Presented as poster P2-12-02 at the 34th Annual San Antonio Breast Cancer Symposium 2011; December 6-11, 2011; San Antonio, Texas.
Data suggest that weight, and specifically body mass index (BMI), plays a role in breast cancer development and outcome. The authors hypothesized that there would be a correlation between BMI and clinical outcome in patients with early stage, human epidermal receptor 2 (HER2)-positive breast cancer enrolled in the N9831 adjuvant trial.
Patients were grouped according to baseline BMI as follows: normal (BMI <25 kg/m2), overweight (BMI ≥25 kg/m2 and <30 kg/m2), and obese (BMI ≥30 kg/m2). Disease-free survival (DFS) was estimated using the Kaplan-Meier method. Comparisons between treatment arms A, B, and C (chemotherapy with or without trastuzumab) were performed using a stratified Cox proportional hazards model.
Analysis was completed on 3017 eligible patients. Obese patients were more likely to be older and postmenopausal (P < .0001 for both), to have larger tumors (P = .002), and to have positive lymph nodes (P = .004). In the pooled analysis cohort, differences in DFS among the BMI groups were statistically significant (5-year DFS rate: 82.5%, 78.6%, and 78.5% for normal weight, overweight, and obese women, respectively; log-rank P = .02). The adjusted hazard ratio comparing the DFS of overweight women with the DFS of normal women was 1.30 (95% confidence interval, 1.06-1.61); and, comparing the DFS of obese women with the DFS normal women, the adjusted hazard ratio was 1.31 (95% confidence interval, 1.07-1.59). There were no statistically significant differences in DFS by weight group for women within any trial arm.
Obesity, as defined as a body mass index (BMI) ≥30 kg/m2 according to the World Health Organization, is a significant public health issue and has been associated with increased death rates for essentially all cancers, including breast cancer.[1-3] Previous studies also have demonstrated that obesity (high BMI) is a risk factor for the development of new cases of breast cancer and also negatively affects disease-free survival (DFS) after a diagnosis of this disease.[4-9] Previous studies have indicated that obese patients, compared with nonobese patients, tend to be older, have larger tumor size, and have increased levels of axillary lymph node involvement.[10, 11]In view of the established relation between estrogen levels and obesity, most studies have examined the correlation of DFS with BMI and hormone receptor status; positive estrogen receptor (ER) status; endocrine therapy; and, most, recently triple-negative breast cancer.[7-9, 12-15] These studies have demonstrated that, among postmenopausal women, an increased BMI is associated with ER-positive/progesterone receptor (PR)-positive status and an increased risk (up to 33%) of breast cancer.[8, 9] However, data on newer, specific subtypes of breast cancer, such as human epidermal growth factor 2 (HER2)-positive disease, are not available. HER2-positive breast cancer, defined as protein overexpression or gene amplification, affects approximately 15% to 20% of patients who have invasive breast cancer. Moreover, a potential impact of BMI on the efficacy of adjuvant trastuzumab had not been reported, which prompted our study; we hypothesized that this may be particularly relevant, based on the cross-signaling pathways between HER2 and other metabolic pathways, such as the estrogen and insulin growth factor pathways.
Our group has conducted a large adjuvant trial (North Central Cancer Treatment Group, now part of the Alliance for Trials in Clinical Oncology]; trial N9831), which enrolled more than 3500 patients who had a diagnosis of HER2-positive, early stage breast cancer, allowing us the opportunity to explore correlations patient outcomes with BMI, HER2-positive breast cancer, and chemotherapy with or without trastuzumab. Our independent N9831 trial, the joint efficacy analysis of the N9831 trial with the National Surgical Adjuvant Breast Project B-31 clinical trial, as well as other well conducted trials, demonstrated that adding trastuzumab to standard chemotherapy significantly improved DFS and overall survival in the overall group of patients with HER2-positive, early stage breast cancer and provided the basis for an analysis of the potential impact of BMI on various pathologic and outcome parameters.[18-21] This report presents baseline BMI and its relation to tumor characteristics and DFS in patients who received either chemotherapy alone or chemotherapy with trastuzumab on the N9831 adjuvant clinical/translational trial.
MATERIALS AND METHODS
The randomized phase 3 North Central Cancer Treatment Group trial N9831 enrolled 3505 women aged ≥18 years with primary, operable, lymph node-positive or high-risk lymph node-negative, HER2 positive adenocarcinoma of the breast who were eligible for adjuvant chemotherapy.[18, 19] All tumors were required to be HER2-positive by either fluorescence in situ hybridization (FISH) demonstrating gene amplification (≥2.0 ratio) or immunohistochemistry (IHC) assay indicating a strongly positive score (3+; 10% of cells with circumferential membrane staining). Complete resection of the primary tumor and axillary-node evaluation were required. All patients gave written, informed consent.
Eligible patients enrolled in the N9831 trial were assigned randomly to 1 of 3 arms. In arm A (the control arm), patients received doxorubicin/cyclophosphamide (AC) (60/600 mg/m2 every 3 weeks × 4) followed by paclitaxel (P) (80 mg/m2 weekly × 12); in arm B (the sequential arm), patients received similar AC, followed by paclitaxel, and then followed by trastuzumab (4 mg/kg loading dose, then 2 mg/kg for 52 weeks); and, in arm C (the concurrent arm), patients received AC followed by paclitaxel concurrently with trastuzumab (4 mg/kg loading dose, then 2 mg/kg for 11 weeks) followed by trastuzumab alone (2 mg/kg for an additional 40 weeks). After the completion of chemotherapy, all patients received radiation therapy and/or hormonal therapy as clinically indicated.[18, 19]
BMI (defined as weight in kilograms divided by the square of the height in meters [kg/m2]) was calculated from baseline body surface area (BSA) and weight obtained from the baseline case report forms, whereas height was not recorded. The formula used to compute BMI from BSA and weight was: BMI = (weight)/(1296 × BSA). Each study site used their own method to determine the BSA of each woman as reported on the baseline case report form, from which we calculated the BMI.
The primary analysis of the report herein was to define whether DFS differed according to BMI and whether there was a treatment-by-BMI interaction. The primary analysis categorized BMI as normal weight (BMI <25 kg/m2), overweight (25 ≤BMI <30 kg/m2), and obese (BMI ≥30 kg/m2). A second analysis was performed that treated BMI as a continuous variable.
DFS, the primary endpoint, was defined as the time from registration to the first disease-related event. A disease-related event was a local, regional, or distant breast cancer recurrence; contralateral breast cancer; a new primary cancer (except squamous or basal cell carcinoma of the skin, carcinoma in situ of the cervix, or lobular carcinoma in situ of the breast); or death from any cause. DFS was estimated using the Kaplan-Meier methods, and DFS curves among different groups were compared using the log-rank test. Comparisons were made of DFS among BMI groups for women pooled across the 3 treatment arms and within each treatment arm.
Patients were grouped according to BMI status based on their baseline BMI value. Categorical variables between groups (eg normal vs overweight vs obese) were compared using the chi-square test. Continuous variables were compared between groups with a 2-sample t test. A stratified Cox proportional hazards analysis, stratified by hormone receptor status and lymph node status and adjusted for race and age, was used to generate hazard ratios (HRs) and 95% confidence intervals (CIs). In addition to determining the effect of treatment and BMI status on DFS, a Cox model was used to assess the potential interaction between treatment arm and BMI status.
A secondary analysis was performed using breast-cancer specific survival (BCSS) as an endpoint. An event was defined as a death from breast cancer, and deaths from other causes were censored. A two-sided P value < .05 was considered statistically significant. Statistical analyses were performed using SAS version 9.2 (SAS Institute, Inc., Cary, NC).
There were 3505 women enrolled on the N9831 trial, and the current investigation was performed on an analysis cohort of 3017 women. The 488 women who were excluded from the original cohort were 1) 283 women who did not have HER2-positive tumors upon central laboratory testing, 2) 61 women who were ineligible for study entry, 3) 28 women who withdrew consent before receiving any protocol-directed treatment, and 4) 116 women who were lost to follow-up. Within the analysis cohort, 877 women (29%) were classified with a normal BMI, 842 women (28%) were classified as overweight, and 1298 women (43%) were classified as obese.
Patient and Tumor Characteristics by Body Mass Index Groups
Patient characteristics for the 3017 eligible patients are listed in Table 1. Overweight and obese women were more likely to be older, postmenopausal, and nonwhite compared with normal weight women. In addition, overweight and obese women were more likely to have larger tumors. Normal and overweight women were also more likely to have breast cancer lymph node involvement compared with obese women. A greater proportion of obese women had hormone receptor-positive disease compared with overweight and normal weight women, but this difference was not statistically significant. No statistically significant differences were observed in predominant tumor histology or histologic tumor grade among the normal weight, overweight, and obese groups.
Table 1. Patient Characteristics by Body Mass Index Groups
No. of Patients (%)
BMI <25 kg/m2 N = 877
BMI ≥25 to BMI<30 kg/m2 N = 842
BMI ≥30 kg/m2 N = 1298
Abbreviations: BMI, body mass index; ER, estrogen receptor; PR, progesterone receptor; SBR, Scarff-Bloom-Richardson grading system.
Age: Median [range], y
Age group, y
Premenopausal or aged <50 y
Postmenopausal or aged ≥50 y
ER or PR positive
ER and PR negative
Lymph node status
Predominant tumor histology
Histologic tumor grade: Elston/SBR
Pathologic tumor size, cm
Table 2 compares the treatment characteristics (type of surgery, receipt of hormone therapy, and timing of trastuzumab) among the 3 groups determined by baseline BMI classifications. Obese women were more likely to undergo breast-conserving surgery compared with normal weight women and overweight women. The differences in the proportions of women who received hormone treatment among the 3 groups were not significant. The proportions of normal weight, overweight, and obese women did not differ across treatment groups (P = .86).
Table 2. Treatment Summary by Body Mass Index
No. of Patients (%)
BMI <25 kg/m2 N = 877
BMI ≥25 to <30 kg/m2 N = 842
BMI ≥30 kg/m2 N = 1298
Abbreviations: BMI, body mass index; HT,< hormone treatment.
A: No trastuzumab
B: Sequential trastuzumab
C: Concurrent trastuzumab
Body Mass Index and Survival
There were 647 disease-related events in the analysis cohort of 3017 women. At the time of analysis, 360 women in the analysis cohort had died, including 292 deaths from breast cancer. The median follow-up for women who remained disease-free was 5.3 years.
In the pooled analysis cohort (ie, pooling patients across the 3 treatment arms), the difference in DFS among normal weight, overweight, and obese women was statistically significant (Table 3, Fig. 1): the adjusted HR comparing the DFS of overweight women with the DFS of normal weight women was 1.30 (95% CI, 1.06-1.61), and the adjusted HR comparing the DFS of obese women with the DFS of normal weight women was 1.31 (95% CI, 1.07-1.59). The 5-year DFS rates were 82.5%, 78.6%, and 78.5% for normal weight, overweight, and obese women, respectively. However, the DFS did not appear to differ significantly between overweight and obese women for the pooled cohort.
Table 3. Disease-Free Survival Within Treatment Arms Based on Body Mass Index
The effect of treatment did not statistically differ according to BMI classified as normal, overweight, and obese. The treatment arm, by obesity status interaction terms, was not significant, although this analysis was underpowered. Table 3 contains a summary of the DFS for the 3 BMI groups within each treatment arm; and Figure 2 displays the DFS according to the BMI groups within each treatment arm: the control group, which did not receive trastuzumab (arm A), the group that received sequential trastuzumab (arm B), and the group that received concurrent trastuzumab (arm C). It appears that normal weight women had a better DFS experience than overweight and obese women in the control arm (Fig. 2, top) and in the sequential trastuzumab arm (Fig. 2, middle), although the differences among the 3 groups were not statistically significant. It is noteworthy that there does not appear to be a difference in the DFS experience among the 3 BMI groups on the concurrent trastuzumab arm (Fig. 2, bottom); in particular, the normal weight women did not appear to have a better DFS than the other 2 groups.
We also analyzed BMI as a continuous variable (results not shown). All BMI-by-treatment variable interaction terms, again, were nonsignificant.
The conclusions were similar for the BCSS analysis. In the pooled analysis, there were differences among the 3 BMI groups, but these were not statistically significant: the 5-year BCSS rates were 93%, 91.3%, and 91.3% for normal weight, overweight, and obese women, respectively (P = .13). The effect of treatment did not differ by BMI group, the treatment arm-by-BMI group interaction terms were not statistically significant. The survival curves of the 3 BMI groups for each treatment arm appear similar to those illustrated in Figure 2 (data not shown). The differences in BCSS for the BMI groups within each arm were not statistically significant (P = .29 for arm A; P = .11 for arm B; and P = .67 for arm C).
To the authors' knowledge, this is the first study to specifically investigate the relation of BMI with the HER2-positive biologic subtype of early stage breast cancer and its association with adjuvant therapy, including trastuzumab. Our data from the N9831 study demonstrated an association between BMI, certain breast cancer features, and clinical outcome. With regard to breast cancer features, overweight and obese patients with HER2-positive tumors were more likely to be aged >50 years, postmenopausal, and more likely to have larger tumors. However, normal and overweight women were more likely to have positive lymph node involvement. We also noted that there was a trend (although not statistically significant) for a greater proportion of obese women to have hormone receptor-negative disease compared with nonobese women, which was a somewhat surprising finding compared with what we had expected.
Regarding the analysis of BMI and clinical outcome, our study demonstrated that, when taking into account all patients across the 3 treatment arms, there was a statistically significant correlation between rising BMI and worse clinical outcome in patients who had early stage, HER2-positive breast cancer. In this overall study population, those patients who had normal BMI had a better 5-year DFS compared with overweight and obese women (82.5% vs 78.5%). Considering that overweight and obese patients in this cohort were more likely to be postmenopausal, these results are similar to the experience reported by many national and international groups, especially in women with early stage, hormone receptor-positive breast cancer.[4, 22, 23]
We also analyzed the relation of BMI with the type of adjuvant therapy received. One of the major weaknesses of this study is that it is underpowered to detect small statistical differences between the 3 different treatment arms, their interaction with the 3 BMI groups, and their respective clinical outcome. Although the results did not reach statistical significance, we note that, for the patients who did not receive adjuvant trastuzumab (arm A), normal weight women had better DFS experience than overweight and obese women. Such differences were no longer noted in the concurrent trastuzumab arm (C). Despite the caveats previously mentioned, this probably represents an important finding of this study: that adjuvant trastuzumab appears to improve the clinical outcome of all patients regardless of their BMI. Although DFS may have been unduly affected by comorbidities and new events, the finding that the addition of trastuzumab seemed to negate much of the impact of obesity argues that this is not the case and that there is some real interaction between BMI and breast cancer outcomes.
Sparano et al recently evaluated the correlation between BMI and outcomes in 6885 patients enrolled in 3 adjuvant trials coordinated by the Eastern Cooperative Oncology Group (E1199, E5188, and E3189). When obesity was evaluated as a categorical variable, it was associated with inferior DFS (HR, 1.24; 95% CI, 1.06-1.46; P = .0008) and OS (HR, 1.37; 95% CI, 1.13-1.67; P = .002) in hormone receptor-positive disease, but not in other subtypes (HER2-positive or triple-negative). However, the difference in outcome may have been caused by the smaller sample size (n = 940), because only patients from the E1199 trial underwent routine HER2 testing, and the multivariate analysis for an interaction of BMI and clinical outcome (DFS, OS, and BCSS) was analyzed only in the context of obese patients (BMI ≥30 kg/m2; n = 302) versus nonobese patients (BMI <30 kg/m2; n = 597). We also found statistical significance was lost when the analysis did not take into account the 3 different BMI subgroups (data not shown).
The exact biologic cause-effect relation between increased BMI and the risk of developing breast cancer, tumor characteristics, and risk of disease recurrence in patients with early stage breast cancer in HER2-positive and other subtypes of breast cancer is a matter requiring additional studies. Several hypotheses to explain the relation of BMI etiology with breast cancer incidence and characteristics have been brought forth, including sex steroids, insulin levels, insulin-like growth factors and their downstream Ras and microtubule-associated protein kinase pathways, adipokines, hypoxia, genetic susceptibility, migrating adipose stem cells, and leptin, among others.[22, 24-30] It has also been hypothesized that increased concentrations of circulating estrogen may contribute to these differences, partially because of the peripheral aromatization of androstenedione to estrogen in adipose tissue.[26, 31] The increased concentration of circulating estrogens also may be caused by lower levels of sex hormone-binding globulin in obese, postmenopausal women. Insulin-like growth factor (IGF) receptor (IGFR) signaling is involved in the growth and resistance to therapy of breast cancer cells. Expression of IGFR has been correlated with obesity, and increased IGF-binding protein 3 expression has been correlated with increasing BMI.[24, 28] IGF also plays an important role in signaling with HER2 with cross-talk between IGFR and HER2 present in trastuzumab resistant cells. Leptin and its associated receptor are overexpressed in breast cancer, are involved in cross-talk with the HER2 pathway, and have been associated with obesity and worse outcomes.[22, 29, 33] Future studies to expand the literature regarding the effect of weight reduction toward normal BMI (and influence pathways that may impact cellular effects of obesity, such as insulin and exercise) for patients diagnosed with breast cancer (and other cancers) while obese deserve significant priority.[22, 34, 35]
Putting our data into clinical perspective, we observed that adjuvant trastuzumab led to an improvement in DFS for all patients, regardless of their BMI, as indicated in Figures 1 and 2. However, the patients who had the best clinical outcome were normal weight patients who were treated with concurrent (arm C) trastuzumab and chemotherapy (5-year DFS rate, 85.4%), followed by the other patients in the concurrent trastuzumab treatment arms but grouped as either overweight or obese (5-year DFS rate, 85.1% and 82.6%, respectively). It remains uncertain whether weight loss intervention programs after a breast cancer diagnosis could meaningfully reduce the risk of recurrence. However, these data support the concept that having a normal BMI at the time of diagnosis and being treated with concurrent anti-HER2 therapy plus chemotherapy leads to the best long-term outcome.
This work was supported by grants from the National Institutes of Health (CA25224 and CA114740) and by the Breast Cancer Research Foundation.