Download 04 December 2007

18 July 2008
Impact of a raised Body Mass Index
on Breast Cancer Survival in relation
to age and disease extent at diagnosis
AK Imkampe*a and T Bates
Breast Unit, William Harvey Hospital, Ashford, Kent TN24 0LZ, UK
*Corresponding author. Breast Unit, William Harvey Hospital, Ashford, Kent TN24
0LZ, UK.
Tel: 0044-1233-633331 Fax: 0044-1233-616019
e-mail address: [email protected]
a
present address: 89 Hunter Road, Ashford, Kent, TN24 0RT, UK
Abstract
Background:
The prognostic value of Body Mass Index (BMI) on breast cancer outcome is
controversial and previous studies from this unit have not shown any significant
relation to survival. The aim of this analysis was to re-examine any impact of a raised
BMI on recurrence and survival related to age and disease stage at the time of
diagnosis.
Methods:
2298 breast cancer patients were reviewed and divided in groups by BMI.
Recurrence-Free Survival (RFS), Breast Cancer Specific Survival (BCSS) and Overall
Survival (OS) were compared by Kaplan-Meier life table analysis. Known prognostic
factors including BMI were tested for independent prognostic significance in a Coxregression model.
Results:
417 obese patients had on average larger tumours (median 2.3 versus 2.1 cm, p
<0.01). A trend to an increased positive node status (37% versus 33%) was not
significant, p =0.18. 7-year RFS was 82% versus 77% in the obese, p < 0.01, BCSS
was 87% versus 85%, p =0.046 and OS 81% versus 77%, p = 0.02. BMI was
independently associated with RFS in multivariate analysis (HR 1.43, p < 0.01). In
subgroup analysis survival differences were most prominent in patients with node
positive disease and in patients less than 60 years old.
Conclusion:
Breast cancer outcome was worse in patients with a raised BMI and this risk was
greater in younger patients and in those with node positive disease. The difference
2
may be related to diagnosis at a more advanced stage in the obese but there was also
an independent effect of BMI on survival.
Key words:
Obesity, breast cancer prognosis, node status, age
3
Introduction
Obesity may be defined as a Body Mass Index (BMI) ≥ 30 m/kg2. The prevalence of
obesity has continued to increase over the past decades1,2 and it is associated with
numerous health risks.
A number of studies have looked at the relationship of obesity and breast cancer and
have described a higher incidence of breast cancer in postmenopausal patients with a
raised BMI3,4. In pre-menopausal patients this correlation was found to be inverted,
possibly explained by either early diagnosis of easier detectable disease in lean
women5 or by an association of a lower BMI in relation to height, with taller patients
being at increased risk of developing breast cancer6.
The impact of BMI on breast cancer outcome is controversial. Some authors have
reported a worse prognosis in patients with a raised BMI7,8. Examinations of patient
subgroups have demonstrated differences in pre- and postmenopausal patients9,10, in
patients with early stage breast cancer7,10 and in patients with advanced disease11.
Other studies including two previous studies from our Unit have not shown any
significant correlation12-14.
The aim of the present study was to update these results and to re-examine any impact
of a raised BMI on breast cancer prognosis in relation to age and severity of the
disease at the time of diagnosis.
4
Methods
A review of 2298 breast cancer patients diagnosed over a 20-year period between
1983 and 2007 was carried out. Data were collected prospectively on an actively
managed database and the follow-up was complete at the time of analysis. Height and
weight was recorded on questionnaires when patients first visited the clinic. Only
patients with primary operable and unilateral disease were included. The patients were
divided in groups according to their BMI: an obese group with BMI ≥ 30 and a nonobese group with BMI < 30 and were subsequently further classified in four BMI
groups (BMI > 35, BMI 30 – 35, BMI 22 – 29 and BMI < 22).
Patient and tumour characteristics as well as initial management (median age, tumour
size, tumour grade, lymph node status at diagnosis, oestrogen receptor (ER) status,
vascular invasion, operative management and adjuvant treatment) were compared
between the groups and analysed by chi-square test for categorical variables and by
Mann-Whitney U test for continuous variables.
7-year Recurrence Free Survival (RFS), Breast Cancer Specific Survival (BCSS) and
Overall Survival (OS) were calculated by Kaplan-Meier Life Table Analysis from
date of diagnosis until date of an event or last follow-up if no event had occurred.
Recurrence was defined as any recurrent disease, local, regional or distant. Mean
follow-up time was 85 months.
Subsequent analyses were carried out on patient subgroups and survival differences
by BMI were tested separately depending on node status, tumour size, tumour grade,
age at diagnosis and menopausal status. Patients who had had a hysterectomy were
regarded as postmenopausal except for patients currently taking hormone replacement
(HRT) who were excluded from this subgroup calculation.
5
To determine whether there was an independent association of BMI with breast
cancer survival a Cox regression model was fitted and BMI was entered as a
categorical and as a continuous variable in a separate model. Results were considered
as statistically significant with a p-value of < 0.01.
6
Results
Of 2298 patients 417 were defined as obese with a BMI ≥ 30. These patients had on
average larger tumours and there was a possible trend to an increased positive lymph
node status although this was not statistically significant. The median age, type of
operation, ER status, use of adjuvant treatment and presence of vascular invasion
were similar in both groups. There was no significant difference in tumour grade but
there was a trend to a higher proportion of grade I tumours in the non-obese, Table 1.
The outcome was significantly different between obese and non-obese patients: RFS,
BCSS and OS were worse in patients with a raised BMI (7-year RFS 77% versus
82%, p = 0.01, BCSS 85% versus 87%, p = 0.046, OS 77% versus 81%, p = 0.02),
Figure 1. Further subgroup analysis by BMI showed a gradual decrease in survival
rates correlating with an increasing BMI (p = 0.1), Figure 2.
These survival differences were not consistent when patients were sub classified by
disease characteristics, menopausal status and age. 7-year RFS in node positive
patients was worse in the obese 53% versus 67% in lean women, p < 0.01 whereas
RFS in node negative patients was similar in both groups (88% versus 89%, p = 0.44).
In patients with grade III tumours there was a strong trend towards worse RFS in
patients with a raised BMI (54% versus 64%, p = 0.03) but this trend was not
apparent in patients with grade I and II tumours (83% versus 85%, p = 0.24).
There was no difference with tumour size and survival by BMI (RFS in ≤ 2 cm
tumours 84% versus 87%, p = 0.15 and in > 2 cm tumours 73% versus 77%, p =
0.27).
Outcome in obese pre-menopausal patients was worse than in their lean counterparts,
RFS 66% versus 77% although this did not reach statistical significance, p = 0.09. A
similar trend was present in post-menopausal patients (79% versus 82%, p = 0.07).
7
However, regardless of menopausal status (suggest omit analysis by menopausal
status). Subgroup analysis by age showed a significant survival difference by BMI in
patients < 60 years old (71% versus 82% in lean patients, p < 0.01). Patients ≥ 60
years of age had equal RFS times, independent of their BMI status (82% both groups,
p = 0.8), Figures 3 and 4.
Younger patients had in general worse prognostic tumour features at the time of
diagnosis and this is demonstrated in Table 2.
In Cox regression analysis BMI was an independent prognostic factor for recurrence
free survival; this was significant with BMI included as a categorical variable and the
model showed a non-significant trend with BMI as a continuous variable, Table 3.
8
Discussion
The results of the present study show a clear association of BMI with breast cancer
survival with increasingly worse outcome the more obese the patients.
The impact of BMI on breast cancer prognosis has been examined in a number of
studies and the results are conflicting. Some authors did not show any relationship of
BMI with breast cancer survival11-15 however of the two negative studies from this
unit the first reviewed only a small number of cases13 and the later study of 1500
patients showed that the prognostic markers of obese patients patient were worse at
presentation and there was a non-significant trend to a worse disease-free survival14.
The findings of the current study correspond to studies that have reported significant
survival differences7-10 and in a review of the literature (Carmichael)
The exact mechanism for this effect is unclear. Several explanations have been
suggested one of which is the diagnosis at a more advanced stage in patients with a
raised BMI16. Small tumours may be more difficult to detect in large breasts leading
to delayed presentation and locally or systemically advanced disease. The average
tumour size in the present study was larger in obese patients and although the
difference in node status was not significant this may be related to comparatively
small patient numbers.
It is possible that tumours are more aggressive in the obese since although the
proportion of Grade III tumours in the present analysis was similar in the two groups
there was a trend for non-obese patients to have more Grade I tumours. This result
corresponds to findings from Daling et al17 who reported tumours of higher
histological grade and higher mitotic cell count in patients with a raised BMI. There
may be further factors of tumour aggressiveness present, not accounted for in the
present analysis, but contributing to the independent effect on prognosis. Leptin, a
9
hormone released by fat cells, has recently been associated with more aggressive
breast tumour behaviour and was found to independently predict worse outcome.
Leptin receptors are expressed in breast cancers cells and higher levels of serum leptin
correlate with obesity18-20.
Some authors suggest a possible enhanced tumour growth by increased oestrogen
levels21. A positive relationship between circulating oestrogen and BMI has been
found in postmenopausal patients with their main source of oestrogen from the
conversion of androstenedione to oestrogen in adipose tissue22. Obese patients also
have lower levels of sex hormone binding globulins (SHBG), increasing the
bioavailability of oestrogen. Pre-menopausal patients, on the contrary, have been
found to have lower oestrogen levels with a rising BMI23.
Survival in patients with raised BMI’s in the present analysis was worse even in the
pre-menopausal patient group, thus making a relationship between BMI and oestrogen
mediated tumour growth as a single causal factor for the survival difference unlikely.
Similar results have been reported in other studies9,24.
Differences by BMI in the current study were generally more pronounced in patients
with more advanced and possibly more aggressive tumours with nodal involvement.
Recent data published by Vitolins et al25 have shown survival differences to be
stronger in patients with a higher number of lymph nodes involved. Dignam et al26
looked at node negative patients only and did not demonstrate any survival
disadvantage by BMI. These results could relate to the distinct difference in survival
by BMI between younger and older age groups found in the present analysis which
did not appear to relate to menopausal status. Younger patients tend to present with
higher grade tumours, are often ER negative and tumours that have already spread to
lymph glands. The majority of patients in this age group had received adjuvant
10
chemotherapy and a confounding factor may also be a reduced response to adjuvant
treatment due to possible under-dosage of drugs in the obese.
One limitation of the current analysis was self-reported height. It has been shown that
patients tend to report their height towards the norm with increased height for shorter
patients and decreased height for tall patients27. This would produce a bias whereby
short obese patients who report themselves as taller would have a lower BMI
recorded, whereas tall obese patients reported as shorter, would appear to have a
higher BMI. Such a bias would dilute and possibly obscure any real effect that BMI
might have and the differences shown in the present study could in reality be more
distinct.
Conclusion:
Breast cancer outcome in this study was significantly worse in patients with a raised
BMI and this was an independent predictor for recurrence free survival. Differences
were more pronounced in advanced disease. Obese patients presented with larger
tumours suggesting an additional risk of delayed diagnosis in this group leading to
worse outcome.
Acknowledgements
We wish to thank Vicky Stevenson for maintaining the accuracy of the breast cancer
database.
Conflict of Interest statement
There are no conflicts of interest.
11
Literature
1. Parikh NI, Pencina MJ, Wang TJ et al. Increasing trends in incidence of
overweight and obesity over 5 decades. Am J Med 2007; 120(3): 242-50
2. Wang y, Lobstein T. Worldwide trends in childhood overweight and obesity.
Int J Pediatr Obes. 2006; 1(1):11-25
3. Folsom AR, Kaye SA, Prineas RJ et al. Increased incidence of carcinoma of
the breast associated with abdominal adiposity in postmenopausal women. Am
J Epidemiol 1990; 131(5): 794-803
4. Ahn J, Schatzkin A, Lacey JV Jr, et al. Adiposity, adult weight change, and
postmenopausal breast cancer risk. Arch Intern Med 2007; 167(19):2091-102
5. Willett WC, Browne ML, Bain C, Lipnick RJ et al. Relative weight and risk of
breast cancer among premenopausal women. Am J Epidemiol 1985;
122(5):731-40
6. Li CI, Malone KE, White E, Daling JR. Age when maximum height is reached
as a risk factor for breast cancer among young U.S. women. Epidemiology
1997; 8(5):559-65
7. Senie RT, Rosen PP, Rhodes P, Lesser ML, Kinne DW. Obesity at diagnosis
of breast carcinoma influences duration of disease-free survival. Ann Intern
Med 1992; 116(1):26-32
8. Majed B, Moreau T, Senouci K, Salmon RJ, Fourquet A, Asselain B. Is
obesity an independent prognosis factor in women breast cancer? Breast
Cancer Res Treat 2007; Epub ahead of print
9. Loi S, Milne RL, Friedlander ML et al. Obesity and outcomes in
premenopausal and postmenopausal breast cancer. Cancer Epidemiol
Biomarkers Prev 2005; 14(7):1686-91
12
10. Tretli S, Haldorsen T, Ottestad L. The effect of pre-morbid height and weight
on the survival of breast cancer patients. Br J Cancer 1990; 62(2):299-303
11. Bastarrachea J, Hortobagyi GN, Smith TL et al. Obesity as an adverse
prognostic factor for patients receiving adjuvant chemotherapy for breast
cancer. Ann Intern Med. 1994; 120 (1):18-25
12. Obermair A, Kurz C, Hanzal E et al. The influence of obesity on the diseasefree survival in primary breast cancer. Anticancer Res 1995; 15(5B):2265-9
13. Menon KV, Hodge A, Houghton J, Bates T. Body mass index, height and
cumulative menstrual cycles at the time of diagnosis are not risk factors for
poor outcome in breast cancer. Breast 1999; 8(6):328-33
14. Carmichael AR, Bendall S, Lockerbie L, Prescott RJ, Bates T. Does obesity
compromise survival in women with breast cancer? Breast 2004; 13(2):93-6
15. Katoh A, Watzlaf VJ, D’Amico F. An examination of obesity and breast
cancer survival in post-menopausal women. Br J Cancer 1994; 70(5):928-33
16. Porter GA, Inglis KM, Wood LA, Veugelers PJ. Effect of obesity on
presentation of breast cancer. Ann Surg Oncol 2006; 13(3):327-32
17. Daling JR, Malone KE, Doody DR, Johnson LG, Gralow JR, Porter PL.
Relation of body mass index to tumor markers and survival among young
women with invasive ductal breast carcinoma. Cancer 2001; 92(4): 720-9
18. Chen DC, Chung YF, Yeh YT et al. Serum adiponectin and leptin levels in
Taiwanese breast cancer patients. Cancer Lett. 2006; 237(1):109-14
19. Revillion F, Charlier M, Lhotellier V et al. Messenger RNA expression of
leptin and leptin receptors and their prognostic value in 322 human primary
breast cancers. Clin Cancer Res. 2006; 12(7Pt1):2088-94
13
20. Miyoshi Y, Funahashi T, Tanaka S et al. High expression of leptin receptor
mRNA in breast cancer tissue predicts poor prognosis for patients with high,
but not low, serum leptin levels. Int J Cancer 2006; 118(6):1414-9
21. McTiernan A, Rajan KB, Tworoger SS et al. Adiposity and sex hormones in
postmenopausal breast cancer survivors. J Clin Oncol 2003; 21(10): 1961-6
22. MacDonald PC, Edman CD, Hemsell DL, Porter JC, Siiteri PK. Effect of
obesity on conversion of plasma androstenedione to estrone in
postmenopausal women with and without endometrial cancer. Am J Obstet
Gynecol. 1978; 130(4):448-55
23. Potischman N, Swanson CA, Siiteri P, Hoover RN. Reversal of relation
between body mass and endogenous estrogen concentrations with menopausal
status. J Natl Cancer Inst 1996; 88(11):756-8
24. Abrahamson PE, Gammon MD, Lund MJ et al. General and abdominal
obesity and survival among young women with breast cancer. Cancer
Epidemiol Biomarkers Prev 2006; 15(10):1871-7
25. Vitolins MZ, Kimmick GG, Case LD. BMI influences prognosis following
surgery and adjuvant chemotherapy for lymph node positive breast cancer.
Breast J 2008; Epub ahead of print
26. Dignam JJ, Wieand K, Johnson KA et al. Obesity, tamoxifen use, and
outcomes in women with estrogen receptor-positive early-stage breast cancer.
J Natl Cancer Inst 2003; 95(19):1467-76
27. Wang DY, DeStavola BL, Allen DS et al. Breast cancer risk is positively
associated with height. Breast Cancer Res Treat 1997; 43(2): 123-128
14