank P=0.010). In multivariate analysis that included 260 patients, EGFR, HER2, HER3, and the number of involved axillary lymph nodes, all independently affected OS (Table 3).


Evaluation of the prognostic and predictive value of HER family mRNA expression in high-risk early breast cancer: a Hellenic Cooperative Oncology Group (HeCOG) study.

Koutras AK, Kalogeras KT, Dimopoulos MA, Wirtz RM, Dafni U, Briasoulis E, Pectasides D, Gogas H, Christodoulou C, Aravantinos G, Zografos G, Timotheadou E, Papakostas P, Linardou H, Razis E, Economopoulos T, Kalofonos HP, Fountzilas G, Hellenic Cooperative Oncology Group (HeCO - Br. J. Cancer (2008)

(A1) OS (P=0.022) and B1. DFS (P=0.076) for patients with EGFR mRNA expression <75th percentile (N=200, blue line) and ⩾75th percentile (N=67, red line). (A2) OS (P=0.024) and B2. DFS (P=0.026) for patients with HER2 mRNA expression <median (N=134, blue line) and ⩾median (N=134, red line). (A3) OS (P=0.026) and B3. DFS (P=0.135) for patients with HER3 mRNA expression <median (N=133, blue line) and ⩾median (N=134, red line). (A4) OS (P=0.010) and B4. DFS (P=0.001) for patients with HER4 mRNA expression <median (N=130, blue line) and ⩾median (N=130, red line).
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fig2: (A1) OS (P=0.022) and B1. DFS (P=0.076) for patients with EGFR mRNA expression <75th percentile (N=200, blue line) and ⩾75th percentile (N=67, red line). (A2) OS (P=0.024) and B2. DFS (P=0.026) for patients with HER2 mRNA expression <median (N=134, blue line) and ⩾median (N=134, red line). (A3) OS (P=0.026) and B3. DFS (P=0.135) for patients with HER3 mRNA expression <median (N=133, blue line) and ⩾median (N=134, red line). (A4) OS (P=0.010) and B4. DFS (P=0.001) for patients with HER4 mRNA expression <median (N=130, blue line) and ⩾median (N=130, red line).
Mentions: For each of the HER family receptors, three cutoff points (25th, 50th and 75th percentiles) were assessed for prognostic value. In the majority of cases, the median (50th percentile) was the optimal cutoff point. However, in the case of EGFR the 75th percentile was the best threshold, allowing us to distinguish two populations of significantly different prognosis. Using the 75th percentile, patients whose tumours had increased EGFR mRNA expression had significantly reduced OS (22 out of 67 deaths in EGFR-positive vs 38 out of 200 deaths in EGFR-negative patients, log-rank P=0.022) (Figure 2A1). The hazard ratio (HR) for death in EGFR-positive patients was 1.83 (95% CI: 1.08–3.09, P=0.024). The median value was used as a cutoff point for HER2, HER3 and HER4. A significant association between HER2 mRNA overexpression and reduced OS was demonstrated (39 out of 134 deaths in HER2-positive vs 22 out of 134 deaths in HER2-negative patients, log-rank P=0.024) (Figure 2A2). The HR for death in HER2-positive patients was 1.81 (95% CI: 1.07–3.05, P=0.027). In contrast, HER3 as well as HER4 mRNA expression had a favourable prognostic value in terms of OS (HR=0.56, 95% CI: 0.33–0.94, P=0.028 and HR=0.50, 95% CI: 0.29–0.86, P=0.011, respectively) (Figure 2A3 and A4). Among 134 HER3-positive patients 23 deaths were recorded, whereas among 133 HER3 negative patients 37 deaths were observed (log-rank P=0.026). Similarly, among 130 HER4-positive patients 21 deaths were observed vs 38 deaths among 130 HER4-negative patients (log-rank P=0.010). In multivariate analysis that included 260 patients, EGFR, HER2, HER3, and the number of involved axillary lymph nodes, all independently affected OS (Table 3).

Bottom Line: At a median follow-up of 8 years, multivariate analysis showed that EGFR and HER2 mRNA expression was associated with reduced overall survival (OS).These data indicate that EGFR as well as HER2 are prognostic factors of worse clinical outcomes, whereas HER3 and HER4 gene transcription is associated with better prognosis in high-risk early breast cancer.However, HER2 mRNA expression did not predict clinical benefit from paclitaxel.

View Article: PubMed Central - PubMed

Affiliation: Division of Oncology, Department of Medicine, University Hospital of Patras, Rion, Greece. angkoutr@otenet.gr

ABSTRACT
The aim of the study was to evaluate the prognostic ability of the transcriptional profiling of the HER family genes in early breast cancer, as well as to investigate the predictive value of HER2 mRNA expression for adjuvant treatment with paclitaxel. RNA was extracted from 268 formalin-fixed paraffin-embedded (FFPE) tumour tissue samples of high-risk breast cancer patients enrolled in the randomised HE10/97 trial, evaluating the effect of dose-dense anthracycline-based sequential adjuvant chemotherapy with or without paclitaxel. The mRNA expression of all four HER family members was assessed by kinetic reverse transcription-polymerase chain reaction (kRT-PCR). The overall concordance between kRT-PCR and IHC/FISH for HER2 status determination was 74%. At a median follow-up of 8 years, multivariate analysis showed that EGFR and HER2 mRNA expression was associated with reduced overall survival (OS). HER3 and HER4 mRNA level had a favourable prognostic value in terms of OS and disease-free survival (DFS), respectively. Adjusting for HER2 mRNA expression, OS and DFS did not differ between treatment groups. These data indicate that EGFR as well as HER2 are prognostic factors of worse clinical outcomes, whereas HER3 and HER4 gene transcription is associated with better prognosis in high-risk early breast cancer. However, HER2 mRNA expression did not predict clinical benefit from paclitaxel. Kinetic RT-PCR represents an alternative method for evaluating the expression of HER family members in FFPE breast carcinomas.

Show MeSH
Related in: MedlinePlus