Body Mass Index and Weight Change in Patients With HER2-Positive Early Breast Cancer: Exploratory Analysis of the ALTTO BIG 2-06 Trial

View More View Less
  • 1 Department of Hemato-Oncology, CISSS Montérégie Centre/Hôpital Charles Le Moyne, Université de Sherbrooke, Greenfield Park, Quebec, Canada;
  • | 2 Department of Internal Medicine and Medical Specialties, School of Medicine, University of Genova, IRCCS Ospedale Policlinico San Martino, Genova, Italy;
  • | 3 Frontier Science, Kingussie, United Kingdom;
  • | 4 Department of Medicine, Camargo Cancer Center, Sao Paulo, Brazil;
  • | 5 Institut Jules Bordet and L’Université Libre de Bruxelles (U.L.B.), Brussels, Belgium;
  • | 6 Breast International Group, Brussels, Belgium;
  • | 7 National Cancer Institute, Bethesda, Maryland;
  • | 8 Novartis Pharma AG, Basel, Switzerland;
  • | 9 Mayo Clinic, Jacksonville, Florida;
  • | 10 University of Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Cologne, Germany;
  • | 11 Laboratory for Translational Breast Cancer Research, Department of Oncology, Leuven, Belgium; and
  • | 12 Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: The association between obesity and prognosis in HER2-positive early breast cancer remains unclear, with limited data available. This study aimed to determine the impact of body mass index (BMI) at baseline and weight change after 2 years on outcomes of patients with HER2-positive early breast cancer. Methods: ALTTO was a randomized phase III trial in patients with HER2-positive early breast cancer. BMI was collected at randomization and 2 years after. WHO BMI categories were used: underweight, <18.5 kg/m2; normal weight, 18.5 to <25 kg/m2; overweight, ≥25 to <30 kg/m2; and obese ≥30 kg/m2. A weight change from baseline of ≥5.0% and ≤5.0% was categorized as weight gain and weight loss. The impact of BMI at randomization and of weight change on disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) were investigated with multivariate analyses, adjusting for baseline patients and tumor characteristics. Results: A total of 8,381 patients were included: 187 (2.2%), 3,797 (45.3%), 2,690 (32.1%), and 1,707 (20.4%) were underweight, normal weight, overweight, and obese at baseline, respectively. Compared with normal weight, being obese at randomization was associated with a significantly worse DDFS (adjusted hazard ratio [aHR], 1.25; 95% CI, 1.04–1.50) and OS (aHR, 1.27; 95% CI, 1.01–1.60), but no significant difference in DFS (aHR, 1.14; 95% CI, 0.97–1.32). Weight loss ≥5.0% at 2 years after randomization was associated with significantly poorer DFS (aHR, 1.34; 95% CI, 1.05–1.71), DDFS (aHR, 1.46; 95% CI, 1.07–1.98), and OS (aHR, 1.83; 95% CI, 1.18–2.84). Hormone receptor and menopausal status but not anti-HER2 treatment type influenced outcomes. Toxicities were more frequent in obese patients. Conclusions: In patients with HER2-positive early breast cancer, obesity at baseline is a poor prognostic factor. Weight loss during treatment and follow-up negatively impacts clinical outcomes. Dietary counseling should be part of survivorship care programs.

Background

The burden of obesity is significant, with an estimated prevalence of 12.0% among adults worldwide.1 The prevalence of obesity is even higher among cancer survivors,2 and the annual increase is greater among survivors of breast cancer compared with women without a history of cancer.3 Furthermore, obesity may have an impact on patient outcomes. Multiple meta-analyses including patients with breast cancer have shown an increased risk of death and breast cancer mortality among women who are obese compared with those of normal weight. This association was observed irrespective of hormone receptor and menopausal status.46 Moreover, a recent meta-analysis including 213,075 patients with breast cancer showed that each 5 kg/m2 increment in baseline body mass index (BMI) after breast cancer diagnosis was associated with worse outcomes.6

Breast cancer is a heterogeneous disease, and studies analyzing the association between obesity and prognosis specifically in HER2-positive early breast cancer have reported inconclusive results. The limited available data derive from randomized trials comparing chemotherapy ± adjuvant trastuzumab. In the NSABP B-31 trial, being overweight or obese at diagnosis was not associated with significantly different overall survival (OS) and breast cancer recurrence compared with being of normal weight.7 In contrast, the NCCTG N9831 trial showed that obese patients at baseline had a significantly worse 5-year disease-free survival (DFS) compared with those of normal weight. In this study, trastuzumab efficacy appears to be present in normal, overweight, and obese subgroups in an underpowered analysis.8 A recent analysis conducted within the HERA trial showed no impact of baseline BMI on the clinical outcomes of patients with HER2-positive breast cancer.9 In this study, information on BMI 1 year after treatment was also available: no effect on clinical outcomes of weight change at this time point was observed.9 Taken together, these studies have several caveats, including the limited sample size of the analyses and the presence of patients not treated with anti-HER2 therapy.

The ALTTO BIG 2-06 trial, which is the largest adjuvant study evaluating trastuzumab and/or lapatinib in HER2-positive early breast cancer, showed that the addition of lapatinib to adjuvant treatment did not improve DFS.10 Information on height and weight was collected as part of the trial. Therefore, this represented a unique opportunity to capture the relationship between BMI and outcomes in HER2-positive breast cancer. Our exploratory analysis of the ALTTO trial aimed to determine the impact of BMI and weight change in patients with HER2-positive early breast cancer treated with chemotherapy + trastuzumab and/or lapatinib.

Methods

Study Design

This is an unplanned exploratory analysis of the ALTTO BIG 2-06 trial. ALTTO was a randomized phase III study that evaluated the role of trastuzumab and/or lapatinib as adjuvant treatment in 8,381 patients with HER2-positive early breast cancer.6,7 Patients were randomized to 1 of 4 anti-HER2 treatment arms of 52-week duration: trastuzumab alone (n=2,097), lapatinib alone (n=2,100), trastuzumab for 12 weeks followed by lapatinib for 34 weeks (n=2,091), or combination trastuzumab + lapatinib (n=2,093).

Approval by the Ethics Committees or Independent Review Boards of all participating institutions was obtained. Before study entry, written informed consent was obtained from all participating patients. The ALTTO Executive Committees and Steering Committees approved the present analysis prior to conduction.

Study Population

All patients participating in ALTTO regardless of randomization arm were eligible. Height and weight were collected for all patients at 2 time points: at baseline, which corresponds to the time of randomization (ie, before starting anti-HER2–targeted therapy), and at 2 years after randomization. BMI was calculated by dividing weight by height squared (kg/m2), as per normal standard.12 Patients were classified into 4 different groups according to the WHO BMI classification: underweight, <18.50 kg/m2; normal, 18.50 to <25 kg/m2; overweight, ≥25 to <30 kg/m2; and obese ≥30 kg/m2.12

BMI at randomization was available for all patients included in ALTTO. Patients with available information on baseline BMI but without information on weight at 2 years after randomization were included only in the analysis related to the prognostic impact of BMI at diagnosis.

Objectives and Endpoints

The present analysis aimed to determine the prognostic impact of baseline BMI and weight change at 2 years after randomization in patients with HER2-positive early breast cancer.

Study endpoints were DFS, distant disease-free survival (DDFS), and OS defined as in the original ALTTO trial.10

Statistical Considerations

Patient baseline characteristics were compared with respect to BMI category (underweight, normal weight, overweight, obese) using the chi-square test.

Weight change was calculated as a percentage (by calculating the difference between baseline weight and weight at 2 years after randomization). According to weight change, patients were classified into 3 categories (weight loss, defined as loss of ≥5.0% from baseline; weight gain, defined as gain of ≥5.0% from baseline; and stable weight, defined as loss or gain <5.0% from baseline). The 5.0% cutoff point was chosen for consistency with a prior study,13 and because this value reflects a clinically significant weight change that accounts for measurement errors or normal fluctuations.14

The relationships between baseline BMI and weight change at 2 years after randomization and DFS, DDFS, and OS were evaluated in the whole study population and then in predefined patients’ subgroups according to type of anti-HER2 treatment received (trastuzumab alone, lapatinib alone, trastuzumab followed by lapatinib, and trastuzumab + lapatinib), hormone receptor status (positive or negative), and baseline menopausal status (premenopausal or postmenopausal). Survival curves for DFS, DDFS, and OS according to baseline BMI categories and weight change categories were estimated using the Kaplan-Meier method. Log-rank tests were performed for comparison. A multivariate analysis using a Cox proportional hazard model was used to generate hazard ratios. Only multivariate analyses are reported.

To evaluate the relationship between weight change and outcomes, a conditional landmark analysis approach was applied to reduce the impact of guarantee-time bias. Two years was the cutoff selected as the landmark. Median follow-up time (Q1–Q3) was derived from the reverse Kaplan-Meier method. DFS, DDFS, and OS were calculated excluding the first 2 years after randomization for each subject. Finally, the impact of weight change at 2 years after randomization within each baseline BMI category was evaluated.

All statistical tests were 2-sided, and P values <.05 were considered statistically significant. Analyses were performed using SAS 9.4 (SAS Institute Inc).

Results

All 8,381 patients randomized in ALTTO were included, of whom 187 (2.2%), 3,797 (45.3%), 2,690 (32.1%), and 1,707 (20.4%) were underweight, normal weight, overweight, or obese at baseline, respectively. Most patients were White (69%) or Asian (26%). Median follow-up at the time of the present analysis was 4.5 years (range, 3.6–5.0 years) (Figure 1).

Figure 1.
Figure 1.

CONSORT flow diagram.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 19, 2; 10.6004/jnccn.2020.7606

Obese patients were more likely to come from Europe (P<.001), to be White (P<.001), to be younger (<65 years; P<.001), to be postmenopausal (P<.001), and to have tumors >2 and ≤5 cm (P<.001) that are more often poorly differentiated (P<.001). Additionally, significant differences existed in this sample between the management of patients with obesity versus normal weight; those with obesity were more likely to have been treated with mastectomy (P<.001), anthracycline-based chemotherapy (P<.001), and aromatase inhibitors (P<.001) (Table 1).

Table 1.

Patient Demographics and Clinical Characteristics by BMIa

Table 1.

Prognostic Impact of Baseline BMI

Compared with patients of normal weight, those who were obese at baseline experienced significantly worse DDFS (adjusted hazard ratio [aHR], 1.25; 95% CI, 1.04–1.50) and OS (aHR, 1.27; 95% CI, 1.01–1.60), with no significant difference in DFS (aHR, 1.14; 95% CI, 0.97–1.32) (Figure 2A, C; supplemental eTable 1, available with this article at JNCCN.org). Compared with patients of normal weight, no significant differences were observed in those who were overweight or underweight, respectively, with regard to DFS (aHR, 1.03; 95% CI, 0.90–1.17, and aHR, 1.06; 95% CI, 0.70–1.59), DDFS (aHR, 1.11; 95% CI, 0.94–1.30, and aHR, 1.14; 95% CI, 0.70–1.86), and OS (aHR, 1.11; 95% CI, 0.91–1.36, and aHR, 1.64; 95% CI, 0.97–2.78).

Figure 2.
Figure 2.

Kaplan-Meier plot of (A) DDFS, (B) DFS, and (C) OS by baseline BMI categories. Underweight: BMI<18.50 kg/m2; normal weight: 18.50≤BMI<25 kg/m2; overweight: 25≤BMI<30 kg/m2; obese: BMI≥30 km/m2.

Abbreviations: BMI, body mass index; DDFS, distant disease-free survival; DFS, disease-free survival; OS, overall survival.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 19, 2; 10.6004/jnccn.2020.7606

No significant interaction was observed between BMI categories and menopausal status at randomization (P=.563 for interaction). In the cohort of postmenopausal patients, obesity at baseline was associated with worse DFS (aHR, 1.26; 95% CI, 1.03–1.53), DDFS (aHR, 1.35; 95% CI, 1.06–1.71), and OS (aHR, 1.41; 95% CI, 1.06–1.88). In the cohort of premenopausal patients, baseline BMI did not impact prognosis (supplemental eTables 2 and 3).

No significant interaction was observed between BMI categories and hormone receptor status (P=.541 for interaction). In the cohort of hormone receptor–positive patients, baseline BMI did not impact prognosis. In the cohort of hormone receptor–negative patients, baseline BMI did not impact prognosis except for baseline obesity and overweight, which were associated with worse DDFS (aHR, 1.34; 95% CI, 1.05–1.73 and aHR, 1.30; 95% CI, 1.04–1.62, respectively) (supplemental eTables 4 and 5).

No significant interaction was observed between BMI categories and anti-HER2 treatment administered (P=.517 for interaction). Outcomes according to baseline BMI were not affected by anti-HER2 treatment; the only exception was for the trastuzumab followed by lapatinib arm, in which being underweight was associated with worse OS (aHR, 3.08; 95% CI, 1.27–7.45) (supplemental eTables 6–9).

Prognostic Impact of Weight Change

The prognostic value of weight change was assessed in 6,720 patients (80%). For the remaining 1,661 patients (20%), BMI at 2 years was not available due to the occurrence of a DFS event with the 2-year visit in 646 (39%), loss to follow-up for 74 (4%), and missing data on baseline weight for 11 (0.7%).

Weight loss ≥5.0% at 2 years after randomization was associated with worse DFS (aHR, 1.34; 95% CI, 1.05–1.71), DDFS (aHR, 1.46; 95% CI, 1.07–1.98), and OS (aHR, 1.83; 95% CI, 1.18–2.84) (Figure 3A, C). Weight gain ≥5.0% at 2 years after randomization did not affect DFS (aHR, 1.16; 95% CI, 0.96–1.40), DDFS (aHR, 1.25; 95% CI, 0.99–1.59) or OS (aHR, 1.21; 95% CI, 0.82–1.77) (Figure 3A, C; supplemental eTable 10).

Figure 3.
Figure 3.

Kaplan-Meier plot of (A) DDFS, (B) DFS, and (C) OS by weight change from baseline. A weight change from baseline of ≥5.0% and ≤5.0% was categorized as weight gain and weight loss, respectively.

Abbreviations: BMI, body mass index; DDFS, distant disease-free survival; DFS, disease-free survival; OS, overall survival.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 19, 2; 10.6004/jnccn.2020.7606

No significant interaction was observed between weight change at 2 years after randomization and menopausal status (P=.425 for interaction). In the cohort of postmenopausal patients, no impact of weight change at 2 years after randomization was observed. In premenopausal patients, weight loss was associated with worse DFS (aHR, 1.57; 95% CI, 1.11–2.22), DDFS (aHR, 1.97; 95% CI, 1.29–3.02), and OS (aHR, 2.97; 95% CI, 1.55–5.68), and weight gain was associated with worse DDFS (aHR, 1.51; 95% CI, 1.06–2.14) (supplemental eTables 11 and 12).

No significant interaction was observed between weight change at 2 years after randomization and hormone receptor status (P=.182 for interaction). In the cohort of hormone receptor–positive patients, weight loss appeared to be associated with significant worse DFS (aHR, 1.46; 95% CI, 1.07–1.99) and OS (aHR, 2.24; 95% CI, 1.25–4.02), and weight gain was associated with significantly worse DFS (aHR, 1.35; 95% CI, 1.06–1.73) and DDFS (aHR, 1.48; 95% CI, 1.09–2.00). In the cohort of hormone receptor–negative patients, weight change did not impact prognosis (supplemental eTables 13 and 14).

No significant interaction was observed between weight change at 2 years after randomization and anti-HER2 treatment administered (P=.591 for interaction). Outcomes according to weight change did not change according to type of anti-HER2 treatment, with the exception of the lapatinib-alone arm, in which a significant association was found for weight loss in terms of DFS (aHR, 1.62; 95% CI, 1.05–2.49), DDFS (aHR, 1.98; 95% CI, 1.19–3.30), and OS (aHR, 2.62; 95% CI, 1.19–5.79) (supplemental eTables 15–18).

Impact of Weight Change According to Baseline BMI

To assess the impact of weight change better, its prognostic value was assessed separately within each cohort of patients according to baseline BMI.

For patients who were obese at baseline (n=1,707), weight loss was associated with significantly worse OS (aHR, 3.01; 95% CI, 1.38–6.57); no significant impact on DFS (aHR, 1.45; 95% CI, 0.91–2.30) or DDFS (aHR, 1.59; 95% CI, 0.91–2.78) was observed. For weight gain, there was no significant difference in DFS (aHR, 1.10; 95% CI, 0.70–1.71), DDFS (aHR, 1.17; 95% CI, 0.68–1.99), or OS (aHR, 0.97; 95% CI, 0.38–2.49) (supplemental eTable 19).

For patients who were overweight at baseline (n=2,690), weight loss ≥5% did not significantly impact DFS (aHR, 1.28; 95% CI, 0.82–2.00), DDFS (aHR, 1.02; 95% CI, 0.55–1.86), or OS (aHR, 0.89; 95% CI, 0.34–2.38). For weight gain, no significant difference was observed in DFS (aHR, 1.40; 95% CI, 0.99–1.97), DDFS (aHR, 1.13; 95% CI, 0.72–1.77), or OS (aHR, 1.27; 95% CI, 0.63–2.54) (supplemental eTable 20).

For patients with normal weight at baseline (n=3,797), weight loss was associated with worse DDFS (aHR, 1.69; 95% CI, 1.04–2.77); no significant difference in either DFS (aHR, 1.33; 95% CI, 0.91–1.95) or OS (aHR, 2.00; 95% CI, 0.95–4.19) was observed. Weight gain did not significantly impact DFS (aHR, 1.05; 95% CI, 0.80–1.38), DDFS (aHR, 1.39; 95% CI, 0.98–1.97), or OS (aHR, 1.29; 95% CI, 0.72–2.32) (supplemental eTable 21).

For patients who were underweight at baseline, available data were too limited for analysis.

Adverse Effects and Treatment Completion

Obese patients had a higher incidence of grade 3/4 adverse effects (AEs; P<.001) and serious AEs (P<.001). Treatment discontinuation due to AEs was also more common (P<.001) (Table 2).

Table 2.

Adverse Effects by Baseline BMIa

Table 2.

Discussion

To our knowledge, the present analysis is the largest to evaluate the impact of baseline BMI and weight change after treatment on the clinical outcomes of patients with HER2-positive early breast cancer. Our results suggest that obesity is associated with worse prognosis. Weight loss, but not weight gain, was associated with worse outcomes. Patients with obesity more frequently experienced grade 3/4 AEs, ≥1 serious AEs, and treatment discontinuation.

Multiple biologic mechanisms are thought to contribute to the negative impact of obesity in patients with cancer. The main plausible mechanisms involve alteration in multiple mediators, such as hyperinsulinemia, increased level of insulin-like growth factors (IGF-1), increased level of leptin, decreased level of adiponectin, and chronic inflammation.15 How and if these mechanisms affect neoplastic HER2-positive tumor cells is still uncertain. However, preclinical data have suggested that the crosstalk between leptin and IGF-1 can lead to hyperactivation of the HER2 pathway, thus reducing sensitivity to targeted therapy and potentially increasing risk of disease relapse.15,16

Multiple meta-analyses have consistently shown that higher baseline BMI is associated with worse outcomes in patients with all subtypes of breast cancer combined.4,17,18 Our study suggests that obesity at baseline was associated with significantly worse DDFS and OS, specifically in the cohort of patients with HER2-positive breast cancer. These results are consistent with results of a secondary analysis from the NCCTG N9831 trial,8 but differ from the those of the NSABP B31 and HERA trials that included a smaller sample size.6,8

The most comprehensive meta-analysis on the impact of weight gain at an average 1.5 years postdiagnosis revealed that an increase of ≥5.0% in weight was associated with a significant 12% higher risk in all-cause mortality in patients with breast cancer nonselected for tumor subtype.13 When stratified by baseline BMI (<25 and ≥25 kg/m2), all-cause mortality risk was not statistically different, although it was suggestive of an association in patients with initial BMI of <25 kg/m2 who gained >5.0% of weight. No impact of weight loss was reported.13 In our study, weight loss ≥5.0% (and not weight gain) at 2 years after randomization was associated with poorer DFS, DDFS, and OS. When analyzed according to baseline BMI, weight loss was associated with worse OS in patients who were obese, and with worse DDFS in those of normal weight. The only available data on weight change in patients with HER2-positive breast cancer derives from the HERA trial, in which BMI at 1 year after treatment did not impact outcomes.9 Smaller sample size (n=1,249 in HERA and n=8,381 in ALTTO) and time at which BMI change was assessed (ie, 1 year) could partly explain the different results, together with the lack of anti-HER2 therapy in half of the HERA population. We observed a worse impact of weight change in premenopausal patients and in those with hormone receptor–positive status. In terms of impact of weight change according to baseline BMI, these results are intriguing because they go against the general goal in survivor care plans to aim for weight loss.18 In an individual patient meta-analysis, the Premenopausal Breast Cancer Collaborative Group showed an inverse relationship between BMI and breast cancer risk that was stronger for hormone receptor–positive breast cancer in premenopausal women.19 The association remained true for women with HER2-positive breast cancer aged ≤35 years. It has been hypothesized that obesity can negatively regulate the hypothalamic-pituitary-axis through increased peripheral estradiol synthesis, and therefore reduce breast cancer risk.20 Our finding regarding the impact of weight loss may reflect the loss of this protective state induced by obesity. This calls for caution if weight loss trials, such as the ongoing phase III Breast cancer WEight Loss study (BWEL; ClinicalTrials.gov identifier: NCT02750826), are to be conducted in survivors of HER2-positive breast cancer. One could also hypothesize that the relationship of weight loss with outcomes is not causal, but rather explained by yet undetected metastatic disease at 2 years after randomization. Ideally, the effect of intentional versus unexplained weight loss would have been studied separately, but this information was not available.

Despite those findings, obesity, as defined based on BMI, is a major health issue because it is associated with an increase in all-cause mortality related to several negative health consequences (eg, cancer, type 2 diabetes, coronary heart disease, stroke) that significantly contribute to the financial burden of medical care.2123 In recognition of the link between obesity and cancer, the ASCO Obesity Initiative has been created to inform and develop concrete actions to address this important issue.24 Dietary changes, with accompanying weight reduction, before or after breast cancer diagnosis could impact outcomes in patients with breast cancer, but little is known about the effect of those interventions according to breast cancer subtype.2527

Our findings also showed that toxicities were more common in patients with obesity. This calls for awareness in patient management, because clinical recommendations state that there is no evidence that patients with obesity experience greater toxicity with actual weight-based doses.29 Early discontinuation and subsequent uncompleted treatment can have adverse consequences and a closer follow-up may be required for patients with obesity.

Our study has potential limitations, among which is that this was not a preplanned analysis. The impact of weight change at longer time points could not be assessed. Information on the intentionality of weight loss after randomization was not collected. Although BMI is the main tool used internationally to assess patients’ nutritional status,30 concerns have been raised about its ability to accurately reflect body fat distribution and its generalization across sex and ethnicity.31 Additionally, White and Asian patients composed the vast majority of our population, limiting the generalizability of our results.

Conclusions

Results of this study suggest that among patients with HER2-positive early breast cancer, obesity at baseline is a poor prognostic factor and that weight loss is correlated with worse clinical outcomes. Together with other data in the field, our findings suggest that dietary counseling should be part of survivorship care programs.

Acknowledgments

We thank all of the investigators affiliated with the ALTTO study group who contributed to the study. Dr. Martel acknowledges the support from the Société des Médecins de l’Université de Sherbrooke (SMUS) for a fellowship at the Institut Jules Bordet in Brussels, Belgium. Dr. Lambertini acknowledges the support from ESMO for a Translational Research Fellowship at the Institut Jules Bordet in Brussels, Belgium. Dr. Di Cosimo is the recipient of the IG 20774 grant form Fondazione Associazione Italiana Ricerca sul Cancro.

References

  • 1.

    GBD 2015 Obesity Collaborators, Afshin A, Forouzanfar MH, et al. .. Health Effects of overweight and obesity in 195 countries over 25 years. N Engl J Med 2017;377:1327.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Courneya KS, Katzmarzyk PT, Bacon E. Physical activity and obesity in Canadian cancer survivors: population-based estimates from the 2005 Canadian Community Health Survey. Cancer 2008;112:24752482.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Greenlee H, Shi Z, Sardo Molmenti CL, et al. . Trends in obesity prevalence in adults with a history of cancer: results from the US National Health Interview Survey, 1997 to 2014. J Clin Oncol 2016;34:31333140.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Protani M, Coory M, Martin JH. Effect of obesity on survival of women with breast cancer: systematic review and meta-analysis. Breast Cancer Res Treat 2010;123:627635.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Niraula S, Ocana A, Ennis M, et al. . Body size and breast cancer prognosis in relation to hormone receptor and menopausal status: a meta-analysis. Breast Cancer Res Treat 2012;134:769781.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Chan DSM, Vieira AR, Aune D, et al. . Body mass index and survival in women with breast cancer-systematic literature review and meta-analysis of 82 follow-up studies. Ann Oncol 2014;25:19011914.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Cecchini RS, Swain SM, Costantino JP, et al. . Body mass index at diagnosis and breast cancer survival prognosis in clinical trial populations from NRG Oncology/NSABP B-30, B-31, B-34, and B-38. Cancer Epidemiol Biomarkers Prev 2016;25:5159.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Crozier JA, Moreno-Aspitia A, Ballman KV, et al. . Effect of body mass index on tumor characteristics and disease-free survival in patients from the HER2-positive adjuvant trastuzumab trial N9831. Cancer 2013;119:24472454.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Yerushalmi R, Dong B, Chapman JW, et al. . Impact of baseline BMI and weight change in CCTG adjuvant breast cancer trials. Ann Oncol 2017;28:15601568.

  • 10.

    Piccart-Gebhart M, Holmes E, Baselga J, et al. . Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial. J Clin Oncol 2016;34:10341042.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Moreno-Aspitia A, McCormick E, Jackisch C et al. . Updated results from the phase III ALTTO trial (BIG 2-06; NCCTG (Alliance) N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T→L) or their combination (L+T) in the adjuvant treatment of HER2-positive early breast cancer [abstract]. J Clin Oncol 2017;35(Suppl):Abstract 502.

    • Search Google Scholar
    • Export Citation
  • 12.

    WHO Expert Consultation. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet 2004;363:157163.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Playdon MC, Bracken MB, Sanft TB, et al. . Weight gain after breast cancer diagnosis and all-cause mortality: systematic review and meta-analysis. J Natl Cancer Inst 2015;107:djv275.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Stevens J, Truesdale KP, McClain JE, et al. . The definition of weight maintenance. Int J Obes 2006;30:391399.

  • 15.

    Klil-Drori AJ, Azoulay L, Pollak MN. Cancer, obesity, diabetes, and antidiabetic drugs: is the fog clearing? Nat Rev Clin Oncol 2017;14:8599.

  • 16.

    Saxena NK, Taliaferro-Smith L, Knight BB, et al. . Bidirectional crosstalk between leptin and insulin-like growth factor-I signaling promotes invasion and migration of breast cancer cells via transactivation of epidermal growth factor receptor. Cancer Res 2008;68:97129722.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Fiorio E, Mercanti A, Terrasi M, et al. . Leptin/HER2 crosstalk in breast cancer: in vitro study and preliminary in vivo analysis. BMC Cancer 2008;8:305.

  • 18.

    Runowicz CD, Leach CR, Henry NL, et al. . American Cancer Society/American Society of Clinical Oncology breast cancer survivorship care guideline. J Clin Oncol 2016;34:611635.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    The Premenopausal Breast Cancer Collaborative Group, Schoemaker MJ, Nichols HB, et al. . Association of body mass index and age with subsequent breast cancer risk in premenopausal women. JAMA Oncol 2018;4:e181771.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Dowsett M, Folkerd E. Reduced progesterone levels explain the reduced risk of breast cancer in obese premenopausal women: a new hypothesis. Breast Cancer Res Treat 2015;149:14.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Berrington de Gonzalez A, Hartge P, Cerhan JR, et al. . Body-mass index and mortality among 1.46 million white adults. N Engl J Med 2010;363:22112219.

  • 22.

    National Task Force on the Prevention and Treatment of Obesity. Overweight, obesity, and health risk. Arch Intern Med 2000;160:898904.

  • 23.

    Finkelstein EA, Trogdon JG, Cohen JW, et al. . Annual medical spending attributable to obesity: payer-and service-specific estimates. Health Aff (Millwood) 2009;28(Suppl 1):w822831.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Ligibel JA, Alfano CM, Courneya KS, et al. . American Society of Clinical Oncology position statement on obesity and cancer. J Clin Oncol 2014;32:35683574.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    Chlebowski RT, Blackburn GL, Thomson CA, et al. . Dietary fat reduction and breast cancer outcome: interim efficacy results from the Women’s Intervention Nutrition Study. J Natl Cancer Inst 2006;98:17671776.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Chlebowski RT, Blackburn GL. Final survival analysis from the randomized Women’s Intervention Nutrition Study (WINS) evaluating dietary intervention as adjuvant breast cancer therapy. Presented at the 2014 San Antonio Breast Cancer Symposium; December 9–13, 2014; San Antonio, Texas.

  • 27.

    Chlebowski RT, Aragaki AK, Anderson GL, et al. . Dietary modification and breast cancer mortality: long-term follow-up of the Women’s Health Initiative randomized trial. J Clin Oncol 2020;38:14191428.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Nadler M, Bainbridge D, Tomasone J, et al. . Oncology care provider perspectives on exercise promotion in people with cancer: an examination of knowledge, practices, barriers, and facilitators. Support Care Cancer 2017;25:22972304.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Griggs JJ, Mangu PB, Anderson H, et al. . Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2012;30:15531561.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    World Health Organization. Body mass index. Accessed April 10, 2020. Available at: www.euro.who.int/en/health-topics/disease-prevention/nutrition

    • Search Google Scholar
    • Export Citation
  • 31.

    Buss J. Limitations of body mass index to assess body fat. Workplace Health Saf 2014;62:264–264.

These authors are co-last authors.

Submitted April 10, 2020; accepted for publication June 10, 2020. Published online January 5, 2021.

Author contributions: Study concept and methodology: Martel, Lambertini, Agbor-Tarh, Di Cosimo, de Azambuja. Writing—original draft: Martel, Lambertini. Project administration: Martel, Lambertini. Investigation, resources, and writing—review and editing: All authors. Formal analysis: Agbor-Tarh. Supervision: Di Cosimo, de Azambuja.

Disclosures: Dr. Martel has disclosed that he has received honoraria from Novartis. Dr. Lambertini has disclosed that he has received consultant fees from Roche, Novartis, Lilly, and AstraZeneca, and received honoraria from Theramex, Roche, Lilly, Pfizer, Novartis, Sandoz, and Takeda. Dr. Ponde has disclosed that he has received honoraria from AstraZeneca, Roche, and Eli Lilly. Dr. Manukyants has disclosed that she is employed by Novartis Pharma AG. Dr. Maurer has disclosed that he has received consulting fees from Amgen, Mundipharma and SERVIER Deutschland GmbH. Dr. Piccart has disclosed that she is a board member of Oncolytics; has received honoraria from AstraZeneca, Camel-IDS, Crescendo Biologics, Debiopharm, Genentech, Immunomedics, Lilly, Menarini, MSD, Novartis, Odonate, Pfizer, Roche, and Seattle Genetics; and has received grant/research support from AstraZeneca, Lilly, MSD, Novartis, Pfizer, Radius, Roche/Genentech, Servier, and Synthon. Dr. de Azambuja has disclosed that he has received grant/research support from Roche/GNE, AstraZeneca, GlaxoSmithKline/Novartis, and Servier, and consulting fees from Roche/GNE, Novartis, Seattle Genetics, Zodiac, and Libbs. The remaining authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: Dr. Desmedt acknowledges support from the Fondation Cancer from Luxemburg. The ALTTO trial is funded by Novartis Pharmaceuticals.

Correspondence: Samuel Martel, MD, Department of Hemato-Oncology, Hôpital Charles-Le Moyne/CISSS Montérégie-Centre, 3120 Boulevard Taschereau, Greenfield Park, Quebec, Canada. Email: samuel.martel3@usherbrooke.ca

Supplementary Materials

  • View in gallery

    CONSORT flow diagram.

  • View in gallery

    Kaplan-Meier plot of (A) DDFS, (B) DFS, and (C) OS by baseline BMI categories. Underweight: BMI<18.50 kg/m2; normal weight: 18.50≤BMI<25 kg/m2; overweight: 25≤BMI<30 kg/m2; obese: BMI≥30 km/m2.

    Abbreviations: BMI, body mass index; DDFS, distant disease-free survival; DFS, disease-free survival; OS, overall survival.

  • View in gallery

    Kaplan-Meier plot of (A) DDFS, (B) DFS, and (C) OS by weight change from baseline. A weight change from baseline of ≥5.0% and ≤5.0% was categorized as weight gain and weight loss, respectively.

    Abbreviations: BMI, body mass index; DDFS, distant disease-free survival; DFS, disease-free survival; OS, overall survival.

  • 1.

    GBD 2015 Obesity Collaborators, Afshin A, Forouzanfar MH, et al. .. Health Effects of overweight and obesity in 195 countries over 25 years. N Engl J Med 2017;377:1327.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Courneya KS, Katzmarzyk PT, Bacon E. Physical activity and obesity in Canadian cancer survivors: population-based estimates from the 2005 Canadian Community Health Survey. Cancer 2008;112:24752482.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Greenlee H, Shi Z, Sardo Molmenti CL, et al. . Trends in obesity prevalence in adults with a history of cancer: results from the US National Health Interview Survey, 1997 to 2014. J Clin Oncol 2016;34:31333140.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Protani M, Coory M, Martin JH. Effect of obesity on survival of women with breast cancer: systematic review and meta-analysis. Breast Cancer Res Treat 2010;123:627635.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Niraula S, Ocana A, Ennis M, et al. . Body size and breast cancer prognosis in relation to hormone receptor and menopausal status: a meta-analysis. Breast Cancer Res Treat 2012;134:769781.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Chan DSM, Vieira AR, Aune D, et al. . Body mass index and survival in women with breast cancer-systematic literature review and meta-analysis of 82 follow-up studies. Ann Oncol 2014;25:19011914.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Cecchini RS, Swain SM, Costantino JP, et al. . Body mass index at diagnosis and breast cancer survival prognosis in clinical trial populations from NRG Oncology/NSABP B-30, B-31, B-34, and B-38. Cancer Epidemiol Biomarkers Prev 2016;25:5159.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Crozier JA, Moreno-Aspitia A, Ballman KV, et al. . Effect of body mass index on tumor characteristics and disease-free survival in patients from the HER2-positive adjuvant trastuzumab trial N9831. Cancer 2013;119:24472454.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Yerushalmi R, Dong B, Chapman JW, et al. . Impact of baseline BMI and weight change in CCTG adjuvant breast cancer trials. Ann Oncol 2017;28:15601568.

  • 10.

    Piccart-Gebhart M, Holmes E, Baselga J, et al. . Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial. J Clin Oncol 2016;34:10341042.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Moreno-Aspitia A, McCormick E, Jackisch C et al. . Updated results from the phase III ALTTO trial (BIG 2-06; NCCTG (Alliance) N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T→L) or their combination (L+T) in the adjuvant treatment of HER2-positive early breast cancer [abstract]. J Clin Oncol 2017;35(Suppl):Abstract 502.

    • Search Google Scholar
    • Export Citation
  • 12.

    WHO Expert Consultation. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet 2004;363:157163.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Playdon MC, Bracken MB, Sanft TB, et al. . Weight gain after breast cancer diagnosis and all-cause mortality: systematic review and meta-analysis. J Natl Cancer Inst 2015;107:djv275.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Stevens J, Truesdale KP, McClain JE, et al. . The definition of weight maintenance. Int J Obes 2006;30:391399.

  • 15.

    Klil-Drori AJ, Azoulay L, Pollak MN. Cancer, obesity, diabetes, and antidiabetic drugs: is the fog clearing? Nat Rev Clin Oncol 2017;14:8599.

  • 16.

    Saxena NK, Taliaferro-Smith L, Knight BB, et al. . Bidirectional crosstalk between leptin and insulin-like growth factor-I signaling promotes invasion and migration of breast cancer cells via transactivation of epidermal growth factor receptor. Cancer Res 2008;68:97129722.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Fiorio E, Mercanti A, Terrasi M, et al. . Leptin/HER2 crosstalk in breast cancer: in vitro study and preliminary in vivo analysis. BMC Cancer 2008;8:305.

  • 18.

    Runowicz CD, Leach CR, Henry NL, et al. . American Cancer Society/American Society of Clinical Oncology breast cancer survivorship care guideline. J Clin Oncol 2016;34:611635.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    The Premenopausal Breast Cancer Collaborative Group, Schoemaker MJ, Nichols HB, et al. . Association of body mass index and age with subsequent breast cancer risk in premenopausal women. JAMA Oncol 2018;4:e181771.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Dowsett M, Folkerd E. Reduced progesterone levels explain the reduced risk of breast cancer in obese premenopausal women: a new hypothesis. Breast Cancer Res Treat 2015;149:14.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Berrington de Gonzalez A, Hartge P, Cerhan JR, et al. . Body-mass index and mortality among 1.46 million white adults. N Engl J Med 2010;363:22112219.

  • 22.

    National Task Force on the Prevention and Treatment of Obesity. Overweight, obesity, and health risk. Arch Intern Med 2000;160:898904.

  • 23.

    Finkelstein EA, Trogdon JG, Cohen JW, et al. . Annual medical spending attributable to obesity: payer-and service-specific estimates. Health Aff (Millwood) 2009;28(Suppl 1):w822831.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Ligibel JA, Alfano CM, Courneya KS, et al. . American Society of Clinical Oncology position statement on obesity and cancer. J Clin Oncol 2014;32:35683574.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    Chlebowski RT, Blackburn GL, Thomson CA, et al. . Dietary fat reduction and breast cancer outcome: interim efficacy results from the Women’s Intervention Nutrition Study. J Natl Cancer Inst 2006;98:17671776.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Chlebowski RT, Blackburn GL. Final survival analysis from the randomized Women’s Intervention Nutrition Study (WINS) evaluating dietary intervention as adjuvant breast cancer therapy. Presented at the 2014 San Antonio Breast Cancer Symposium; December 9–13, 2014; San Antonio, Texas.

  • 27.

    Chlebowski RT, Aragaki AK, Anderson GL, et al. . Dietary modification and breast cancer mortality: long-term follow-up of the Women’s Health Initiative randomized trial. J Clin Oncol 2020;38:14191428.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Nadler M, Bainbridge D, Tomasone J, et al. . Oncology care provider perspectives on exercise promotion in people with cancer: an examination of knowledge, practices, barriers, and facilitators. Support Care Cancer 2017;25:22972304.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Griggs JJ, Mangu PB, Anderson H, et al. . Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2012;30:15531561.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    World Health Organization. Body mass index. Accessed April 10, 2020. Available at: www.euro.who.int/en/health-topics/disease-prevention/nutrition

    • Search Google Scholar
    • Export Citation
  • 31.

    Buss J. Limitations of body mass index to assess body fat. Workplace Health Saf 2014;62:264–264.

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 3077 3077 58
PDF Downloads 521 521 32
EPUB Downloads 0 0 0