Epidermal growth factor receptor expression correlates with poor survival in patients who have breast carcinoma treated with doxorubicin‐based neoadjuvant chemotherapy

Buchholz, Thomas A.; Tu, Xiaoyu; Ang, K. Kian; Esteva, Francisco J.; Kuerer, Henry Mark; Pusztai, Lajos; Cristofanilli, Massimo; Singletary, S. Eva; Hortobágyi, Gabriel N.; Şahin, Ayşegül

doi:10.1002/cncr.21217

Cited by 46 publications

(35 citation statements)

References 17 publications

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“…HCCDXR showed overexpression of EGFR and overactivation of AKT and ERK1/2 when compared with its parental cell line. Overexpression of EGFR in patients with breast cancer after chemotherapy has been already described to be related with higher local recurrence, metastasis, and so poor outcome (30,31). On the other hand, AKT and ERK1/2 have been shown to be overactivated and also linked to chemoresistance in several cancers (32,33).…”

Section: Discussionmentioning

confidence: 99%

Preclinical Evaluation of Fatty Acid Synthase and EGFR Inhibition in Triple-Negative Breast Cancer

Giró-Perafita

Palomeras

Lum

et al. 2016

Clinical Cancer Research

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Purpose: Triple-negative breast cancer (TNBC) lacks an approved targeted therapy. Despite initial good response to chemotherapy, 30% of the patients relapse within 5 years after treatment. EGFR overexpression is a common marker in TNBC, and its expression has been correlated with poor outcome. Inhibition of fatty acid synthase (FASN) activity leads to apoptosis of human carcinoma cells overexpressing FASN. We tested the hypothesis that blocking FASN in combination with anti-EGFR signaling agents would be an effective antitumor strategy in sensitive and chemoresistant TNBC.Experimental Design: Several TNBC cell lines and 29 primary tumors were included to determine whether FASN is a potential target in TNBC. Doxorubicin-resistant TNBC cell lines (231DXR and HCCDXR) have been developed and characterized in our laboratory. Cellular and molecular interactions of anti-FASN compounds (EGCG and C75) with cetuximab were analyzed. In vivo tumor growth inhibition was evaluated after cetuximab, EGCG, or the combination in TNBC orthoxenograft models.Results: TNBC cell lines showed overexpression of FASN enzyme and its inhibition correlated to FASN levels. FASN staining was observed in all of the 29 TNBC tumor samples. In vitro, EGCG and C75 plus cetuximab showed strong synergism in sensitive and chemoresistant cells. In vivo, the combination of EGCG with cetuximab displayed strong antitumor activity against the sensitive and chemoresistant TNBC orthoxenografts, without signs of toxicity.Conclusions: Our results show that the simultaneous blockade of FASN and EGFR is effective in preclinical models of sensitive and chemoresistant TNBC.

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Section: Discussionmentioning

confidence: 99%

Preclinical Evaluation of Fatty Acid Synthase and EGFR Inhibition in Triple-Negative Breast Cancer

Giró-Perafita

Palomeras

Lum

et al. 2016

Clinical Cancer Research

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“…We attempted to obtain pretreatment tissue blocks from the other 134 cases and received suitable pretreatment tissue in 82 cases. The material from these patients has been used in other investigations (16,17). Clinical features and outcome of the 82 studied cases were not significantly different than the features and outcome of the entire group enrolled on these protocols.…”

Section: Methodsmentioning

confidence: 99%

“…EGFR was considered positive for any tumor that had membranous staining. Additional details of HER2/neu, mitosin, and EGFR staining and interpretation were provided in our earlier reports (16,17).…”

Section: Methodsmentioning

confidence: 99%

The Nuclear Transcription Factor κB/bcl-2 Pathway Correlates with Pathologic Complete Response to Doxorubicin-Based Neoadjuvant Chemotherapy in Human Breast Cancer

Buchholz

Garg

Chakravarti

et al. 2005

Clinical Cancer Research

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Purpose: Molecular factors involved in apoptosis may affect breast cancer response to chemotherapy. Herein, we studied the nuclear factor nB (NF-nB)/bcl-2 pathway to determine whether or not activation of this antiapoptotic pathway was associated with a poor response of human breast cancer to anthracycline-based neoadjuvant chemotherapy. Experimental Design: We studied 82 human breast cancer samples from patients treated with neoadjuvant doxorubicin-based chemotherapy and studied whether or not nuclear location of the transcription factor NF-nB was associated with expression of bcl-2 and bax and whether or not expression of these proteins correlated with chemotherapy response. Protein expression was measured with immunohistochemical staining. A dedicated breast cancer pathologist who was unaware of the clinical outcome data dichotomized the slides as positive or negative based on the presence or absence of cytoplasmic staining for bcl-2 and bax or nuclear staining for NF-nB. Results: Sixty-one percent of the tumors were positive for bcl-2, 85% were positive for bax, and 16% were positive for NF-nB. All bcl-2-positive tumors were also bax positive (P < 0.0001) and all NF-nB-positive tumors were both bcl-2 positive (P = 0.001) and bax positive (P = 0.113). Eleven of the 82 patients (13%) had a pathologic complete response (pCR) to chemotherapy. Patients with positive staining tumors for any of the markers less commonly achieved a pCR to chemotherapy than those with negative tumor staining. The pCR rates were NF-nB positive 0% (0 of 13) versus NF-nB negative13% (11of 69; P = 0.130); bcl-2 positive 4% (2 of 49) versus bcl-2 negative 27% (9 of 33; P = 0.004); and bax positive 6% (4 of 69) versus bax negative 58% (7 of 12; P < 0.001). Conclusion:We conclude that nuclear localization of NF-nB correlates with bcl-2 and bax expression and that the NF-nB/bcl-2 pathway may be associated with a poor response to neoadjuvant doxorubicin-based chemotherapy.

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“…HER-2 is overexpressed in 15-30% of invasive breast cancers, and it has been associated with poor prognosis with shorter disease-free and overall survival; moreover, it has been a predictive factor for response to chemotherapy, antiestrogens, and herceptin. 5,6 Although, in breast cancer, EGFR is reported to be expressed in 5-91%, 4,7,8 and in several studies is also associated with poor prognosis, 9,10 there is still no clear evidence regarding its prognostic relevance. On the other hand, emerging evidence suggest the existence of a new mode of EGFR-signaling pathway in which activated EGFR undergoes nuclear translocation and subsequently regulates gene expression.…”

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confidence: 99%

Nuclear EGFR in ductal invasive breast cancer: correlation with cyclin-D1 and prognosis

et al. 2010

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The epidermal growth factor receptor (EGFR)-family and cyclin-D1 have been extensively studied in breast cancer; however systematic studies that examine protein expression and gene status in the same cohort of patients are lacking. Also emerging evidences suggest existence of a direct EGFR-signaling pathway, which involves cellular transport of EGFR from cell membrane to the nucleus, and transcriptional regulation of the target genes. Thus, we examined the protein expression of membrane EGFR, nuclear EGFR, cyclin-D1 and the corresponding gene status in 113 breast carcinomas by immunohistochemistry and fluorescence in situ hybridization using tissue microarrays. Membrane EGFR overexpression and EGFR gene amplification were detected in 2% cases, while nuclear EGFR was detected in 40% of cases, with 12% having high nuclear EGFR staining. Nuclear EGFR correlated with tumor size (P ¼ 0.0005), lymph node metastasis (P ¼ 0.0288), Nottingham prognostic index (P ¼ 0.0011) and estrogen receptor (ER) expression (P ¼ 0.0258) but the letter correlation was observed only in premenopausal group of patients. Strong cyclin-D1 expression and cyclin-D1 gene (CCND1) amplification were found in 64 and 13% of the cases, respectively. Cyclin-D1 expression showed positive correlation with ER (P ¼ 0.0113) and inverse correlation with Nottingham prognostic index (P ¼ 0.0309) and membrane EGFR (P ¼ 0.0201). CCND1 amplification also showed inverse correlation with membrane EGFR (P ¼ 0.0420). A strong correlation between membrane EGFR expression and gene amplification (P ¼ 0.0035), as well as cyclin-D1 overexpression and gene amplification (P ¼ 0.0362), was demonstrated. On univariate analysis cyclin-D1 expression showed a correlation with longer overall survival in the premenopausal group and nuclear EGFR correlated with shorter overall survival in whole cohort as well in the premenopausal group of patients. Multivariate analysis revealed nuclear EGFR to be an independent prognostic factor and showed 3.4 times greater mortality risk for nuclear EGFR þ þ þ patients as compared with nuclear EGFR negative patients (hazard ratio ¼ 3.402; P ¼ 0.0026).

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Epidermal growth factor receptor expression correlates with poor survival in patients who have breast carcinoma treated with doxorubicin‐based neoadjuvant chemotherapy

Cited by 46 publications

References 17 publications

Preclinical Evaluation of Fatty Acid Synthase and EGFR Inhibition in Triple-Negative Breast Cancer

Preclinical Evaluation of Fatty Acid Synthase and EGFR Inhibition in Triple-Negative Breast Cancer

The Nuclear Transcription Factor κB/bcl-2 Pathway Correlates with Pathologic Complete Response to Doxorubicin-Based Neoadjuvant Chemotherapy in Human Breast Cancer

Nuclear EGFR in ductal invasive breast cancer: correlation with cyclin-D1 and prognosis

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