Association between c-myc amplification and pathological complete response to neoadjuvant chemotherapy in breast cancer
Introduction
The c-myc gene encodes nuclear DNA binding proteins that regulate the expression of a variety of genes implicated in cell proliferation, apoptosis, metabolism, stemness, invasiveness and inhibition of differentiation.1, 2 Since amplification of c-myc has been observed in a significant proportion (8–37%) of primary human breast cancers, it is thought that c-myc is involved in the development and progression of breast cancer.3, 4 Rose-Hellekant and Sandgren have reported that c-myc transgenic mice develop mammary tumours5, a direct indication of an important role for c-myc in mammary carcinogenesis.
Since c-myc promotes tumour cell proliferation and invasiveness, both of which are typical features often associated with biological aggressiveness, it is speculated that breast tumours with c-myc amplification have a poor prognosis. In fact, it has been reported by several investigators that breast tumours with c-myc amplification are more likely to be oestrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and to have a high histological grade and a significant association with poor prognosis.6, 7, 8
Interestingly, c-myc has a dual function, i.e. it promotes cell apoptosis as well as proliferation.9 Since rapidly proliferating cells are generally more sensitive to chemotherapy and since it has been reported that c-myc sensitises tumour cells to apoptosis induced by chemotherapy,10, 11 it is hypothesised that breast tumours with c-myc amplification are more sensitive to chemotherapy than those without such amplification. The association between c-myc amplification and response to chemotherapy has been mostly studied in vitro, and greater sensitivity of breast tumour cells with c-myc amplification to paclitaxel has been reported by Olah et al.12 and to doxorubicin by Fornari et al.13, 14
These in vitro results regarding the association between c-myc amplification and response to chemotherapy prompted us to investigate whether such an association can be observed in human breast cancer, for such investigation has rarely been conducted.15, 16 First, the development of clinically useful predictors for response to chemotherapy in breast cancer is very important since no such predictors are currently available. In the study presented here, we investigated whether c-myc amplification can predict the response to neoadjuvant chemotherapy consisting of paclitaxel followed by 5-FU/epirubicin/cyclophosphamide, which is one of the most commonly used chemotherapeutic regimens for human breast cancer.
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Patients and tumour samples
During the period of from 2004 to 2009, 125 patients (stage II/III) were treated with neoadjuvant chemotherapy [paclitaxel (80 mg/m2) q1w × 12 cycles followed by 5-FU (500 mg/m2)/epirubicin (75 mg/m2)/cyclophosphamide (500 mg/m2) q3w × 4 cycles] (P-FEC) followed by surgery. Before neoadjuvant chemotherapy, each patient underwent tumour biopsy with a vacuum-assisted core biopsy (8G) (Mammotome®; Ethicon Endosurgery, Cincinnati, OH, USA) under ultrasonographic guidance. Of these 125 patients, Mammotome
C-myc amplification and clinicopathological parameters
Representative results of FISH examination of c-myc are shown in Fig. 1, and the relationships between c-myc amplification and the various clinicopathological parameters of breast tumours are listed in Table 1. Breast tumours with c-myc amplification were significantly more likely to be ER-negative tumours (P = 0.004) and tended to be PR-negative (P = 0.059). Further, breast tumours with c-myc amplification were significantly more likely to be of a high histological grade (P = 0.043) and TOP2A-high (P
Discussion
In the study reported here, we first examined the relationship between c-myc amplification and the various clinicopathological characteristics in breast tumours, and detected associations between c-myc amplification and ER negativity, PR negativity, high histological grade, TOP2A positivity and Ki67 positivity. These results are essentially consistent with those previously reported,8, 21 suggesting that breast tumours with c-myc amplification harbour biologically aggressive phenotypes. In fact,
Conflict of interest statement
S. Noguchi received research grants from Pfizer and Bristol-Myers Squibb, and honoraria from Pfizer.
Acknowledgements
This work was supported in part by Grants-in-Aid from the Comprehensive 10-Year Strategy for Cancer Control program of the Ministry of Health, Labour and Welfare, Japan.
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