Purpose: Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer. Nuclear expression of p53 protein in breast cancer correlates with more aggressive tumors. We retrospectively analyze the expression of p53 as a prognostic marker to predict pathological complete response and survival in patients with IBC.

Experimental Design: Fifty-nine patients with IBC were treated from January 1994 to April 2000. Forty-eight patients were included. Diagnostic core biopsies were taken before treatment was started. Expression of hormone receptors and p53 was determined by immunohistochemistry. All patients received an anthracycline-based regimen preoperatively; 22 patients (46%) also received paclitaxel. Forty-four patients (92%) achieved an objective clinical response and underwent mastectomies.

Results: Median age at diagnosis was 48 years. Thirty patients (63%) had hormone receptor-negative tumors. Twenty-eight patients (58%) had p53-positive tumors, and 20 patients (42%) had p53-negative tumors. Nine patients (19%) achieved a pathological complete response. At a median follow-up of 77 months, 28 recurrences (58%) and 26 deaths (54%) had occurred. Patients with p53-positive tumors were younger (P = 0.02) and tended to have lower 5-year progression-free survival rates (35% versus 55%; P = 0.3) and overall survival rates (44% versus 54%; P = 0.4).

Conclusions: This retrospective analysis demonstrates that nuclear p53 protein expression may represent an adverse prognostic marker in IBC and may provide a valuable tool for selecting treatment for this aggressive disease.

Inflammatory breast cancer (IBC) is the most aggressive form of primary breast cancer. It is rare, with an incidence rate of 1% to 6% in the United States (1). However, data from the Surveillance, Epidemiology and End Results Program comparing trends and patterns for breast cancer revealed that the incidence of IBC has increased from 0.3 to 0.7 case per 100,000 person-years (1). Compared with non-IBC stage II breast cancer, primary IBC is associated with lower overall survival (OS) rates (2, 3).

IBC is a clinical diagnosis characterized by the presence of symptoms and signs such as erythema, tenderness, edema, pain, and ulceration that rapidly extend to the entire breast (4, 5). Pathologically, IBC is frequently diagnosed by the presence of cancer cells penetrating dermal lymphatic channels (Fig. 1), causing the inflammatory signs (6).

The management of IBC has evolved over the past 25 years. A multidisciplinary approach has improved both local control and survival, with about 30% of patients living more than 5 years (7, 8). Primary chemotherapy (PC) is considered to be the main component of the treatment. The presence of pathological residual disease in the breast and lymph nodes after PC is considered an important adverse prognostic factor (7, 8, 9).

Missense mutations of the p53 gene and cytoplasmic sequestration are thought to be the main mechanism behind the inactivation of p53 protein and loss of function in IBC (10, 11). Nuclear expression of mutated p53 in breast cancer has been associated with more aggressive tumors, early metastases, anthracycline resistance, and less favorable long-term outcome (12). The prognostic role of p53 expression and/or mutation in IBC has not been clearly established. Higher levels of nuclear p53 expression have been detected in IBC compared with other locally advanced breast cancers (13, 14, 15). Only one report describes an association between poor prognoses and p53 mutation and nuclear overexpression of the p53 protein in a relatively small group of patients with primary IBC (16). We retrospectively analyzed whether the nuclear expression of p53 protein predicts for pathological complete response (pCR) and is a prognostic marker for disease recurrence and survival for patients with IBC.

Study Population.

Fifty-nine patients with IBC identified through the University of Texas M. D. Anderson Cancer Center Breast Cancer Management System Database were treated between January 1994 and April 2000 in clinical trials at The University of Texas M. D. Anderson Cancer Center. Diagnostic biopsies were taken before treatment was started. All investigations were performed after approval by the institutional review board. Forty-eight patients for whom biopsy specimens and adequate follow-up data were available were included in this study.

Clinical diagnosis of IBC required the presence of erythema, heat, ridging, and peau d’orange with or without evidence of dermal lymphatic invasion on pathological evaluation. All patients were presented at the Breast Center’s multidisciplinary conference to confirm their diagnosis of primary IBC and later to assess their response to treatment. Patients were treated with PC and then underwent mastectomy if they achieved an objective clinical remission (partial or complete response). After surgery, patients received adjuvant radiotherapy and hormonal treatment with tamoxifen if their disease was hormone receptor positive. In all patients, PC included an anthracycline-based therapy with of 5-fluorouracil (500 mg/m2), doxorubicin (500 mg/m2), and cyclophosphamide (500 mg/m2) [FAC] every 21 days. Twenty-two patients (46%) also received paclitaxel (175–250 mg/m2) every 21 days (17). Forty-four patients (92%) obtained objective clinical responses (partial or complete response) and underwent mastectomies. After mastectomy, 16 patients received adjuvant paclitaxel.

Tumor Response.

Extent of primary tumor and regional lymph node involvement was measured at the time of presentation using mammography, clinical examination, and ultrasonography. The same methods were used to monitor response to PC. Clinical response was documented and classified as follows: a complete response was defined as complete disappearance of evident disease for at least 4 weeks based on physical exam, ultrasound, and X-ray. A partial response was a >50% decrease of bidimensionally measurable disease for at least 4 weeks. Stable disease was defined as a change in measurable disease that was too small to be called a partial response or progressive disease, with no new lesions appearing for a period of at least 4 weeks. Progressive disease required an unequivocal 50% or greater increase in the size of any measurable lesion (two diameters), the worsening of existing lesions, the appearance of new lesions, or deterioration of symptoms related to cancer. Clinical assessment was recorded monthly, and complete tumor assessment was repeated before surgery. Surgical specimens were histologically examined to determine pCR. A pCR was defined as the absence of invasive disease in the breast and the axillary lymph nodes at the time of definitive surgery.

Immunohistochemistry Methods.

Forty-eight paraffin-embedded tissue samples were available for the study. Histologic sections of 4-μm thickness were cut from paraffin blocks and incubated overnight at 4°C with a 1:50 dilution of the human-specific monoclonal antibody DO7 (Dako, Carpinteria, CA), which recognizes mutant forms of the p53 protein. Sections from breast cancers with known p53 mutation and immunoreactivity and sections from normal breast tissue were included as positive and negative controls to confirm the consistency of the analysis. A specimen was scored as positive (Fig. 2) when nuclear staining was equal to or greater than 10% (18, 19). The estrogen receptor (ER) status and progesterone receptor (PR) status were available by immunohistochemical stain for 45 patients. Immunohistochemistry was performed following standard procedures on 4-μm sections of paraffin-embedded tissue with monoclonal antibody 6F11 (Novocastra Laboratories Ltd., Burlingame, CA) for ER and monoclonal antibody 1A6 (Novocastra Laboratories Ltd.) for PR. Nuclear staining equal to or greater than 10% was considered positive.

Statistical Methods.

The patient population was described by tabulating categorical variables with p53 status (Table 1). A χ2 test was used to evaluate the significance of differences between the variables. The Kaplan-Meier product limit method was used to assess differences between both OS and progression-free survival (PFS) rates of the two groups and, after adjustment for ER and PR status, nuclear grade and pCR. The log-rank test and the stratified log-rank test were used to compare survival estimates between the groups. OS was measured in months from the date of diagnosis to the date of death or last follow-up. PFS was measured in months from the date of diagnosis to the date of recurrence or last follow-up. Statistical analyses were carried out using SPSS software version 12.0 (SPSS Inc., Chicago, IL).

The median age of the patients was 48 years (range, 29–71 years), and 77% were Caucasian. Hormone receptor status results were available in 45 cases (94%), and 30 patients (67%) had hormone receptor-negative disease. Twenty-eight patients (58%) had nuclear p53-positive tumors, and 20 patients (42%) had p53-negative tumors. There were no cytoplasmic p53-positive tumors. Patients with p53-positive tumors tended to be younger (median age, 45.2 versus 52.2 years; P = 0.02) and have tumors with high nuclear grade (85% versus 61%; P = 0.09). Hormone receptor status was available in 45 patients and inversely correlated with p53 expression (P = 0.02): 23 of 26 (88%) p53-positive tumors were ER negative, and 24 of 26 (92%) p53-positive tumors were PR negative. There were no differences in histology, presence of lymphovascular invasion, or race between the two groups.

Nine patients (19%) achieved a pCR. Pathological complete response was not associated with p53 expression: four patients who achieved pCR had p53-negative tumors, and the remaining five patients had p53-positive tumors. The use of neoadjuvant or adjuvant taxanes between the two groups did not differ significantly. At a median follow-up of 77 months, 28 recurrences (58%) and 26 deaths (54%) had occurred.

The estimated 5-year PFS rate was 35% for patients with p53-positive tumors versus 55% for patients with p53-negative IBC (P = 0.33; Fig. 3). Similarly, the estimated 5-year OS rate was 44% among patients with p53-positive IBC and 54% among patients with p53-negative disease (P = 0.4; Fig. 4). Significantly, patients with p53-positive IBC had a 55% higher risk of dying from their disease (hazard ratio, 1.55) than patients with p53-negative disease.

Kaplan-Meier product limit estimates of OS and PFS were also done after adjustment for hormone receptor status and nuclear grade; similar trends were observed (Tables 2 and 3). In patients with hormone receptor-negative tumors, the 5-year estimated OS rate was 38% for the p53-positive group and 56% for the p53-negative group. The 5-year estimated PFS rates were 33% and 44%, respectively. In patients with modified Black’s nuclear grade 3 tumors, the 5-year estimated OS rate was 37% for the p53-positive group and 53% for the p53-negative group. The 5-year PFS rates were 25% and 55%, respectively.

The prognostic interaction between pCR and p53 status was also analyzed (Figs. 5 and 6); although p53 status did not influence pCR rate, pCR remains the strongest predictor of long-term outcome. The estimated 5-year PFS and OS rates were, respectively, 78% and 86% for patients who achieved a pCR compared with 36% and 40% for patients who did not. Overexpression of p53 was associated with a higher rate of recurrence and death even in patients who obtained a pCR. Interestingly, there were two recurrences (40%) and one death (20%) among the patients with p53-positive tumors. There were no recurrences or deaths in the p53-negative group (P = 0.3 and 0.5, respectively).

Our retrospective data suggested that patients with p53-positive IBC have a less favorable prognosis, as demonstrated by the shorter OS and PFS rates, than patients with p53-negative IBC. The differences were not statistically significant, most likely because of the small number of cases studied, a common limitation in IBC studies. The adjustments for hormone receptor status and nuclear grade were also limited by the number of cases.

Several studies have investigated the incidence of p53 overexpression in breast cancer, including locally advanced disease (20, 21, 22). Faille et al. (14) performed an initial analysis of alterations in p53 in 39 patients with locally advanced breast cancer; the majority of these patients had inflammatory changes. The authors found that the presence of a p53 mutation was significantly associated with larger tumor diameter (P = 0.0062) and evidence of metastatic disease (P = 0.0015). Also, a nonsignificant association existed between the mutation and negative ER status and lower response rates to therapy (14). Aziz et al. (13) compared the level of p53 expression in 40 IBC patients with that in non-IBC controls: p53 was expressed in 70% of patients with IBC and in 48% of non-IBC controls (P = 0.0238). The authors hypothesized that the clinical aggressiveness of IBC may be due to overexpression of p53 (13). More recently, McCarthy et al. (15) again showed overexpression of p53 nuclear protein in 24 (53%) of IBC tumors compared with 8 (36%) of 22 non-IBC tumors; however, the difference was not statistically significant (P = 0.19). Nuclear exclusion and cytoplasmic sequestration of p53 have been described as the potential mechanisms of protein function inactivation; this phenomenon has been found to occur in 37% of IBCs (13, 15). These observations have not been confirmed by subsequent studies. In the small cohort reported by Riou et al., (26) tissue for 24 patients with IBC was tested for p53 gene mutation and nuclear overexpression of p53 protein. Overexpression of p53 was not found to be associated with any of the main pathobiologic characteristics, including age, tumor size, histologic grade, inflammation, and hormone receptor and c-erbB2 status. Multivariate analysis indicated that patients with tumors overexpressing p53 had an 8.6-fold higher risk of death (P = 0.02). This prognostic value was observed even in the ER-negative group (16).

Our study confirmed that the most important prognostic factor for survival in IBC is pCR after PC (7, 8, 23, 24, 25). Interestingly, when PFS and OS were analyzed among patients who achieved a pCR, all of the recurrences and deaths occurred in the group of patients with p53-positive tumors. This important observation suggested that patients with p53-overexpressing IBC have a particularly aggressive form of IBC and that their risk of death from the disease is only marginally reduced by an excellent response to PC. In contrast, patients with IBC who do not have dysfunctional p53 protein expression have a better prognosis when treated with optimal systemic and locoregional treatments and may have a higher chance of cure if they achieve a pCR.

Larger prospective studies need to be performed to confirm these observations and to contribute to a better understanding of the peculiar biology of this particularly aggressive form of breast cancer. Only through coordinated multidisciplinary and multicenter efforts will it be possible to develop more specific and targeted treatments able to significantly affect the prognosis of these patients.

Fig. 1.

Tissue section showing IBC with prominent involvement of vascular spaces.

Fig. 1.

Tissue section showing IBC with prominent involvement of vascular spaces.

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Fig. 2.

Immunostain for p53 showing strong positive nuclear staining of the tumor cells.

Fig. 2.

Immunostain for p53 showing strong positive nuclear staining of the tumor cells.

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Fig. 3.

Kaplan-Meier estimates of the PFS of patients with IBC by p53 status.

Fig. 3.

Kaplan-Meier estimates of the PFS of patients with IBC by p53 status.

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Fig. 4.

Kaplan-Meier estimates of the OS of patients with IBC by p53 status.

Fig. 4.

Kaplan-Meier estimates of the OS of patients with IBC by p53 status.

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Fig. 5.

Kaplan-Meier estimates of the PFS of patients with IBC by p53 status and pathological response (pCR versus no pCR).

Fig. 5.

Kaplan-Meier estimates of the PFS of patients with IBC by p53 status and pathological response (pCR versus no pCR).

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Fig. 6.

Kaplan-Meier estimates of the OS of patients with IBC by p53 status and pathological response (pCR versus no pCR).

Fig. 6.

Kaplan-Meier estimates of the OS of patients with IBC by p53 status and pathological response (pCR versus no pCR).

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Grant support: The Nellie B. Connally Breast Cancer Research Foundation and the Susan G. Komen Breast Cancer fellowship.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Requests for reprints: Massimo Cristofanilli, Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 424, Houston, TX 77030. Phone: 713-792-2817; Fax: 713-794-4385; E-mail: mcristof@mdanderson.org

Table 1

Patient characteristics

Overall no. of patients (%)p53 negativep53 positiveP
Total 48 20 28  
Age (y)     
 <50 28 (58) 9 (45) 19 (68)  
 >50 20 (42) 11 (55) 9 (32) 0.11 
Race     
 Asian 2 (4) 1 (5) 1 (4)  
 Black 3 (6) 1 (5) 2 (7)  
 Hispanic 6 (13) 3 (15) 3 (11)  
 Caucasian 37 (77) 15 (75) 22 (79) 0.43 
Lymphovascular invasion     
 No 2 (6) 0 (0) 2 (12)  
 Yes 29 (94) 14 (100) 15 (88) 0.49 
Nuclear grade     
 2 11 (24) 7 (39) 4 (15)  
 3 34 (76) 11 (61) 23 (85) 0.09 
Histology     
 Ductal 41 (89) 16 (84) 25 (93)  
 Lobular 4 (9) 3 (16) 1 (4)  
 Metaplastic 1 (2) 0 (0) 1 (4) 0.29 
ER     
 Negative 32 (58) 9 (47) 23 (64)  
 Positive 23 (42) 10 (53) 13 (36) 0.003 
PR     
 Negative 37 (82) 13 (68) 24 (92)  
 Positive 8 (18) 6 (32) 2 (8) 0.05 
Taxane use     
 No 10 (21) 5 (25) 5 (18)  
 Yes 38 (79) 15 (75) 23 (82) 0.72 
pCR     
 Yes 9 (19) 4 (20) 5 (18)  
 No 39 (81) 16 (80) 23 (82) 1.00 
Overall no. of patients (%)p53 negativep53 positiveP
Total 48 20 28  
Age (y)     
 <50 28 (58) 9 (45) 19 (68)  
 >50 20 (42) 11 (55) 9 (32) 0.11 
Race     
 Asian 2 (4) 1 (5) 1 (4)  
 Black 3 (6) 1 (5) 2 (7)  
 Hispanic 6 (13) 3 (15) 3 (11)  
 Caucasian 37 (77) 15 (75) 22 (79) 0.43 
Lymphovascular invasion     
 No 2 (6) 0 (0) 2 (12)  
 Yes 29 (94) 14 (100) 15 (88) 0.49 
Nuclear grade     
 2 11 (24) 7 (39) 4 (15)  
 3 34 (76) 11 (61) 23 (85) 0.09 
Histology     
 Ductal 41 (89) 16 (84) 25 (93)  
 Lobular 4 (9) 3 (16) 1 (4)  
 Metaplastic 1 (2) 0 (0) 1 (4) 0.29 
ER     
 Negative 32 (58) 9 (47) 23 (64)  
 Positive 23 (42) 10 (53) 13 (36) 0.003 
PR     
 Negative 37 (82) 13 (68) 24 (92)  
 Positive 8 (18) 6 (32) 2 (8) 0.05 
Taxane use     
 No 10 (21) 5 (25) 5 (18)  
 Yes 38 (79) 15 (75) 23 (82) 0.72 
pCR     
 Yes 9 (19) 4 (20) 5 (18)  
 No 39 (81) 16 (80) 23 (82) 1.00 
Table 2

PFS by p53 status, hormone receptor status, nuclear grade, and pCR

No. of patientsNo. of events5-year PFSP
Estimate95% CI
All patients      
 p53 negative 20 10 55% 37–82  
 p53 positive 28 18 35% 21–59 0.33 
Hormone receptor negative      
 p53 negative 44% 21–92  
 p53 positive 21 14 33% 18–61  
Hormone receptor positive      
 p53 negative 10 60% 36–100  
 p53 positive 40% 14–100 0.61 
Nuclear grade 2      
 p53 negative 57% 30–100  
 p53 positive 75% 43–100  
Nuclear grade 3      
 p53 negative 11 55% 32–94  
 p53 positive 23 17 25% 12–52 0.33 
No pCR      
 p53 negative 16 10 44% 25–76  
 p53 positive 23 16 30% 16–56  
pCR      
 p53 negative    
 p53 positive 60% 29–100 0.38 
No. of patientsNo. of events5-year PFSP
Estimate95% CI
All patients      
 p53 negative 20 10 55% 37–82  
 p53 positive 28 18 35% 21–59 0.33 
Hormone receptor negative      
 p53 negative 44% 21–92  
 p53 positive 21 14 33% 18–61  
Hormone receptor positive      
 p53 negative 10 60% 36–100  
 p53 positive 40% 14–100 0.61 
Nuclear grade 2      
 p53 negative 57% 30–100  
 p53 positive 75% 43–100  
Nuclear grade 3      
 p53 negative 11 55% 32–94  
 p53 positive 23 17 25% 12–52 0.33 
No pCR      
 p53 negative 16 10 44% 25–76  
 p53 positive 23 16 30% 16–56  
pCR      
 p53 negative    
 p53 positive 60% 29–100 0.38 

Abbreviation: CI, confidence interval.

Table 3

OS by p53 status, hormone receptor status, nuclear grade, and pCR

No. of patientsNo. of events5-year OSP
Estimate95% CI
All patients      
 p53 negative 20 10 54% 35–82  
 p53 positive 28 16 44% 27–70 0.4 
Hormone receptor negative      
 p53 negative 56% 31–100  
 p53 positive 21 13 38% 21–69  
Hormone receptor positive      
 p53 negative 10 48% 25–94  
 p53 positive 75% 43–100 0.73 
Nuclear grade 2      
 p53 negative 57% 30–100  
 p53 positive 67% 30–100  
Nuclear grade 3      
 p53 negative 11 53% 30–94  
 p53 positive 23 15 37% 21–67 0.51 
No pCR      
 p53 negative 16  41% 22–76  
 p53 positive 23  40% 23–68  
pCR      
 p53 negative     
 p53 positive  67% 30–100 0.51 
No. of patientsNo. of events5-year OSP
Estimate95% CI
All patients      
 p53 negative 20 10 54% 35–82  
 p53 positive 28 16 44% 27–70 0.4 
Hormone receptor negative      
 p53 negative 56% 31–100  
 p53 positive 21 13 38% 21–69  
Hormone receptor positive      
 p53 negative 10 48% 25–94  
 p53 positive 75% 43–100 0.73 
Nuclear grade 2      
 p53 negative 57% 30–100  
 p53 positive 67% 30–100  
Nuclear grade 3      
 p53 negative 11 53% 30–94  
 p53 positive 23 15 37% 21–67 0.51 
No pCR      
 p53 negative 16  41% 22–76  
 p53 positive 23  40% 23–68  
pCR      
 p53 negative     
 p53 positive  67% 30–100 0.51 

Abbreviation: CI, confidence interval.

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