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10.1245/ASO.2006.03.049
Annals of Surgical Oncology 13:327-332 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Effect of Obesity on Presentation of Breast Cancer

Geoffrey A. Porter, MD, FRCSC1, Karen M. Inglis, RN1, Lori A. Wood, MD, FRCPC2 and Paul J. Veugelers, PhD3

1 Department of Surgery, Dalhousie University, 7-007 Victoria Building, Queen Elizabeth II Health Sciences Center, 1278 Tower Road, Halifax, Nova Scotia, B3H 2Y9, Canada
2 Department of Medicine, Dalhousie University, 4th Floor Bethune, 1278 Tower Road, Halifax, Nova Scotia, B3H 2Y9, Canada
3 Department of Public Health Sciences, University of Alberta, 13-106D Clinical Sciences Building, Edmonton, Alberta, Canada

Correspondence: Address correspondence and reprint requests to: Geoffrey A. Porter, MD, FRCSC; E-mail: geoff.porter{at}dal.ca.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Obesity has been shown to be associated with reduced survival in patients with invasive breast cancer (IBC), although the mechanisms for this finding are unclear. The objective of this study was to examine the effect of obesity on the presentation and pathologic staging of IBC.

Methods: From February 15, 2002, to February 15, 2004, all patients undergoing surgery for primary IBC at two institutions were enrolled in a prospective cohort study. National Institutes of Health criteria were used to categorize patients: normal or underweight (NW; body mass index <25 kg/m2), overweight (OW; body mass index 25–29.9 kg/m2), and obese or severely obese (OB; body mass index ≥30 kg/m2). Presentation and pathologic factors were then compared among groups.

Results: The study cohort consisted of 519 patients; 166 (32%) were NW, 177 (34%) were OW, and 176 (34%) were OB. OW (46%) and OB (39%) patients were more likely to be diagnosed with IBC via screening mammography compared with NW (31%) patients (P = .01), although no differences were found between groups with respect to previous use of screening mammography. Aggressive pathologic features, including lymph node metastases, advanced tumor-node-metastasis stage, and grade were found more commonly among OB patients.

Conclusions: OW and OB patients were more likely to receive a diagnosis via screening mammography, thus suggesting that mammography may play a more important role in OW and OB patients. Despite this, OB patients presented with larger, more advanced tumors; this may help to explain obesity-associated survival differences in IBC patients. This is important information given the prevalence of obesity in North America.

Key Words: Breast cancer • Presentation • Obesity • Mammography


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Obesity has reached epidemic proportions in North America. Obesity rates have more than doubled between the late 1970s and 2000, with a more marked increase in women than men.1,2 Although this phenomenon is multifactorial, there is evidence that a lack of physical activity has played a major role.3 With regard to cancer, there is evidence of an increased risk of the development of specific malignancies with obesity. This has been well demonstrated in endometrial carcinoma, adenocarcinoma of the esophagus, renal cell carcinoma, and colorectal carcinoma.4 In Canada, it has been estimated that excess body mass accounts for 7.7% of all cancers.5 In breast cancer, the relationship is more complex, with an increased risk of breast cancer among overweight postmenopausal women but with an apparent protective effect of obesity on breast cancer risk in premenopausal women.6–9

In addition to cancer risk, a recent large prospective cohort study by the American Cancer Society (the American Cancer Society Prevention Study) revealed significant increases in cancer mortality when all cancers were grouped together.10 The detrimental effect of obesity on prognosis seems to be most marked in esophageal, colorectal, gastric, liver, and kidney carcinoma, as well as breast carcinoma in women. Explanations for the detrimental prognosis have not been clearly elucidated, but several potential mechanisms have been suggested.11

The presentation of breast carcinoma is varied, but it can be broadly categorized as symptomatic, most commonly with a self-detected or physician-detected breast mass, or asymptomatic, based on an abnormal screening and subsequent diagnostic work-up. We hypothesized that there are obesity-related differences in breast cancer presentation, perhaps at least in part explaining the detrimental prognostic effect of obesity in breast carcinoma. Thus, the objective of this study was to examine the effect of obesity on the presentation and subsequent pathologic staging of operable invasive breast carcinoma.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
This consecutive cohort study included all patients who underwent surgery for invasive breast cancer at the Queen Elizabeth II Health Sciences Center or Dartmouth General Hospital, Halifax, Nova Scotia, Canada, from February 15, 2002, to February 15, 2004. All breast cancer surgery in the Capital Health District is performed at one of these two institutions; approximately 65% of all surgery in the province of Nova Scotia is performed in the Capital Health District. Exclusion criteria included patients <18 years of age, patients residing in provinces other than Nova Scotia, and patients who were mentally incapable of giving their own consent.

All surgeons of potential study participants agreed to participate in this process. Informed consent for medical record review and patient interview was obtained from all patients for the portion of the study involving a patient interview. This protocol had full approval of the Research Ethics Committee at the Queen Elizabeth II Health Science Center.

This study was a prospective/retrospective cohort design. All patients undergoing surgical resection for breast cancer were identified during their hospital admission on the basis of procedure and diagnosis information from the computerized operating room log. Once the patient was identified, a more detailed review of the hospital chart and the surgeon’s office chart, including all correspondence, was performed. If the patient met eligibility criteria, the study nurse visited the patient before surgery to explain the study and ask for patient participation. Upon informed consent from the patient, the study nurse conducted a 30-minute interview with the patient. Data involving presentation, diagnosis, and staging were collected from office charts, hospital charts, and a face-to-face patient interview. Strict criteria were used to define initial symptomatology, use of screening mammography, presentation to the first physician, diagnosis, and treatment. Diagnosis was defined by the histological presence of invasive breast carcinoma tissue biopsy, generally by preoperative core biopsy. For the purposes of this study, presentation with breast cancer was categorized as (1) asymptomatic via abnormal screening mammogram or (2) clinical.

Most required data regarding demographics, presentation, diagnosis, and treatment were obtained from the review of the surgeon’s and hospital charts. Any incomplete or discordant information, specifically regarding the timing of specific physician visits or investigations, was resolved in a systematic fashion by the principal investigator (G.A.P.) by using the following guiding principles:

  1. Objective dates from documents such as diagnostic test reports, operative reports, and physician visit notes were preferentially used.
  2. Where patient recall was involved, recollection to the nearest week (preferred) or month was sought; the middle day of the week or month was used as the reference for subsequent time interval calculations.
  3. Body mass index (BMI) was measured at the time of hospital admission for surgery. National Institutes of Health criteria were used to categorize patients: normal or underweight (NW; BMI <25 kg/m2), overweight (OW; BMI 25–29.9 kg/m2), and obese or severely obese (OB; BMI ≥30 kg/m2).

A small proportion of the study population underwent preoperative chemotherapy, radiotherapy, or both. These patients were identified and included in all time analyses up to and including the date of diagnosis.

Presentation and pathologic factors were then compared among the weight groups. Two-tailed tests were used at all times, and statistical significance was set a priori at P < .05. Statistical analyses were performed with SPSS for Windows 11.0 (SPSS Inc., Chicago, IL). All univariate analyses used Student’s t-test, analysis of variance, or {chi}2 tests, as appropriate. 12,13 Nonparametric methods were used when the distribution of continuous data did not approximate the normal distribution (e.g., most time data). Multivariate analysis, by logistic regression, was performed to evaluate factors associated with the presence of nodal metastases. This was performed by using a forward stepwise approach that incorporated all demographic and presentation variables examined; acceptance in the final model required significance at P >.10.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Over the time period of the study, 519 patients underwent resection for primary invasive breast carcinoma. The mean age of the study cohort was 60 years (SD, 15.5 years); other characteristics of the study cohort are listed in Table 1Go. Among patients presenting symptomatically, the most common presentation was a breast mass (85%), followed by pain (4%), nipple discharge (3%), skin changes (3%), and other (5%). The distribution of weight groups is depicted in Fig. 1Go; overall, 166 (32%) of patients were NW, 177 (34%) were OW, and 176 (34%) were OB. Overall, 144 (28%) patients had lobular pathologic characteristics.


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  		TABLE 1. Demographic and patient characteristics of the study cohort (n = 519)
 

Figure 1
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  		FIG. 1. Distribution of weight groups in the study cohort (n = 519).

 
Associations between demographic/presentation factors and weight groups are listed in Table 2Go. No significant differences in age, education level, geographical residence, ethnicity, or socioeconomic status were identified among weight groups. A trend, although not statistically significant, was noted between a higher 5-year breast cancer risk by the Gail model with increasing weight. A greater proportion of OW (46%) and OB (39%) patients had their breast cancer diagnosed as a result of an abnormal screening mammogram, compared with NW patients (31%). This occurred despite a similar previous use of screening mammography among weight groups.


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  		TABLE 2. Associations between weight groups and demographic/presentation factors (n = 519)
 
In attempting to further examine breast cancer presentation among weight groups, we compared time intervals between weight groups: specifically, the time from symptoms or abnormal screening mammogram results to diagnosis and the time from diagnosis to surgery. These are listed in Table 3Go. No differences were identified between weight groups in any examined time interval.


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  		TABLE 3. Presentation time intervals (median days) among weight groups
 
Aggressive pathologic features were identified more commonly with increasing weight (Table 4Go). Specifically, a larger tumor size, a higher incidence of lymph node metastases, a more advanced tumor-node-metastasis stage, and a smaller proportion of well-differentiated tumors were identified among OB patients. Estrogen receptor status seemed similarly distributed across weight groups.


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  		TABLE 4. Associations between pathologic factors and weight groups
 
Multivariate analysis was performed to identify demographic and presentation variables associated with the presence of lymph node metastases. Only increasing BMI and symptomatic presentation were found to be independently associated with nodal metastases (Table 5Go).


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  		TABLE 5. Multivariate analysis of demographic/presentation factors associated with lymph node metastases (n = 504)a
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
From a public health perspective, the effect of obesity is staggering, perhaps justifying its description as "the malnutrition of the developed world." 6 The average number of years of life lost per person as a result of obesity may be as high as 13, depending on age, sex, and the degree of obesity.14 The detrimental cancer risk and prognosis associated with obesity adds to the impetus for public health policy, planning, and health education to successfully address the problem of obesity.

In our study, we noted two basic weight-associated differences in the presentation of breast cancer. First, despite a similar use of screening mammography, obese patients were more likely to have their diagnosis made via screening mammography. A similar finding was noted in a study of >88,000 consecutive screening mammograms, in which increasing adiposity correlated with progressive increases in the rate of recall, biopsy, and cancer detection in women undergoing screening mammography.15 However, Elmore et al.16 noted a 20% increase in the risk of a false-positive screening mammography among obese women, although sensitivity was unchanged. Operating characteristics of screening mammography were significantly improved in normal-weight patients. Taken together, this would suggest that the importance of screening mammography may be greater for overweight and obese patients, even though adiposity detrimentally affects its operational characteristics. Unfortunately, a retrospective blinded review of all mammograms was not performed in this study for logistical reasons related to the availability of mammograms performed throughout the province. Such an approach may have provided insight into the effect of obesity of mammogram patterns and interpretability.

The second major weight-associated difference found in this study, somewhat contradictory to the first, was that obese patients had larger, more advanced stage tumors and were more likely to have other adverse pathologic features, including lymph node metastases and a higher grade. The increased incidence of nodal metastases persisted on multivariate analysis (Table 5Go), thus suggesting an independent association between obesity and nodal disease. Several studies have examined the pathologic stage of breast cancer associations with obesity. Most such studies suggest an association with being overweight and having a later stage at diagnosis, although there is some disagreement.17–19 The data regarding a positive association between obesity and lymph node status are not as consistent. Daniell et al.20 demonstrated an independent association between lymph node metastases and obesity that was supported by Schapira et al.,21 who showed that, in a study of 248 women, obese postmenopausal women were more likely to have axillary node metastases than normal weight patients. However, in a retrospective cohort study of 966 newly diagnosed breast cancer cases between 1991 and 1997 in Baltimore, MD, there was no statistically significant increase in lymph node metastases when patients were dichotomized in terms of median BMI (27.3 kg/m2).19 However, a significantly increased risk of stage ≥II disease was found among patients with BMI ≥30 kg/m2 (adjusted odds ratio of 1.53 compared with normal weight).

Several hypothetical mechanisms could explain the association of obesity and more advanced pathologic features of breast cancer at diagnosis. One is that obese patients may be more likely to have a delayed diagnosis because of the difficulty in identifying palpable lesions in larger breasts. Delayed diagnosis has been found in several studies to be associated with a more advanced stage of disease.22–24 However, the standardized, comprehensive time interval data collection used in this study did not suggest any more delay in prediagnostic intervals among overweight or obese patients.

There may also be obesity-associated differences in the hormonal milieu which result in tumor progression. It is well understood that in postmenopausal women, most estrogen production is in the peripheral adipose tissue, via the aromatization of androstenedione to estrone, which is then converted to estradiol. 25,26 This process is increased in obese and overweight patients. Also, low levels of sex hormone–binding globulins are associated with obesity, and this results is a higher proportion of unbound and, thus, bioavailable estradiol.27,28 Increased levels of estradiol are key to the development and growth of breast cancer.29 Other potential mechanisms for weight-associated pathologic differences include increased levels of insulin and insulin-like growth factors and increased levels of cortisol and leptin among overweight and obese women.11,30

Several recent studies have identified that the increased risk of breast cancer attributable to hormone-replacement therapy seems to involve a disproportionate increase in lobular carcinoma pathology.31,32 Unfortunately, our data collection did not include previous or current use of hormone-replacement therapy. No significant differences in histological subtype were identified according to weight group, although this study may be underpowered to identify clinically significant differences.

Limitations in our study include the single peri-operative measure of weight used to determine BMI. This does not take into account any breast cancer–related weight loss or the effect of a rapid change in weight over a short period of time before diagnosis. Given that there were only a very small number of patients with metastatic disease in our study and that all that such patients were asymptomatic, we believe that it is unlikely that a significant disease-related weight loss existed in this cohort. The limited sample size and the fact that the study cohort was not truly population based may limit the generalizability of this study. Finally, clarity regarding the causality and biological mechanisms for the findings identified in this study requires further research.

In conclusion, this study demonstrated some differences related to weight in the presentation of breast cancer. The paradoxical increased tumor size seen among obese patients despite a higher reliance on mammography for diagnosis would seem to underscore the importance of screening mammography in this group. In addition, pathologic findings, including stage, nodal metastasis, and grade, were worse among obese patients. This perhaps at least partially explains the reproducible poorer prognosis among obese breast cancer patients.


   ACKNOWLEDGMENTS
 
The authors thank Janet Hartnett and John Fris for administrative assistance related to the manuscript. Supported by Nova Scotia Health Research Foundation grant 40561 and the Clinical Scholars program at Dalhousie University.

Received for publication March 4, 2005. Accepted for publication August 31, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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