Evaluation of PTEN loss and PIK3CA mutations and their correlation with efficacy of trastuzumab treatment in HER2-positive metastatic breast cancer: A retrospective study (KBC-SG 1001)

Nishimura,Reiki; Arima,Nobuyuki; Toyoshima,Satoshi; Ohi,Yasuyo; Anan,Keisei; Sagara,Yasuaki; Mitsuyama,Shoshu; Tamura,Kazuo

doi:10.3892/mco.2012.10

Evaluation of PTEN loss and PIK3CA mutations and their correlation with efficacy of trastuzumab treatment in HER2-positive metastatic breast cancer: A retrospective study (KBC-SG 1001)

Authors:
- Reiki Nishimura
- Nobuyuki Arima
- Satoshi Toyoshima
- Yasuyo Ohi
- Keisei Anan
- Yasuaki Sagara
- Shoshu Mitsuyama
- Kazuo Tamura
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Affiliations: Department of Breast and Endocrine Surgery, Kumamoto City Hospital, Kumamoto, Japan, Department of Pathology, Kumamoto City Hospital, Kumamoto, Japan, Department of Pathology, Kitakyushu Municipal Medical Center, Kitakyushu, Japan, Department of Pathology, Hakuaikai Sagara Hospital, Kagoshima, Japan, Department of Surgery, Kitakyushu Municipal Medical Center, Kitakyushu, Japan, Department of Breast/Thyroid Gland, Hakuaikai Sagara Hospital, Kagoshima, Japan, Division of Medical Oncology, Hematology and Infectious Diseases, Department of Medicine, Fukuoka University Hospital, Fukuoka, Japan
Published online on: August 9, 2012 https://doi.org/10.3892/mco.2012.10
Pages: 47-52

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Abstract

Trastuzumab (T) has contributed to improving the prognosis of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Although some patients have been unresponsive or resistant to T. Loss of phosphatase and tensin homolog (PTEN) deleted on chromosome 10, PIK3CA mutation and p95HER2 expression have been reported to potentially be responsible for the poor response to T. This is a small-scale pilot study to be followed by a large-scale investigation examining the association between the biomarkers and clinical response. Based on the response to T, patients were divided into 3 groups in terms of progression-free survival (PFS): PFS >8 months (group A, n=15), 3-8 months (group B, n=7) and PFS <3 months (group C, n=11). PTEN protein expression was detected by immunohistochemistry and PIK3CA mutation by direct sequencing. The median age was 61, 60 and 47 years in groups A, B and C, respectively, with statistically significant differences among the groups. No additional patient background factors differed between the groups. A decreased PTEN expression (H score, <100) was observed in 33.3 and 72.7% of patients in groups A and C, respectively. PTEN loss was slightly correlated with poor response to T. PIK3CA mutation frequency in exons 9/20 was 33.3% in group A and 27.3% in group C, with no significant correlation between PIK3CA mutation and clinical response. In this small-scale pilot study, a weak correlation was demonstrated between PTEN loss and poor response to T. This potential correlation is likely to be confirmed in the planned large-scale study, while the association of PIK3CA mutation and p95HER2 expression with poor response to T also requires examination.

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1.	Harries M and Smith I: The development and clinical use of trastuzumab (Herceptin). Endocr Relat Cancer. 9:75–85. 2002.
2.	Sáez R, Molina MA, Ramsey EE, et al: p95HER2 predicts worse outcome in patients with HER2-positive breast cancer. Clin Cancer Res. 12:424–431. 2006.
3.	Molina MA, Sáez R, Ramsey EE, et al: NH2-terminal truncated HER2 protein but not full-length receptor is associated with nodal metastasis in human breast cancer. Clin Cancer Res. 8:347–353. 2002.
4.	Christianson TA, Doherty JK, Lin YJ, et al: NH2-terminally truncatedHER2/neu protein: relationship with shedding of the extracellular domain and with prognostic factors in breast cancer. Cancer Res. 58:5123–5129. 1998.
5.	Nahta R and Esteva FJ: HER2 therapy: molecular mechanisms of trastuzumab resistance. Breast Cancer Res. 8:215–222. 2006.
6.	Fujita T, Doihara H, Kawasaki K, et al: PTEN activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing breast cancer open. Br J Cancer. 94:247–252. 2006.
7.	Nagata Y, Lan KH, Zhou X, et al: PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 6:117–127. 2004.
8.	Xia W, Husain I, Liu L, et al: Lapatinib antitumor activity is not dependent upon phosphatase and tensin homologue deleted on chromosome 10 in ErbB2-overexpressing breast cancers. Cancer Res. 67:1170–1175. 2007.
9.	Pérez-Tenorio G, Alkhori L, Olsson B, et al: PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer. Clin Cancer Res. 13:3577–3584. 2007.
10.	Berns K, Horlings HM, Hennessy BT, et al: A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 12:395–402. 2007.
11.	Toi M, Iwata H, Fujiwara Y, et al: Lapatinib monotherapy in patients with relapsed, advanced, or metastatic breast cancer: efficacy, safety, and biomarker results from Japanese patients phase II studies. Br J Cancer. 101:1676–1682. 2009.
12.	Xu BH, Jiang ZF, Chua D, et al: Lapatinib plus capecitabine in treating HER2-positive advanced breast cancer: efficacy, safety, and biomarker results from Chinese patients. Chin J Cancer. 30:327–335. 2011.
13.	Maruyama N, Miyoshi Y, Taguchi T, Tamaki Y, Monden M and Noguchi S: Clinicopathologic analysis of breast cancers with PIK3CA mutations in Japanese women. Clin Cancer Res. 13:408–414. 2007.
14.	Saal LH, Holm K, Maurer M, et al: PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res. 65:2554–2559. 2005.
15.	Scaltriti M, Rojo F, Ocaña A, et al: Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J Natl Cancer Inst. 99:628–638. 2007.
16.	Sperinde J, Jin X, Banerjee J, et al: Quantitation of p95HER2 in paraffin sections by using a p95HER2-specific antibody and correlation with outcome in a cohort of trastuzumab-treated breast cancer patients. Clin Cancer Res. 16:42262010.
17.	Hayashi M, Okumura Y, Osako T, Toyozumi Y, Arima N, Iwase H and Nishimura R: Time to first tumor progression as a predictor of efficacy of continued treatment with trastuzumab beyond progression in human epidermal growth factor receptor2-positive metastatic breast cancer. Int J Clin Oncol. 16:694–700. 2011.
18.	Metro G, Giannarelli D, Gemma D, et al: Time to first tumor progression as outcome predictor of a second trasuzumab-based therapy beyond progression in HER-2 metastatic breast cancer. Breast J. 16:66–72. 2010.
19.	Shousha S: Oestrogen receptor status of breast carcinoma: Allred/H score conversion table. Histopathology. 53:346–347. 2008.
20.	Hennessy BT, Gonzalez-Angulo AM, Stemke-Hale K, et al: Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res. 69:4116–4124. 2009.
21.	Dave B, Migliaccio I, Gutierrez MC, et al: Loss of phosphatase and tensin homolog or phosphoinositol-3 kinase activation and response to trastuzumab or lapatinib in human epidermal growth factor receptor 2-overexpressing locally advanced breast cancers. J Clin Oncol. 29:166–173. 2010.
22.	Yining S, Weidong H, Yuping T, et al: A novel proximity assay for the detection of proteins and protein complexes: quantitation of HER1 and HER2 total protein expression and homodimerization in formalin-fixed, paraffin-embedded cell lines and breast cancer tissue. Diagnostic Molecular Pathology. 18:11–21. 2009.
23.	Loibl S, Bruey J, Von Minckwitz G, et al: Validation of p95HER2 as a predictive marker for trastuzumab-based therapy in primary HER2-positive breast cancer: a translational investigation from the neoadjuvant GeparQuattro study. J Clin Oncol. 29:5302011.
24.	Guarneri V, Frassoldati A, Bottini A, et al: Final results of a phase II randomized trial of neoadjuvant anthracycline-taxane chemo-therapy plus lapatinib, trastuzumab, or both in HER2-positive breast cancer (CHER-LOB trial). J Clin Oncol. 29:5072011.
25.	Biernat W, Duchnowska R, Szostakiewicz B, et al: Quantitative measurements of p95HER2 (p95HER2) and total HER2 (H2T) protein expression in patients with trastuzumab-treated, metastatic breast cancer (MBC): Independent confirmation of clinical cutoffs. J Clin Oncol. 29:5862011.