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Japanese Journal of Clinical Oncology Advance Access originally published online on March 20, 2009
Japanese Journal of Clinical Oncology 2009 39(4):217-224; doi:10.1093/jjco/hyp007
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© The Author (2009). Published by Oxford University Press. All rights reserved

p53 as a Specific Prognostic Factor in Triple-negative Breast Cancer

Byung Joo Chae1, Ja Seong Bae1, Ahwon Lee2, Woo Chan Park1, Young Jin Seo1, Byung Joo Song1, Jung Soo Kim1 and Sang Seol Jung1

1 Department of Surgery, Catholic University of Korea
2 Department of Pathology, Catholic University of Korea, Seoul, Republic of Korea

For reprints and all correspondence: Sang Seol Jung, Department of Surgery, Breast Center, KangNam St Mary's Hospital, 505 Banpo-dong, Seocho-gu, Seoul, Republic of Korea. E-mail: ssjung{at}catholic.ac.kr

Received November 16, 2008; accepted January 11, 2009


   Abstract
TOP
 Abstract
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 References
 
Objective: A recent suggestion is that the predictive value of a single biomarker may rely on the genetic background on the tumor and that different breast cancer subgroups may have different predictive markers of response to chemotherapy. The prognostic value of p53 in the outcome of adjuvant anthracycline-containing chemotherapy was evaluated according to molecular subclasses defined using the expression of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2.

Methods: Subjects were patients (n = 135) with invasive ductal carcinoma treated with adjuvant anthracycline-based chemotherapy between 1994 and 2000 in our hospital. Clinico-pathological features were reviewed by retrospective examination of medical records.

Results: Overall survival rate was not independently predictive by p53 status (P = 0.182). However, in triple-negative cases, there was statistically significant survival difference (P = 0.034) and no statistically significant difference (P = 0.783) in non-triple-negative cases by p53 status. In the Cox proportional hazard analysis, p53 was also strongly predictive for relapse-free survival (P = 0.013) and overall survival (P = 0.049) in triple-negative patients.

Conclusions: p53 status could be a specific prognostic factor in triple-negative breast cancer patients treated by adjuvant anthracycline-based regimen. When p53 is positive in triple-negative breast cancer, we could expect poor survival, prompting aggressive or alternative treatment.

Key Words: breast cancer • p53 protein • anthracycline • prognosis • biologic marker


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 References
 
Combination regimens that include anthracyclines (epirubicin and doxorubicin) and alkylating agents (cyclophosphamide) administered in an adjuvant setting improve overall survival in patients with early breast cancer (1). p53 status has been one of the most investigated predictive biomarkers for the efficacy of anthracycline-containing chemotherapy (2–8). Despite the many studies, results have been inconsistent, with no association between p53 expression and tumor response to neoadjuvant anthracyclines reported (2,6–9), whereas other reports have associated p53 overexpression with both resistance (3–5,10) and sensitivity (11,12) to preoperative anthracycline-containing chemotherapy. There is no unique explanation to account for these inconsistencies. p53 is involved in regulating cell proliferation and apoptosis, and in promoting chromosomal stability. Disruption of these functions appears to play an important role in carcinogenesis. Mutations in the tumor suppressor gene p53 are present in 18–25% of primary breast carcinomas (13,14). Breast cancer encompasses a spectrum of distinct phenotypes with disparate histopathological, clinical and molecular features. The triple-negative subtype of invasive breast cancers is defined by a lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) (15–17). These account for approximately 10–17% of all breast carcinomas (15,17–22) and this subtype is significantly associated with p53 overexpression (23). Recently, it has been suggested that the predictive value of a single biomarker could rely on the genetic background on the tumor and that different breast cancer subgroups may have different predictive markers of response to chemotherapy (24,25).

Presently, we have evaluated the prognostic value of p53 for the outcome of adjuvant anthracycline-containing chemotherapy according to molecular subclasses defined by the expression of ER, PR and HER2.


   PATIENTS AND METHODS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Funding
 References
 
Patients
Patients (n = 135) with invasive ductal carcinoma treated with adjuvant anthracycline-based chemotherapy between 1994 and 2000 in KangNam St Mary's Hospital were enrolled. This study was approved by the Institutional Review Board. Clinico-pathological features of the patients were reviewed by the retrospective review of medical records. All patients were received four- or six-cycle anthracycline-containing chemotherapy.

Tissue Microarrays
To construct the tissue microarray block, 3 mm core biopsies obtained from viable morphologically representative areas of paraffin-embedded tumor tissues were assembled on a recipient paraffin block containing 30 biopsies. This was carried out using a precision instrument (Micro Digital, Gunpo-si, Gyeonggi-do, Republic of Korea). After construction, 5 µm sections were cut and the histology was verified by hematoxylin–eosin staining.

Fluorescence In Situ Hybridization (Fish) of c-erbB2
FISH was performed using the PathVysionTM HER2/CEN probe (Vysis, Downers Grove, IL, USA). The c-erbB2 to chromosome 17 centromere ratio was measured in at least 60 nuclei from the tumor cells, and an average score was taken. More than two copies of c-erbB2 for each chromosome 17 were considered to be a positive sign for c-erbB2 gene amplification.

Immunohistochemistry
Five-micrometer sections of paraffin-embedded tissue arrays were deparaffinized, rehydrated in a graded series of alcohol solutions and microwave-treated for 10 min in a pH 6.0 citrate buffer. The endogenous peroxidase activity was blocked using 0.3% hydrogen peroxide. The tissue arrays were processed in an automatic immunohistochemistry (IHC) staining machine using standard procedures (Lab Vision autostainer; Lab Vision, Fremont, CA, USA) and a ChemMateTM EnVisionTM system (DAKO, Carpinteria, CA, USA). p53 antibody (DO-1; DAKO) was used at a dilution of 1:50. Sections were visualized with 3-3'-diaminobenzidine and counterstained with Mayer's hematoxylin. The p53 expression levels were determined semi-quantitatively based on the positive nuclear staining fraction of tumor cells (score 0 ≤ 10%; score 1 = 11–25%; score 2 = 26–50%; score 3 ≥ 51%) and score 0 considered as negative and score 1, 2 and 3 were considered as positive.

Enzyme Immunoassay
ER and PR status were reviewed by medical records. The receptor status had been determined using a commercial enzyme immunoassay according to the instructions of the manufacturer (Abbott Laboratories, Chicago, IL, USA). A result exceeding 15 fmol/mg was considered positive for the presence of the particular receptor.

Statistical Analyses
The duration of survival was defined as the time from operation to death attributed to breast cancer. The overall survival rate and relapse-free survival rate of each subgroup were estimated by the Kaplan–Meier method and the statistical significance of the difference in survival outcomes among subgroups were evaluated by the log-rank test. To evaluate the relationship between each prognostic variable and survival prognosis, the Cox proportional hazard regression analysis was performed. The relative risks were calculated with 95% confidence intervals. A value of P > 0.05 was regarded as statistically significant.


   RESULTS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Funding
 References
 
Clinico-pathological characteristics of the patients and IHC profiles are summarized in Table 1. There was no statistical difference in distribution for all respective clinico-pathological parameters between the triple-negative and non-triple-negative groups. IHC for p53 was positive for 57 of 135 (42.2%) breast cancer cases. Overexpression of p53 occurred in 13 of 32 (40.6%) patients in the triple-negative group and 44 of 103 (42.7%) patients in the non-triple-negative group. In the triple-negative subgroup, the overall survival rate of p53-positive patients was statistically significantly lower than that of p53-negative patients (P = 0.034; Fig. 1a). In the non-triple-negative subgroup and overall patients group, there was no statistical difference (Fig. 1a and c). Only the triple-negative subgroup showed a statistical difference for relapse-free survival (P = 0.005; Fig. 2).


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  		Table 1. Clinico-pathological features of objective patients

 

Figure 1
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  		Figure 1. Kaplan–Meier overall survival curve. (a) Overall group, (b) triple-negative group and (c) non-triple-negative group.

 

Figure 2
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  		Figure 2. Kaplan–Meier relapse-free survival curve. (a) Overall group, (b) triple-negative group and (c) non-triple-negative group.

 
Table 2 summarizes the risk factors for overall survival and relapse-free survival in the overall patients group. Univariate analysis revealed that nodal status, disease stage, nuclear grade, vein invasion, lymphatic invasion, differentiation and HER2 status had prognostic values for overall survival. In multivariate analysis, vein invasion and lymphatic invasion were implicated as independent prognostic factors. For relapse-free survival, similar results were obtained for overall survival in the univariate analysis, and lymphatic invasion and HER2 status were statistically significant in multivariate analysis.


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  		Table 2. Cox proportional hazard analysis results for the overall patients group

 
In the triple-negative subgroup, p53 status had statistically significant independent prognostic value for relapse-free survival [P = 0.013, RR 5.4 (1.4–20.8)], but, for overall survival, p53 status was significant only in the univariate analysis (Table 3). In the non-triple-negative subgroup, vein invasion was a prognostic factor for overall survival and tumor size, and differentiation was a prognostic factor for relapse-free survival (Table 4).


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  		Table 3. Cox proportional hazard analysis results for the triple-negative subgroup

 

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  		Table 4. Cox proportional hazard analysis results for the non-triple-negative subgroup

 

   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Funding
 References
 
The class discovery expression profile studies pioneered by the Stanford group (26–28) have demonstrated that the well-established morphological and immunohistochemical phenotypic heterogeneity of breast cancer can be confirmed and systematically reclassified into five main groups at the transcription level (26,27). Given that basal-like cancers are preferentially ER-, PR- and HER2-, it has been claimed that the basal-like tumors composed almost entirely of triple-negative phenotype could reliably be used as a surrogate for basal-like breast cancer (18). Despite the controversy regarding the similarities between basal-like and triple-negative cancers, the latter group is of clinical relevance, as chemotherapy is currently the only modality of systemic therapy available for patients with triple-negative cancers. Triple-negative cancers display more aggressive clinical behavior, distinctive metastatic patterns and poorer prognosis when compared with other breast cancer subtypes (22). Thus, it is of the highest importance to elucidate prognostic factors and key biomarkers of triple-negative cancers. To this end, we presently sought to evaluate the relevance of p53 in triple-negative breast cancers in comparison to non-triple-negative cancers.

Heterogeneity of breast cancer molecular subclasses among studies could account for the heterogeneity of results when the predictive value of a single biomarker is investigated (25,29). In addition, p53+/triple-negative tumors exhibit a higher rate of pCR (22%) when compared with both p53–/triple-negative (10%) and non-triple-negative tumors in neoadjuvant settings (25,29). Likewise, the present results implicate p53 status as having prognostic value in the treatment of triple-negative breast cancer using adjuvant anthracycline-containing chemotherapy. However, the present study differs from previous observations in several ways. First, our study was done in the adjuvant setting, so an immediate response could not be discerned. Second, the outcome of anthracycline-containing chemotherapy differs from that reported previously (29). Our results indicate that overall survival and relapse-free survival rate of patients overexpressing p53 are worse than patients harboring triple-negative breast cancer cells. In other words, p53 in the triple-negative breast cancer was a poor prognostic factor in our study. In thinking about the past inconsistencies of study results, we are prompted by our present observations to suggest that p53-positive, triple-negative breast cancer carries a poor long-term outcome, even if the cancer displays an initially higher response rate for anthracycline-containing regimens. This paradox is consistent with the data suggesting that the result of higher sensitivity to neoadjuvant anthracycline in subtypes known to have a poor prognosis is explained by the high relapse among those with residual disease (30), and that triple-negative phenotype is associated with shorter survival despite being associated with a higher response rate to neoadjuvant chemotherapy (31).

There have been many studies concerning the predictive role of p53 for anthracyclines (2–8). However, most of these were preclinical studies or were in a neoadjuvant setting. The present study is the first to evaluate the subclass-specific prognostic value of p53 for the outcome of adjuvant anthracycline-containing chemotherapy. In contrast to previous observations (23), our results demonstrate that p53 expression rate of triple-negative breast cancer is similar to non-triple-negative cancer (40.6% versus 42.7%). A principle explanation for the discrepancies reported to date concerns the various methods used to assess p53 status. Other explanations (and limitations) for our findings are that our sample size was small and involved a retrospective examination. Nevertheless, the present and previous studies agree that the predictive role of p53 involves a complex interplay between the genetic background and molecular classification.

In conclusion, we have found that p53 status is a strong prognostic factor for relapse-free survival and overall survival only for the triple-negative group in patients treated with adjuvant anthracycline-containing chemotherapy. Under these treatment conditions, expression of p53 could provide information concerning a poor outcome in triple-negative breast cancer. In such cases, consideration might well be given to more aggressive or alternative treatment such as Bevacizumab or dasatinib. There is no definite answer to optimal management of triple-negative tumors at this moment. However, this is a field that is rapidly evolving and evidence-based answers may emerge in the near future.


   Funding
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
References
 
This manuscript was supported by a grant from research fund donated by Gangneung Dong-In hospital.

Conflict of interest statement

None declared.


   References
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 References
 
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