Abstract

Background: This study aimed to identify prognostic factors for outcome in Tunisian patients with nonmetastatic inflammatory breast cancer (IBC) receiving multimodality therapy.

Patients and methods: From 1994 to 2000, 100 patients with nonmetastatic IBC were reviewed. Patients underwent neo-adjuvant chemotherapy including anthracyclines (99%), then mastectomy (93%) when feasible, radiotherapy (83%) and adjuvant chemotherapy (84%). Sixty patients (60%) had hormone therapy.

Results: Median age at diagnosis was 44 years (range 23–71). Seventy patients had premenopausal status (70%). Ten cases occurred during pregnancy (10%). Body mass index indicated overweight or obesity in 76 patients (76%). After neo-adjuvant chemotherapy, pathologic complete response (pCR) rate was 20%. Median time of follow-up for surviving patients was 44 months. Median progression-free survival (PFS) was 19 months and overall survival (OS) 30 months. Factors associated with improved survival were no pregnancy (P = 0.0095), estrogen receptor positivity (P = 0.028), tumor size <5 cm (P = 0.021), clinical complete response (cCR) (P = 0.022), pCR (P = 0.011), negative nodes (P = 0.053) and hormone therapy (P < 0.001). In multivariate analysis, cCR, negative nodes and hormone therapy were independently associated with better OS and PFS. Factors predictive to pCR were age >45 years, negative nodes and cCR.

Conclusions: Tunisian patients with IBC have particular epidemiologic characteristics, with earlier disease and context of overweight and obesity, but prognostic factors are similar to those reported in the literature. Hormone therapy seems to improve patient outcome.

Introduction

Inflammatory breast cancer (IBC) appears to be the most aggressive presentation of primary breast cancer. Rapid disease progression and early distant dissemination are well-described hallmarks of IBC, and hence prognosis is worse than in non-IBCs. Clinically, IBC is characterized by diffuse erythema and edema of the skin of the breast, called ‘peau d'orange’, with or without associated palpable mass. The clinical appearance is due to pathologic plugging of the dermal lymphatics of the breast with tumor emboli but its documentation is not necessary for a diagnosis of inflammatory breast carcinoma [1].

IBC is a relatively rare form of breast cancer. Possibly because of varying case definitions, population-based estimates for IBC incidence range widely from <1% to 10%. Using data of the Surveillance, Epidemiology and End Results (SEER) program on the basis of a more conservative definition of IBC, the international classification of disease for oncology (ICD-O-2) has shown an incidence of 0.5% and 0.7% in white and black women, respectively [2]. More recently, population-based studies conducted in the USA have indicated that IBC accounts for 1%–1.3% of all breast cancers [3].

In Tunisia, a high incidence of IBC was reported in the 1970s, with numbers up to 50% [4]. This incidence was calculated using the French PEV (for ‘poussée evolutive’) breast cancer classification system [5]. IBC corresponded to PEV2 or PEV3, but most PEV2 cases, defined as tumors with associated inflammatory signs involving the skin of less than half of the breast surface, were actually neglected tumors. Since the 1990s, we have used the International union against cancer T4d definition, and only PEV3 tumors have been considered as true IBC. An epidemiologic study which reviewed all new cases of breast cancer diagnosed in 1994 in the country reported an incidence of IBC cases up to 6.2% [6].

The management of IBC has substantially evolved over the past three decades. Before the availability of combination chemotherapy, IBC was almost uniformly fatal. Local treatment modalities alone—surgery, radiotherapy (RT) or surgery and RT—achieved >5% 5-year disease-free survival (DFS). The addition of systemic chemotherapy to locoregional therapy improved patient DFS rates up to 30%–50% at 5 years [7, 8]. The current strategy combining neo-adjuvant chemotherapy with anthracycline-based regimens followed by radical mastectomy and RT has proved successful. The outcome of patients with IBC, however, remains worse than with other breast cancers.

At the Salah Azaiz Institute [National Cancer Institute (NCI) of Tunisia], we have significant experience with this rare disease, with ∼30 new cases each year [9]. Since the 1970s, different combined modality protocols have been used [10–12].

The aim of the current study was to describe the clinicopathologic characteristics of a relatively large and homogeneous series of true nonmetastatic IBC patients over a period of 7 years, and to analyze prognostic factors and survival in the context of multimodality therapy.

patients and methods

patient population

The medical records of 100 patients with IBC treated with curative intent at the Salah Azaiz Institute from 1994 to 2000 were reviewed. IBC cases were identified according to consistent inclusion criteria on the basis of the signs of inflammation (i.e. erythema, skin edema or peau d'orange and ridging) confirmed by biopsy (i.e. microscopic identification of carcinoma with or without malignant invasion of the breast dermal lymphatic ducts). Staging work-up included clinical examination, chest X-radiograph, bone scintigraphy and abdominal ultrasound. Patients with supraclavicular metastases at the time of diagnosis were excluded, consistent with the fifth edition of the American Joint Committee on Cancer (AJCC) classification system [13]. Baseline clinicopathologic information was collected at the time of diagnosis, before treatment. The database included patient age, clinical presentation, clinical lymph node stage, menopausal status (pre- or postmenopausal), estrogen receptor (ER) status, pathologic type and pathologic axillary lymph node involvement. A context of pregnancy was noted if the discovery of the tumor occurred during pregnancy or lactation. Patient height and weight at diagnosis were used to calculate the body mass index (BMI) obtained by dividing the weight in kilograms by the square of height in meters (kg/m2). Women were classified as obese if BMI was ≥30 kg/m2, overweight if BMI was between 25 and 30 kg/m2 (i.e. 25 ≤ BMI ≤ 30) and normal/lean if BMI was ≤25 kg/m2 according to the criteria of the US National Institute of Health/National Heart Lung and Blood Institute (NCI/NHLBI) [14].

Pathologic response was assessed for 93 patients who underwent surgery after neo-adjuvant chemotherapy using Chevallier classification [15], and pathologic complete response (pCR) was defined as grade 1.

treatment

Of the 100 patients, 99 received anthracycline combination chemotherapy based upon either epirubicin (FEC 100, FEC 75 or FEC-HD) or doxorubicin (FAC 50). Patients included in the GC303 trial (n = 36) [12] were randomized to receive four cycles of FEC-HD (n = 20) or FEC 75 (n = 16). The other patients received a maximum of six cycles.

Following completion of chemotherapy, patients received locoregional therapy as follows: all patients were offered radical mastectomy and homolateral axillary clearance when feasible (n = 93). Locoregional RT was delivered to the internal mammary chain, the chest wall and the supraclavicular area after surgery (n = 81) or after neo-adjuvant chemotherapy (n = 3) when surgery was impossible (tumor adherence to chest wall). Maintenance chemotherapy was administered to 84 patients. Patients included in the CG303 trial received four cycles of FEC 75. The other patients received FEC 100 (n = 40), FAC (n = 6), navelbine–cisplatin (n = 1) and docetaxel (n = 1). In summary, 79 patients received trimodality treatment (neo-adjuvant chemotherapy, mastectomy and RT). Patients with unknown or positive ER status (n = 60) received adjuvant hormone therapy consisting of tamoxifen alone (20 mg/day for a period of 5 years) (n = 31), tamoxifen associated with ovarian ablation/suppression (n = 15) or ovarian ablation/suppression alone (n = 14).

statistical analysis

All assessable patients were entered into the analysis using SPSS 12.0 software (SPSS, Inc., Chicago, IL). Median follow-up time corresponded to the median time of follow-up for living patients. Progression-free survival (PFS) was defined as the time from diagnosis to first recurrence (local, regional or distant) or death for any cause. Overall survival (OS) was defined as the time from diagnosis to death or last contact. Survival estimates were computed using the Kaplan–Meier method, with comparison between curves calculated by the log-rank test. For survival analysis, potential continuous explanatory variables were converted to categorical data using median values as cut-off points. The prevalence of the following prognostic factors was analyzed: age, pregnancy, menopausal status, BMI, clinical response, pathologic response, nodal stage, neo-adjuvant chemotherapy regimen and hormone therapy. For multivariate analysis of survival, after comparing ln–ln survival curves to check the proportional hazards assumption, we used Cox proportional hazards modeling and the likelihood ratio to evaluate survival differences between the different groups (backward Wald method). A setup procedure was used and variables were added to the model if the two-sided significance level was <0.1 in univariate analysis. To control for potential confounding factors, we adjusted hazard ratio (HR) estimates per chemotherapy protocol and hormone therapy, whether these factors were statistically significant in the model or not.

We also evaluated through univariate and multivariate analysis the relationship with pCR to the following baseline features: age, menopausal status, BMI, histologic type, pathologic tumor size, Scarff Bloom and Richardson (SBR), node involvement, vascular and lymphatic embols, clinical complete response (cCR), induction chemotherapy regimen and hormone therapy. For multivariate analysis, backward method was used entering the variables with P < 0.2 at univariate analysis. Odds ratio (OR) and its 95% confidence interval (CI) were calculated.

results

patients

One hundred patients with nonmetastatic IBC were treated at the Salah Azaiz Institute from 1994 to 2000. All patients were female. Patient and tumor characteristics are listed in Table 1.

Table 1.

Patient and tumor characteristics

Characteristics n 
Age (years) Median 43.5 years (23–71) 
    ≤45 61 
    >45 39 
Menopausal status  
    Premenopausal 70 
    Postmenopausal 30 
Pregnancy period  
    Yes 10 
    No 90 
Body size (BMI)  
    Lean (BMI ≤ 25) 16 
    Overweight (25 ≤ BMI ≤ 30) 34 
    Obese (BMI > 30) 42 
    Unknown 
Clinical presentation  
    Palpable mass 76 
    No palpable mass 23 
    Unknown 
Estrogen receptor status  
    Positive 17 
    Negative 40 
    Not done/unknown 43 
Progesterone receptor type  
    Positive 12 
    Negative 27 
    Not done/unknown 61 
Pathologic type  
    Infiltrating ductal 86 
    Infiltrating lobular 
    Not otherwise specified 
Grade (Scarf and Bloom)  
    1 
    2 39 
    3 37 
    Unknown 20 
Pathologic tumor size (cm) Median 5.0 cm (0–15 cm) 
    ≤5 30 
    >5 46 
    Unknown 24 
Pathologic axillary lymph node involvement  
    Node negative 
    1–3 positive lymph nodes 23 
    >4 positive lymph nodes 60 
    Unknown 
Characteristics n 
Age (years) Median 43.5 years (23–71) 
    ≤45 61 
    >45 39 
Menopausal status  
    Premenopausal 70 
    Postmenopausal 30 
Pregnancy period  
    Yes 10 
    No 90 
Body size (BMI)  
    Lean (BMI ≤ 25) 16 
    Overweight (25 ≤ BMI ≤ 30) 34 
    Obese (BMI > 30) 42 
    Unknown 
Clinical presentation  
    Palpable mass 76 
    No palpable mass 23 
    Unknown 
Estrogen receptor status  
    Positive 17 
    Negative 40 
    Not done/unknown 43 
Progesterone receptor type  
    Positive 12 
    Negative 27 
    Not done/unknown 61 
Pathologic type  
    Infiltrating ductal 86 
    Infiltrating lobular 
    Not otherwise specified 
Grade (Scarf and Bloom)  
    1 
    2 39 
    3 37 
    Unknown 20 
Pathologic tumor size (cm) Median 5.0 cm (0–15 cm) 
    ≤5 30 
    >5 46 
    Unknown 24 
Pathologic axillary lymph node involvement  
    Node negative 
    1–3 positive lymph nodes 23 
    >4 positive lymph nodes 60 
    Unknown 

BMI, body mass index.

Ninety-nine patients started primary chemotherapy and all but one received at least two cycles, with a median number of four cycles. Ten patients were treated with FAC 50 (10%), 45 with FEC 100 (45%), 16 with FEC 75 (16%) and 28 with FEC-HD (28%). Only one patient had up front mastectomy because of contraindication to anthracyclines. After chemotherapy, 93 patients underwent radical mastectomy associated with axillary lymph node dissection (n = 91). Adjuvant RT was administered to 83 patients.

Most of the patients with known ER status were negative (71%). After neo-adjuvant chemotherapy, pathologic tumor size was known in the majority of cases (77%). Median tumor size was 5.0 cm (range 0–15 cm). The median number of nodes removed was 13 (range 0–30). Patients were more likely to have positive axillary lymph nodes (91%).

response to induction chemotherapy

Among the 99 patients who received neo-adjuvant chemotherapy, 93 were assessable for clinical response. Forty-seven (50%) achieved objective tumor response, including nine (10%) patients with cCR. Of the 93 patients who underwent radical mastectomy (93%), 18 had pCR (20%). In multivariate analysis, factors associated with pCR included age superior to 45 years old (OR = 10.060, 95% CI = 1.841–54.968, P = 0.008), node involvement (OR = 0.009, 95% CI = 2.310–310.140, P = 0.009) and cCR (OR = 9.378, 95% CI = 1.145–76.844, P = 0.037) (Table 2).

IBC and pregnancy

In our series, 10 patients had a diagnosis of IBC during pregnancy (n = 2) or lactation (n = 8). Median age was 35 years (30–53 years). ER status was known in five patients and were all negative. The majority of tumors were invasive ductal carcinomas (9 of 10). After neo-adjuvant chemotheray, all the patients underwent radical mastectomy. There was one pCR. Median pathologic tumor size was 5 cm (2–13 cm). Lymph node status was known for nine patients, of whom eight (88%) were node positive.

All but one patient relapsed with a median delay of 9 months. Most of the relapses were locoregional (7 of 9). Median OS and DFS were 12 and 9 months, respectively.

outcome

Median time of follow-up for surviving patients was 44 months (range 5–116 months). The 3-year PFS was 28% and the median time to recurrence was 15 months. Seventy-one patients (71%) developed recurrent disease. There were more failures with distant metastases alone (37%) than with locoregional disease progression alone (24%) or with both local and distant metastases (10%). All but one relapse occurred in the first 5 years.

Seventy patients died (70%), with a 3-year survival rate of 44% and a median survival of 30 months. Potential prognostic factors were examined to determine whether any patient-related or treatment-related factor was predictive for outcome. These factors are listed in the ‘patients and methods’ section. Patients with cCR, pCR, negative nodes and those who received hormone therapy had improved 3-year OS (Figures 1–3; Table 3). Among the 57 patients with known hormonal status, positive ER was correlated with improved survival. For premenopausal women, pregnancy status was associated with lower survival (median OS, 12 versus 41 months, P = 0.0095). Age, SBR grade, menopausal status, BMI and type of initial chemotherapy regimen were not significantly associated with OS.

Table 2.

Patient and tumor characteristics associated with 3-year PFS and OS

Explanatory variables n OS PFS 
  Survival rate at 3 years HR 95% CI P Survival rate at 3 years HR 95% CI P 
Age (years) 
    ≤45R 61 45.45    20.09    
    >45 39 38.42 0.954 (0.529–1.718) 0.875 33.28 0.732 (0.454–1.183) 0.203 
Menopausal status 
    PremenopausalR 70 48.11    25.55    
    Postmenopausal 30 29.22 1.080 (0.641–1.819) 0.774 34.73 0.961 (0.578–1.598) 0.878 
BMI (kg/m2
    <25R 16 51.7   0.685 14.9   0.144 
    25–30 34 37.5 1.276 (0.629–2.589) 0.499 21.25 1.109 (0.561–2.193) 0.766 
    >30 42 47.11 1.032 (0.511–2.084) 1.032 33.68 0.661 (0.335–1.305) 0.233 
SBR grade 
    1R 66.67   0.322 **   0.708 
    2 39 30.07 1.550 (0.455–5.286) 0.483 15.65 0.952 (0.287–3.159) 0.936 
    3 37 48.48 1.039 (0.308–3.505) 0.951 26.14 0.772 (0.233–2.558) 0.672 
Clinical CR 
    YesR 75    75    
    No 84 38.77 5.257 (1.277–21.642) 0.022 21.45 5.628 (1.374–23.055) 0.016 
Pathologic CR 
    YesR 75 58.82    53.13    
    No 18 39.92 2.551 (1.244–5.235) 0.011 20.49 2.557 (1.257–5.202) 0.010 
Pathologic tumor size (cm) 
    ≤5R 31 49.5    41.8    
    >5 46 41.2 1.472 (0.825–2.624) 0.191 23 1.968 (1.107–3.498) 0.021 
Node involvement 
    0R 85.71   0.066 71.43   0.053 
    1–3 23 47.62 4.778 (1.095–20.840) 0.037 33.59 5.422 (1.249–23.540) 0.024 
    ≥4 60 38.16 5.405 (1.305–22.389) 0.020 19.62 5.808 (1.402–24.069) 0.015 
Chemotherapy regimen 
    FEC 100R 45 41.82   0.257 26.93   0.204 
    FEC-HD 28 42.56 0.763 (0.432–1.347) 0.352 27.24 0.749 (0.428–1.311) 0.311 
    FEC 75 16 20 1.169 (0.596–2.293) 0.649 18.75 1.154 (0.605–2.204) 0.664 
    FAC 50 10 14.81 1.782 (0.781–4.067) 0.170 ** 1.865 (0.820–4.245) 0.137 
Hormone therapy 
    YesR 60 54.43    33.42    
    No 36 18.70 2.521 (1.550–4.102) <0.001 8.75 2.094 (1.299–3.376) 0.002 
Explanatory variables n OS PFS 
  Survival rate at 3 years HR 95% CI P Survival rate at 3 years HR 95% CI P 
Age (years) 
    ≤45R 61 45.45    20.09    
    >45 39 38.42 0.954 (0.529–1.718) 0.875 33.28 0.732 (0.454–1.183) 0.203 
Menopausal status 
    PremenopausalR 70 48.11    25.55    
    Postmenopausal 30 29.22 1.080 (0.641–1.819) 0.774 34.73 0.961 (0.578–1.598) 0.878 
BMI (kg/m2
    <25R 16 51.7   0.685 14.9   0.144 
    25–30 34 37.5 1.276 (0.629–2.589) 0.499 21.25 1.109 (0.561–2.193) 0.766 
    >30 42 47.11 1.032 (0.511–2.084) 1.032 33.68 0.661 (0.335–1.305) 0.233 
SBR grade 
    1R 66.67   0.322 **   0.708 
    2 39 30.07 1.550 (0.455–5.286) 0.483 15.65 0.952 (0.287–3.159) 0.936 
    3 37 48.48 1.039 (0.308–3.505) 0.951 26.14 0.772 (0.233–2.558) 0.672 
Clinical CR 
    YesR 75    75    
    No 84 38.77 5.257 (1.277–21.642) 0.022 21.45 5.628 (1.374–23.055) 0.016 
Pathologic CR 
    YesR 75 58.82    53.13    
    No 18 39.92 2.551 (1.244–5.235) 0.011 20.49 2.557 (1.257–5.202) 0.010 
Pathologic tumor size (cm) 
    ≤5R 31 49.5    41.8    
    >5 46 41.2 1.472 (0.825–2.624) 0.191 23 1.968 (1.107–3.498) 0.021 
Node involvement 
    0R 85.71   0.066 71.43   0.053 
    1–3 23 47.62 4.778 (1.095–20.840) 0.037 33.59 5.422 (1.249–23.540) 0.024 
    ≥4 60 38.16 5.405 (1.305–22.389) 0.020 19.62 5.808 (1.402–24.069) 0.015 
Chemotherapy regimen 
    FEC 100R 45 41.82   0.257 26.93   0.204 
    FEC-HD 28 42.56 0.763 (0.432–1.347) 0.352 27.24 0.749 (0.428–1.311) 0.311 
    FEC 75 16 20 1.169 (0.596–2.293) 0.649 18.75 1.154 (0.605–2.204) 0.664 
    FAC 50 10 14.81 1.782 (0.781–4.067) 0.170 ** 1.865 (0.820–4.245) 0.137 
Hormone therapy 
    YesR 60 54.43    33.42    
    No 36 18.70 2.521 (1.550–4.102) <0.001 8.75 2.094 (1.299–3.376) 0.002 

PFS, progression-free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval; BMI, body mass index; SBR, Scarff Bloom and Richardson; CR, complete response; R, reference item; **; no value.

Figure 1.

Overall and progression-free survival according to clinical complete response.

Figure 1.

Overall and progression-free survival according to clinical complete response.

Figure 2.

Overall and progression-free survival according to lymph node status.

Figure 2.

Overall and progression-free survival according to lymph node status.

Figure 3.

Overall and progression-free survival according to hormone therapy.

Figure 3.

Overall and progression-free survival according to hormone therapy.

Factors that were found to be associated with better 3-year PFS included cCR, pCR, negative nodes, tumor size and hormone therapy (Figures 1–3; Table 3).

multivariate analysis of survival

A multivariate analysis was carried out to identify independent prognostic factors. Three parameters remained significantly associated with survival: cCR, negative nodes and hormone therapy. Patients with cCR had better DFS (HR = 5.33, 95% CI = 1.22–22.9, P = 0.024) and OS (HR = 4.77, 95% CI = 1.09–20.80, P = 0.038). Patients with negative nodes also had better DFS (HR = 7.94, 95% CI = 1.788–35.28, P = 0.024) and OS (HR = 8.57, 95% CI = 1.88–38.96, P = 0.021). Similarly, patients who received hormone therapy had better DFS (HR = 2.17, 95% CI = 1.26–3.72, P = 0.005) and OS (HR = 3.07, 95% CI = 1.75–5.39, P < 0.001) (Table 4).

Table 3.

Multivariate analysis of 3-year OS and PFS

Explanatory variables OS PFS 
 Survival rate at 3 years HR 95% CI PSurvival rate at 3 years HR 95% CI P
Hormone therapy 
    YesR 54.43    33.42    
    No 18.70 3.074 (1.752–5.395) <0.001 8.75 2.171 (1.267–3.722) 0.005 
Clinical CR 
    YesR 75    75    
    No 38.77 4.770 (1.094–20.804) 0.038 21.45 5.337 (1.244–22.903) 0.024 
Node involvement 
    0R 85.71   0.021 71.43   0.024 
    1–3 47.62 8.579 (1.889–38.963) 0.005 33.59 7.942 (1.788–35.280) 0.006 
    ≥4 38.16 6.705 (1.572–28.607) 0.010 19.62 6.361 (1.513–26.735) 0.012 
Pathologic CR 
    YesR 58.82    53.13    
    No 39.92   NS (1) 20.49   NS (1) 
Pathologic tumor size (cm) 
    ≤5R     41.8    
    >5     23   NS (2) 
Explanatory variables OS PFS 
 Survival rate at 3 years HR 95% CI PSurvival rate at 3 years HR 95% CI P
Hormone therapy 
    YesR 54.43    33.42    
    No 18.70 3.074 (1.752–5.395) <0.001 8.75 2.171 (1.267–3.722) 0.005 
Clinical CR 
    YesR 75    75    
    No 38.77 4.770 (1.094–20.804) 0.038 21.45 5.337 (1.244–22.903) 0.024 
Node involvement 
    0R 85.71   0.021 71.43   0.024 
    1–3 47.62 8.579 (1.889–38.963) 0.005 33.59 7.942 (1.788–35.280) 0.006 
    ≥4 38.16 6.705 (1.572–28.607) 0.010 19.62 6.361 (1.513–26.735) 0.012 
Pathologic CR 
    YesR 58.82    53.13    
    No 39.92   NS (1) 20.49   NS (1) 
Pathologic tumor size (cm) 
    ≤5R     41.8    
    >5     23   NS (2) 

OS, overall survival; PFS, progression-free survival; HR, hazard ratio; CI, confidence interval; CR, complete response; R, reference item; NS, not significant.

Table 4.

Multivariate analysis of factors predictive to pathologic CR

 OR (95% CI) P 
Age (years) 
    ≤45R   
    >45 10.060 (1.841–54.968) 0.008 
Node involvement 
    4+R  0.026 
    1–3 3.110 (0.11–15.823) 0.172 
    0 26.765 (2.310–310.140) 0.009 
Clinical CR 
    nCRR   
    CR 9.378 (1.145–76.844) 0.037 
Lymphatic embols 
    YesR   
    No  NS (1) 
Pathologic tumor size (cm) 
    ≥50R   
    <50  NS (2) 
 OR (95% CI) P 
Age (years) 
    ≤45R   
    >45 10.060 (1.841–54.968) 0.008 
Node involvement 
    4+R  0.026 
    1–3 3.110 (0.11–15.823) 0.172 
    0 26.765 (2.310–310.140) 0.009 
Clinical CR 
    nCRR   
    CR 9.378 (1.145–76.844) 0.037 
Lymphatic embols 
    YesR   
    No  NS (1) 
Pathologic tumor size (cm) 
    ≥50R   
    <50  NS (2) 

OR, odds ratio; CI, confidence interval; CR, complete response; R, reference item; NS, not significant.

discussion

Patients with IBC have substantial risks of recurrence and death. Here, we present the data of a series of nonmetastatic IBC patients homogeneously treated with multimodality therapy. Patients presenting with supraclavicular lymph node metastases were not included in the study cohort because they were considered as having metastatic disease according to the fifth AJCC classification and were treated accordingly.

This rare disease accounts for 6% of all breast cancers in Tunisia [6], which is one of the highest incidences reported in the literature [2, 16]. Women in our series were mostly overweight (34%) and obese (42%) according to the NCI/NHLBI criteria. A study of the M.D. Anderson Cancer Center has shown that high BMI is associated with an increased risk of IBC [17]. It has been indicated that key carcinogenic events probably occur before rather than after the menopause [18] and reproductive hormones are implicated in the initiation and progression of IBC. The high rate of obesity and overweight (up to 50%) observed in women in Tunisia, due in part to high fat intake [19], could at least partly explain the relatively high incidence of IBC in this population.

Patients in our series were younger than those reported in the literature [16], with a median age ∼44 years associated with predominance of premenopausal status (70%). The younger age of Tunisian patients treated for breast cancer has been reported previously. The mean age of patients is 50 years [6] with 10% younger than 35 years [20]. Furthermore, a recent study comparing IBC in Tunisia and Egypt has shown differences in mean age (respectively, 47.9 versus 51) and premenopausal status (59% versus 44%) [21]. Altogether, these data confirmed the specific epidemiological context in Tunisia.

The relationship between pregnancy and IBC remains controversial. We have observed a context of pregnancy in 10 patients (10%). Many anecdotal reports have indicated that IBC was more likely during pregnancy [16]. A case–control study has shown that the prevalence of IBC in the pregnant-associated (PA) group was higher than the non-PA group (26% versus 9.1%, P < 0.0001) [22]. Also, a previous Tunisian study reported that 30% of the PEV+ tumors in premenopausal women were associated with pregnancy versus 13% of the PEV− tumors [23]. One hypothesis is that hormonal and immunologic changes associated with pregnancy could promote the growth and spread of breast cancer.

In our series, pregnancy status was associated with poorer survival among premenopausal women (median OS, 12 versus 41 months, P = 0.0095). The prognosis for breast cancer is generally thought to be worsened by the coexistence of pregnancy. Delay in diagnosis is frequent. The average time from the onset of symptoms to diagnosis is much longer in pregnant than in nonpregnant women: 11 versus 4 months [24]. This delay when observed in IBC could at least in part explain the poorer outcome observed in this subtype of patients.

Currently, anthracycline-containing regimens are widely used as induction chemotherapy in patients with IBC because of the benefits formerly reported in larger series of standard risk breast cancers [25]. Some studies have reported that high-dose epirubicin induction chemotherapy without stem-cell support achieves up to 23% pCR with a median OS of 61 months [26]. Unfortunately, few randomized clinical trials comparing different chemotherapy regimens in IBC patients have been published.

The EORTC-NCIC-SAKK clinical trial involving 448 patients treated for locally advanced breast cancer (45% of whom had IBC) has demonstrated that dose-intensified epirubicin–cyclophosphamide provides no therapeutic benefit over FEC with no significant differences in pCR and survival rates [27]. A more recent phase III clinical trial comparing four cycles of FEC-HD (epirubicin 105 mg/m2) to four cycles of FEC 75 showed up to 16.7% pCR and a 22-month median event-free survival in the FEC-HD group [12]. These results are similar to those reported in the literature using conventional FAC or FEC regimens. In our series, we did not find any impact of high-dose chemotherapy (FEC-HD) on survival and pCR.

It has been indicated that taxanes may improve outcome in IBC patients treated with anthracycline-based regimens [28, 29]. Most of the studies, however, have included limited number of patients and no randomized clinical trial has confirmed these results. Only one patient in our series received taxanes as adjuvant chemotherapy. In the 1990s, taxanes were expensive and were available at the Salah Azaiz Institute only for the treatment of metastatic patients.

Response to chemotherapy is one of the most important predictors of outcome. IBC patients with good responses who are able to complete a full course of treatment, including radical mastectomy and locoregional irradiation, have better survival, especially patients with cCR or pCR [8]. Studies from the M.D. Anderson Cancer Center have reported a 15-year survival DFS rate of 44% for patients in complete response to any induction chemotherapy versus 0% for those with no response [7]. In the present study, we analyzed outcome as a function of pCR, defined as no pathologic evidence of cancer in the breast. Among the 93 patients who underwent radical mastectomy after induction chemotherapy, no difference was noted in the response rates based on the type of chemotherapy regimen used for induction. Eighteen patients (20%) achieved pCR. The 3-year OS and PFS of patients with pCR were significantly higher than those who had residual disease in the breast.

Few studies were interested on predictive factors for pCR in IBC. This is probably due to the rarety of IBC and small patient population.

We found that factors predictive to pCR were age superior to 45 years old, node involvement and cCR. The 95% CI of the OR is quite large due to few events, so these results must be confirmed. These factors have been described in non-IBC. The association between pathologic-negative node and pCR has been reported in the NSABP protocol B-18 [30]. A strong relation between cCR and pCR was also reported in the analysis of this large trial [30].

The poorer OS and DFS rates associated with lymph node metastases compared with negative lymph node status were expected. Although neo-adjuvant chemotherapy probably downstages lymph node status, as reported in non-IBC [30], there is direct relationship between the number of involved axillary nodes and the risk of recurrence.

In this study, we found that hormonal receptor status is an important prognostic factor in IBC. Thirty percent of patients with known hormonal receptor status were positive for ER. Positive ER was a favorable prognostic factor for survival (P = 0.0095). Patients with ER-positive breast cancer had 55% OS at 3 years, which was significantly higher than the 24% reported in ER-negative patients. These results are consistent with data of the SEER program wherein 5-year survival was 48.5% for ER-positive and 25.3% for ER-negative IBC cases [15].

Although many studies have analyzed the role of chemotherapy, including high-dose chemotherapy with autologous stem-cell transplantation, on the outcome of IBC patients [31–33], few studies have focused on the impact of hormone therapy [34, 35]. In many clinical trials investigating IBC, multimodality therapy did not include hormone therapy [26, 33, 36].

By contrast, many trials have shown that hormone therapy improves survival in ER-positive non-IBC patients. Moreover, several clinical trials have shown that adjuvant endocrine therapy is at least as effective as chemotherapy in premenopausal breast cancer patients [37, 38]. Ongoing randomized trials are testing the impact of ovarian ablation or suppression, either used alone or combined with chemotherapy, and the impact of triple therapy (ovarian suppression, chemotherapy and hormone therapy). In postmenopausal women with ER-positive breast cancer, it is well established that adjuvant endocrine therapy provides the most effective results [33]. Our study showed a significant positive impact of hormone therapy on survival in IBC patients. Nevertheless, the number of patients with known ER status (n = 57) was small and we could not evaluate the impact of hormone therapy according to ER status. It would be interesting to further investigate the impact of adjuvant hormone therapy in ER-positive IBC patients.

This study is subject to the limitations of all retrospective analyses, including nonrandom treatment allocation and lack of data. It is a single-institution experience on a cohort of nonmetastatic homogeneously treated IBC patients. These patients were referred to the Salah Azaiz Institute and are thus representative of the population at large because more than half of Tunisian cancer patients are treated at our institution. The survival of Tunisian patients is poorer than that in American and European series due to many factors including more aggressive disease, socioeconomic conditions with limited access to new drugs like taxanes, capecitabine (and recently trastuzumab) and lack of supportive care services. Socioeconomic problems are not specific to Tunisia and concern most developing countries.

Although there is no standard therapy for IBC, several principles of treatment, such as anthracycline-containing neo-adjuvant regimen followed by locoregional therapy, have become an established practice. Adjuvant hormone therapy could improve outcome. Randomized clinical trials enrolling a sufficient number of patients and associating multimodality-targeted therapies such as hormone therapy for ER-positive patients and trastuzumab or lapatinib for human epidermal growth factor receptor-positive patients are warranted.

The authors thank Dr Pierre Biron, from the department of medical oncology, Centre Leon Berard, Lyon, for critical revision of the manuscript and Marie Dominique Reynaud for editorial assistance.

References

1.
Bonnier
P
Charpin
C
Lejeune
C
, et al.  . 
Inflammatory carcinomas of the breast: a clinical, pathological, or a clinical and pathological definition?
Int J Cancer
 , 
1995
, vol. 
62
 (pg. 
382
-
385
)
2.
Chang
S
Parker
SL
Pham
T
, et al.  . 
Inflammatory breast carcinoma incidence and survival: the surveillance, epidemiology, and end results program of the National Cancer Institute, 1975–1992
Cancer
 , 
1998
, vol. 
82
 (pg. 
2366
-
2372
)
3.
Hance
KW
Anderson
WF
Devesa
SS
, et al.  . 
Trends in inflammatory breast carcinoma incidence and survival: the surveillance, epidemiology, and end results program at the National Cancer Institute
J Natl Cancer Inst
 , 
2005
, vol. 
97
 (pg. 
966
-
975
)
4.
Mourali
N
Levine
PH
Tabbane
F
, et al.  . 
Rapidly progressing breast cancer (poussee evolutive) in Tunisia: studies on delayed hypersensitivity
Int J Cancer
 , 
1978
, vol. 
22
 (pg. 
1
-
3
)
5.
Denoix
P
Treatment of Malignant Breast Tumors. Recent Results in Cancer Research. No. 31
 , 
1970
Berlin, Germany
Springer
6.
Maalej
M
Frikha
H
Ben Salem
S
, et al.  . 
Breast cancer in Tunisia: clinical and epidemiological study
Bull Cancer
 , 
1999
, vol. 
86
 (pg. 
302
-
306
)
7.
Ueno
NT
Buzdar
AU
Singletary
SE
, et al.  . 
Combined-modality treatment of inflammatory breast carcinoma: twenty years of experience at M.D. Anderson Cancer Center
Cancer Chemother Pharmacol
 , 
1997
, vol. 
40
 (pg. 
321
-
329
)
8.
Harris
EE
Schultz
D
Bertsch
H
, et al.  . 
Ten-year outcome after combined modality therapy for inflammatory breast cancer
Int J Radiat Oncol Biol Phys
 , 
2003
, vol. 
55
 (pg. 
1200
-
1208
)
9.
Ben Abdallah
M
Epidemiology of Cancer in Tunisia. Registre de l'institut Salah Azaiz
 , 
1997
Tunis, Tunisia
Association tunisienne de lutte contre le cancer
(pg. 
67
-
75
)
10.
Mourali
N
Tabbane
F
Muenz
LR
, et al.  . 
Ten-year results utilizing chemotherapy as primary treatment in nonmetastatic, rapidly progressing breast cancer
Cancer Invest
 , 
1993
, vol. 
11
 
4
(pg. 
363
-
370
)
11.
Spector
NL
Blackwell
K
Hurley
J
, et al.  . 
EGF103009, a phase II trial of lapatinib monotherapy in patients with relapsed/refractory inflammatory breast cancer (IBC): clinical activity and biologic predictors of response
Proc Am Soc Clin Oncol
 , 
2006
, vol. 
24
 
18S
 
(Abstr 502)
12.
Ben Ayed
F
Mezlini
A
Chinet-Charrot
P
, et al.  . 
Five-year of a randomized phase III trial comparing high-dose chemotherapy plus lenogastrim support with conventional dose chemotherapy in non-metastatic, unilateral, inflammatory breast cancer patients: interim analyses
Breast Cancer Res Treat
 , 
2002
, vol. 
76
 
Suppl 1
 
S93 (Abstr 345)
13.
Fleming
ID
Cooper
JS
Henson
DE
, et al.  . 
AJCC Cancer Manual for Staging
 , 
1997
5th edition
Philadelphia, PA
Lippincott–Raven
14.
NCI/NHLBI Obesity Education Initiative Task Force Members
Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults
 , 
1998
Bethesda, MD
NHLBI
15.
Chevallier
B
Roche
H
Olivier
JP
, et al.  . 
Inflammatory breast cancer. Pilot study of intensive induction chemotherapy (FEC-HD) results in a high histologic response rate
Am J Clin Oncol
 , 
1993
, vol. 
16
 (pg. 
223
-
228
)
16.
Anderson
WF
Schairer
C
Chen
BE
, et al.  . 
Epidemiology of inflammatory breast cancer (IBC)
Breast Dis
 , 
2006
, vol. 
22
 (pg. 
9
-
23
)
17.
Chang
S
Buzdar
AU
Hursting
SD
Inflammatory breast cancer and body mass index
J Clin Oncol
 , 
1998
, vol. 
16
 (pg. 
3731
-
3735
)
18.
Pike
MC
Spicer
DV
Dahmoush
L
, et al.  . 
Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk
Epidemiol Rev
 , 
1993
, vol. 
151
 (pg. 
17
-
35
)
19.
Mokhtar
N
Elati
J
Chabir
R
, et al.  . 
Diet culture and obesity in northern Africa
J Nutr
 , 
2001
, vol. 
131
 (pg. 
887S
-
892S
)
20.
Ben Ayed
F
Abaza
H
Khalfallah
S
, et al.  . 
Breast cancer in patients under 35 years of age
Proc Am Soc Clin Oncol
 , 
2002
, vol. 
21
  
(Abstr 276)
21.
Schairer
C
Soliman
A
Khaled
H
Clinical characteristics of inflammatory breast cancer in Egypt and Tunisia: a case series (submitted)
 
22.
Bonnier
P
Romain
S
Dilhuydy
JM
, et al.  . 
Influence of pregnancy on the outcome of breast cancer: a case-control study
Int J Cancer
 , 
1997
, vol. 
72
 (pg. 
720
-
727
)
23.
Mourali
N
Muenz
LR
Tabbane
F
, et al.  . 
Epidemiologic features of rapidely progressing breast cancer in Tunisia
Cancer
 , 
1980
, vol. 
46
 (pg. 
2741
-
2746
)
24.
Applewhite
RR
Smith
LR
DiVencenti
F
Carcinoma of the breast associated with pregnancy and lactation
Am Surg
 , 
1973
, vol. 
39
 (pg. 
101
-
104
)
25.
Bonadonna
G
Zambetti
M
Valagussa
P
Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes. Ten-year results
JAMA
 , 
1995
, vol. 
273
 (pg. 
542
-
547
)
26.
Veyret
C
Levy
C
Chollet
P
, et al.  . 
Inflammatory breast cancer outcome with epirubicin-based induction and maintenance chemotherapy: ten-year results from the French Adjuvant Study Group GETIS 02 Trial
Cancer
 , 
2006
, vol. 
19
 
3
(pg. 
473
-
480
)
27.
Therasse
P
Mauriac
L
Welnicka-Jaskiewicz
M
, et al.  . 
Final results of a randomized phase III trial comparing cyclophosphamide, epirubicin, and fluorouracil with a dose-intensified epirubicin and cyclophosphamide + filgrastim as neoadjuvant treatment in locally advanced breast cancer: an EORTC-NCIC-SAKK multicenter study
J Clin Oncol
 , 
2003
, vol. 
21
 
5
(pg. 
843
-
850
)
28.
Cristofanilli
M
Gonzalez-Angulo
AM
Buzdar
AU
, et al.  . 
Paclitaxel improves the prognosis in estrogen receptor negative inflammatory breast cancer: the M.D. Anderson Cancer Center experience
Clin Breast Cancer
 , 
2004
, vol. 
4
 (pg. 
415
-
419
)
29.
Cristofanilli
M
Bzdar
AU
Sneige
N
, et al.  . 
Paclitaxel in the multimodality treatment for inflammatory breast cancer
Cancer
 , 
2001
, vol. 
92
 (pg. 
1775
-
1782
)
30.
Fisher
ER
Wang
J
Bryant
J
, et al.  . 
Pathobiology of preoperative chemotherapy
Cancer
 , 
2002
, vol. 
95
 (pg. 
681
-
695
)
31.
Bertucci
F
Tarpin
C
Charaffe-Jaufret
E
, et al.  . 
Multivariate analysis of survival in inflammatory breast cancer: impact of intensity of chemotherapy in multimodality treatment
Bone Marrow Transplant
 , 
2004
, vol. 
33
 (pg. 
913
-
920
)
32.
Somlo
G
Frankel
P
Chow
W
, et al.  . 
Prognostic indicators and survival in patients with stage IIIB inflammatory breast carcinoma after dose-intense chemotherapy
J Clin Oncol
 , 
2004
, vol. 
22
 (pg. 
1839
-
1848
)
33.
Arun
B
Slack
R
Gehan
E
, et al.  . 
Survival after autologous hematopoietic stem cell transplantation for patients with inflammatory breast carcinoma
Cancer
 , 
1999
, vol. 
85
 (pg. 
93
-
99
)
34.
Perez
CA
Fields
JN
Fracasso
PM
, et al.  . 
Management of locally advanced carcinoma of the breast. II. Inflammatory carcinoma
Cancer
 , 
1994
, vol. 
74
 
Suppl 2
(pg. 
466
-
476
)
35.
Low
JA
Berman
AW
Steinberg
SM
, et al.  . 
Long-term follow-up for locally advanced and inflammatory breast cancer patients treated with multimodality therapy
J Clin Oncol
 , 
2004
, vol. 
22
 (pg. 
4067
-
4074
)
36.
Attia-Sobol
J
Ferrier
JP
Cure
H
, et al.  . 
Treatment results, survival and prognostic factors in 109 inflammatory breast cancers: univariate and multivariate analysis
Eur J Cancer
 , 
1993
, vol. 
29A
 (pg. 
1081
-
1088
)
37.
Jakesz
R
An update on ovarian suppression/ablation
Int J Gynecol Cancer
 , 
2006
, vol. 
16
 
Suppl 2
(pg. 
511
-
514
)
38.
Early Breast Cancer Trialist's Collaborative Group (EBCTCG)
Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials
Lancet
 , 
2005
, vol. 
365
 (pg. 
1687
-
1717
)