Journal of Cancer Therapy, 2011, 2, 302-307
doi:10.4236/jct.2011.23040 Published Online August 2011 (http://www.SciRP.org/journal/jct)
The Effect of Overweight on the Risk of
Recurrence in Tunisian Patients with Operable
Breast Cancer
Inès Ayadi Masmoudi1, Amine Masmoud i1, Nabil Toumi1, Afef Khanfir1, Mounir Frikha1,
Jamel Daoud2
1Department of Medical Oncology; 2Department of Radiation Oncology, Habib Bourguiba University Hospital, Sfax, Tunisia.
Received May 3rd, 2011; revised June 22nd, 2011; accepted July 1st, 2011.
ABSTRACT
Obesity is associated with worse breast cancer outcomes in Western and Asian women. The present study was to deter-
mine the relation of body mass index (BMI) to disease-free survival (DFS) in Tunisian patients with operable breast
cancer. We retrospectively reviewed data from 227 patients with operable breast cancer treated with primary surgery
and adjuvant epirubicin-based chemotherapy. Patients were categorized into lower-BMI (<27.5 kg/m2; N = 114) v
higher-BMI (>27.5 kg/m2; N = 113). Patients’ and disease characteristics, including tumor size and lymph node status,
were similar between the 2 groups. With a median follow-up of 56 months, there were 42 and 30 DFS events in the
lower- and higher-BMI group, respectively (adjusted hazard ratio (HR): 0.74; 95% CI, 0.43 to 1.26; p = 0.26). A sig-
nificant interaction (p < 0.001) was found between BMI category and time, with a significant DFS advantage for the
higher-BMI group after 3 years (adjusted HR: 0.28; 95% CI, i to 0.86; p = 0.03). We conclude that overweight is asso-
ciated with a decreased risk of late recurrence in Tunisian patients with operable breast cancer.
Keywords: Adjuvant Chemotherapy, Early Breast Cancer, Obesity, Recurrence, Tunisia
1. Introduction
In Tunisia, breast cancer is the leading female cancer
with an adjusted incidence of 30 per 100,000 per year [1].
Although patients with operable disease account for ap-
proximately two thirds of the cases, they usually present
with large tumors and/or lymph node involvement [2],
thus requiring a multimodality therapeutic approach.
In another hand, overweight, defined by a body mass
index (BMI) higher than 25 kg/m2, is a common problem
among Tunisian women, with a prevalence of 51%, and
the half of them being obese (BMI > 30 kg/m2) [3]. Dur-
ing the last two decades, a growing amount of literature
had demonstrated a negative impact for overweight at
diagnosis on the outcome of breast cancer [4]. The prog-
nostic value of high BMI was consistently reported in
various settings, including post-menopausal and pre-
menopausal patients, early stage and locally-advanced
disease, and different ethnic groups, mainly Caucasians
and Asians [5-9]. Whether such correlation exists in
North-African women with breast cancer is not docu-
mented.
In this context, the present study aimed to investigate
the relation of BMI to the outcome in a cohort of Tuni-
sian women with operable breast cancer uniformly
treated with primary surgery followed by epirubicin-
based adjuvant chemotherapy.
2. Patients and Methods
Between January 1995 and December 2005, 322 patients
with operable breast carcinoma received adjuvant epiru-
bicin-based chemotherapy in our centre. Information on
weight and height at diagnosis was available for 227 pa-
tients, who form the basis for this retrospective study.
Operable breast cancer was defined as clinical
T0-3N0-1 or T4b N0-1 disease with limited skin in-
volvement. A baseline negative staging work-up includ-
ing chest x-ray, liver ultra sonography and bone scan was
mandatory for all patients, regardless of clinical stage.
Primary surgery consisted of radical modified mastec-
tomy or breast-sparing operation, with axillary lymph
node dissection.
All patients received adjuvant chemotherapy, which

The Effect of Overweight on the Risk of Recurrence in Tunisian Patients with Operable Breast Cancer303
was mandated by the presence of one or more of the fol-
lowing risk factors: age <35, pathological tumor size >2
cm, lymph node involvement, negative hormone receptor
status, histological grade 2 or 3. Radiotherapy was indi-
cated after chemotherapy in the presence of any of the
following: breast-conserving surgery, lymph node in-
volvement, clinical stage T3 or T4b, multifocal/multi-
center tumor, or microscopic positive margins (R1 resec-
tion). For patients with hormone-receptor positive dis-
ease, tamoxifen 20 mg daily was given regardless of
menopausal status.
BMI at diagnosis, calculated as the weight (kg) di-
vided by the height (m) squared, was dichotomised above
and below the median value. The comparison between
higher-BMI (BMI-H) and lower-BMI (BMI-L) groups
was performed using Wilcoxon rank sum test for con-
tinuous variables, and khi-square or Fisher exact test, as
appropriate, for categorical variables. Variables with
p-values < 0.20 were considered of borderline signifi-
cance and were included as covariates for subsequent
analyses. We used the Kaplan-Meier method to compute
survival plots. DFS was defined as the time from surgery
until relapse (local or distant), contralateral breast cancer
or death, whichever occurred first. OS was calculated
from surgery until death from any cause or last follow-up.
We performed a Cox regression that adjusted for pa-
tients’ characteristics that were different (p < 0.20) be-
tween the two groups to calculate hazard ratios (HR) for
DFS between BMI-H and BMI-L groups. To test the
interaction between BMI category and time, we com-
pared the effect of BMI on DFS in two consecutive time
intervals using a piecewise Cox regression model.
3. Results
3.1. Patients’ and Disease Characteristics
Median age at diagnosis was 48 (range: 24 - 75). Among
162 patients for whom findings from initial physical
examination were known, the majority had stage II or
stage III disease (65% and 32%, respectively). Among
216 (97%) patients with available information for hor-
mone receptor status, estrogen and/or progesterone re-
ceptors were positive in 134 (62%) of the cases. As it can
be seen in Table 1, most patients had histologic grade 2
or 3 (87%) ductal infiltrating carcinoma (86%), with a
tumor size >2 cm (70%) and lymph node involvement
(60%).
According to the World Health Organisation (WHO)
classification, 85 patients had grade 1 overweight (BMI
between 25 and 29.9 kg/m2) and 76 were obese (BMI ≥
30 kg/m2), for a total overweight rate of 71%. Sixty two
(27%) patients were in the normal BMI range, while the
remaining 4 (2%) patients were in the lowest BMI cate-
Table 1. Patients and disease characteristics.
BMI
<27.5 kg/m2
(N = 114)
N (%)
≥27.5 kg/m2
(N = 113)
N (%)
p-value
Age
Mean 48 50 0.193¶
≤34 11 (10) 7 (6)
35 - 49 56 (49) 50 (44)
≥50 47 (41.2) 56 (50)
Menopausal status* 0.017
Pre/peri-menopausal62 (61) 44 (44)
Post-menopausal 40 (39) 56 (56)
Unknown 12 13
Histological type 0.803
Infiltrating ductal 99 (87) 97 (86)
Infiltrating lobular 6 (5) 7 (6)
Mixed carcinoma 6 (5) 4 (4)
Other 3 (3) 5 (4)
Tumor size (pT)* 0.359
≤2 cm 37 (34) 28 (26)
>2 cm but ≤5 cm 59 (55) 68 (64)
>5 cm 12 (11) 10 (9)
Unknown 6 7
Positive nodes 0.204
0 41 (36) 50 (44)
1 to 3 41 (36) 42 (37)
≥4 32 (28) 21 (19)
Histologic grade* 0.219
1 11 (11) 16 (15)
2 57 (54) 46 (43)
3 37 (35) 46 (43)
Unknown 9 5
Hormone receptors* 0.115
Positive 62 (57) 72 (67)
Negative 47 (43) 35 (33)
Unknown 5 6
Type of surgery 0.394
Mastectomy 93 (82) 87 (77)
Breast-sparing 21 (18) 26 (23)
Chemotherapy 0.404
FEC50/60 78 (68) 83 (74)
FEC100 36 (32) 30 (27)
Radiotherapy 0.683
Yes 99 (87) 96 (85)
No 15 (13) 17 (15)
Endocrine therapy 0.518
Tamoxifen 40 (58) 41 (53)
Tamoxifen then AI 26 (38) 31 (40)
Up-front AI 0 (0) 2 (3)
OS/OA alone 2 (3) 1 (1)
None 1 (1) 3 (4)
¶ Wilcoxon rank sum test; * Percentages were calculated among patients for
whom information on studied variable was available, Abbreviation: AI:
aromatase inhibitor, OS/OA: ovarian suppression/ ovarian ablation
gory (<18.5 kg/m2).
Median BMI value was 27.5 kg/m2. Compared with
those whom BMI was above the median, leaner patients
tended to be younger, more likely to be pre- or peri-meno-
pausal, and more likely to have hormone-unresponsive
tumors (0.05 < p < 0.20). Other disease characteristics,
including tumor size and lymph node involvement, did not
significantly differ between the two groups (Table 1).

The Effect of Overweight on the Risk of Recurrence in Tunisian Patients with Operable Breast Cancer 304
3.2. Treatment
Surgery consisted of total mastectomy in the majority
(79%) of the patients. Radiotherapy was given in 88%
and 100% of the cases after mastectomy and breast-
sparing surgery, respectively. All patients underwent
fluoro-uracil, epirubicin and cyclophosphamide (FEC)
adjuvant chemotherapy, with varying epirubicin doses
(50, 60 or 100 mg/m2). No statistically-significant dif-
ferences were found between the two BMI groups with
respect to treatment modalities (Table 1).
3.3. Survival Outcomes
At a median follow-up of 56 months, 5-year DFS for the
entire cohort was 70%. DFS and OS events in each BMI
group are summarised in Table 2.
There was a non-statistically significant 6% absolute
difference between the two BMI groups in terms of DFS,
with a 5-year DFS of 73% and 67% for the BMI-H and
BMI-L groups, respectively (HR for BMI-H versus
BMI-L: 0.72; 95% CI, 0.45 to 1.15; log-rank p = 0.17)
(Figure 1(a)). Comparable results were found after ad-
justing for age, menopausal status and hormone-receptor
status (HR = 0.70; 95% CI, 0.41 to 1.18). The rate of
overall survival (OS) at 5 years was 82% in the
higher-BMI group and 77% in the lower-BMI group (HR
= 1.00, 95% CI, 0.57 to 1.79; log-rank p = 0.98) (Figure
1(b)).
On the basis on Figure 1(a), we analysed DFS using a
piecewise Cox regression with change point at 3 years.
There was a statistically significant interaction between
BMI category and time (p < 0.001), implying that the
effect of BMI changes across time. Within the first 3
years, the adjusted HR for DFS between BMI-H and
BMI -L groups was 1.13 (95% CI, 0.59 to 2.15). After 3
years, the likelihood of a DFS event was nearly 4 fold
lower for the BMI-H group compared with the BMI-L
group (log-rank p = 0.03; adjusted HR = 0.28; 95% CI,
0.09 to 0.84).
The unadjusted HR for DFS between BMI-H and
BMI-L groups in various patients subgroups are shown
in Table 3. No significant interaction was found between
BMI and any of the patients’ and disease characteristics
analysed (p values not shown).
4. Discussion
Unexpectedly, the present study shows that overweight is
not associated with advanced tumor stage or lymph node
involvement at diagnosis in Tunisian women with oper-
able breast cancer. Moreover, a major finding from our
study is that overweight is associated with a reduced risk
of late recurrence. In view of the existing evidence dem-
onstrating a negative effect of overweight on breast can-
Table 2. Disease-free survival events summary.
BMI < 27.5 kg/m2
(N = 114)
BMI > 27.5 kg/m2
(N = 113)
Recurrence
Distant only 25 19
Both distant and local 11 7
Local only 5 2
Contralateral 1 1
Death
After recurrence 25 22
Without previous
recurrence
0 1
Total events 42 30
Table 3. Hazard ratios for breast cancer recurrence by
body mass index category .
Overall >3 years
HR*95% CI HR* 95% CI
Age
<50 0.810.45 - 1.45 0.54 0.18 - 1.59
≥50 0.600.27 - 1.35 0.22 0.05 - 1.01
Menopausal status
Pre/peri-menopausal0.830.43 - 1.60 0.49 0.13 - 1.80
Post- menopausal 0.590.24 - 1.43 0.12 0.01 - 1.00
Hormone receptors
Positive/unknown 0.640.32 - 1.27 0.39 0.12 - 1.25
Negative 0.920.47 - 1.78 0.45 0.12 - 1.71
Tumor size
≤2 cm 0.370.08 - 1.73 0.43 0.16 - 1.17
>2 cm 0.700.41 - 1.21 0.31 0.04 - 2.63
Lymph Node status
Negative 0.600.23 - 1.59 0.14 0.02 - 1.20
Positive 0.840.48 - 1.44 0.61 0.23 - 1.62
Histologic grade
Grade ½ 0.640.32 - 1.26 0.45 0.14 - 1.42
Grade 3 0.750.36 - 1.55 0.36 0.09 - 1.43
*Unadjusted hazard ratio of higher- to lower-body mass index. Abbre-
viation: HR, hazard ratio.
cer patients’ DFS and OS, our results are seemingly sur-
prising.
In view of reported association between increased
body weight at diagnosis and advanced disease, it has
been hypothesised that the higher exposure to endoge-
nous estrogens mediated by adipose tissue may explain
the prognostic effect of obesity. In our study, tumor stage
and lymph node involvement were similar between
BMI-H and BMI-L groups. One may argue that the dif-
ference in DFS may be due to the fact that more BMI-H
patients had hormone-receptor positive disease. However,
the effect of overweight was not modified after adjust-
ment for hormone receptor status.
It has been suggested that the effect of obesity on breast
cancer outcomes may be mediated by leptin, a neuroen-
docrine hormone linked to obesity [10]. However, ele-
vated levels of leptin were not associated with outcome in
471 women with operable breast cancer [11]. Recently, a
Tunisian group investigated the prognostic value of
polymorphisms in leptin gene 5’ promoter region,

The Effect of Overweight on the Risk of Recurrence in Tunisian Patients with Operable Breast Cancer305
(a)
(b)
Figure 1. Kaplan-Meier estimates of (a) disease-free sur-
vival and (b) overall survival according to body mass index.
and found a decreased DFS in breast carcinoma patients
with the 2548A allele [12]. In another hand, it had been
shown that the genotype 2548 G/A is significantly asso-
ciated with obesity, compared with the homozygous G/G
genotype [13]. Taken together, the results of these two
studies suggest that the risk of breast cancer recurrence is
increased in obese patients, which is in opposition with
our findings. Nonetheless, the report by Snoussi et al. [12]
was limited by patients’ heterogeneity for disease and
treatment characteristics and the loss of leptin gene
polymorphism prognostic value after multivariate analy-
sis. Thus, this study should be only regarded as hypothe-
sis-generating and further research is needed to properly
assess the prognostic value of leptin and its receptor in
Tunisian breast cancer patients.
Although our findings are in contrast with published
literature with respect to the relation of overweight to
early breast cancer outcomes, it is interesting to note that
results similar to ours have been reported in patients with
inflammatory breast cancer (IBC). Indeed, in a sin-
gle-institution study of 100 Tunisian women with IBC,
mostly pre-menopausal, the 3-year progression-free sur-
vival was 15%, 21% and 34% in normal, overweight and
obese patients, respectively [14]. Similarly, in a report
from the M.D. Anderson group, long-term OS was ap-
proximately doubled in pre-menopausal obese patients
with IBC compared with their leaner counterparts. Of
note, as in our study, survival curves were overlapping
during the first 3 years of follow-up, but did clearly
separate thereafter [15].
One of the key biologic features of IBC is the over ex-
pression of RhoC GTPase (RhoC), which is thought to be
responsible of the high aggressiveness of the disease [16].
Interestingly, weight gain is associated with increased
expression of caveolin-1 [17], and caveolin-1 inhibits
RhoC activation and subsequent p38 MAPK pathway
[18]. Another major component of the “inflammatory
signature” is the insulin-like growth factor (IGF) path-
way, which promotes invasion and metastasis [19, 20].
Interestingly, in a recently reported large study, obese
women had lower circulating levels of IGF-1 than their
counterparts with normal range BMI [21]. Thus, both
RhoC-Caveolin-1 and IGF-1 pathways may account for
the favourable prognostic effect of overweight in IBC.
But how would this apply to patients with operable breast
cancer?
Tunisian patients with breast cancer have fewer grade
1 and fewer hormone-responsive tumors then their coun-
terparts from Western countries [22]. High grade and low
endocrine responsiveness are typically encountered in
IBC [23]. Moreover, breast cancer incidence peaks in
Tunisian women aged between 45 and 49 years, and
shows a plateau thereafter [1], a figure that is remarkably
similar to IBC in Western countries [24]. Taken together,
these data suggest that operable breast cancer in Tunisian
women may share major biologic features with IBC, thus
resulting in similar effect of overweight on outcome.
One of the strengths of our study is the ethnic homo-
geneity of our patients and the uniformity of loco-re-
gional and systemic treatment. A baseline work-up was
systematically performed, thus excluding patients with
unsuspected distant metastasis, albeit such practice is not
currently recommended for patients with stage II breast
cancer [25]. Therefore, we had an excellent opportunity
to assess the prognostic value of overweight with mini-
mal effect of potential confounding parameters.

The Effect of Overweight on the Risk of Recurrence in Tunisian Patients with Operable Breast Cancer 306
Nonetheless, as with any study, our study has some
limitations. The relatively small number of patients and
short follow-up made it difficult to detect a difference in
OS between BMI groups. Moreover, our analysis was
based on BMI dichotomization on its median rather than
WHO-defined BMI categories. However, the relevance
of WHO-defined BMI categories to non-European popu-
lations has been questioned [26], and remains to be
proved in North African population.
5. Conclusions
A negative impact for overweight at diagnosis on the
outcome of breast cancer has been demonstrated in the
literature. In our study, we found an inverse correlation
between overweight and the risk of recurrence in Tuni-
sian women with operable breast cancer. Another finding
in contrast with previous literature was the lack of asso-
ciation between obesity and disease stage at presentation,
reinforcing the hypothesis of a biologically different dis-
ease. International partnership is urgently needed to
promote research aiming to study the molecular profile
and identify cell pathways involved in breast carcino-
genesis in Tunisian women.
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