Association of Obesity With Breast Cancer Outcome in Relation to Cancer Subtypes

A Meta-Analysis

Ana Elisa Lohmann, MD, PhD; Sara V. Soldera, MD, FRCPC; Isabel Pimentel, MD; Domen Ribnikar, MD; Marguerite Ennis, PhD; Eitan Amir, MD, PhD; Pamela J. Goodwin, MD, FRCPC, MSc

Disclosures

J Natl Cancer Inst. 2021;113(11):1465-1475. 

In This Article

Abstract and Introduction

Abstract

Background: Obesity at breast cancer (BC) diagnosis has been associated with poor outcome, although the magnitude of effect in different BC subtypes is uncertain. We report on the association of obesity or overweight at diagnosis of nonmetastatic BC with disease-free (DFS) and overall survival (OS) in the following defined subtypes: hormone receptor positive/HER2 negative (HR+HER2−), HER2 positive (HER2+), and triple negative (TNBC).

Methods: We searched MEDLINE, EMBASE, and COCHRANE databases up to January 1, 2019. Study eligibility was performed independently by 2 authors. Studies reporting hazard ratios (HRs) of OS and/or DFS for obesity or overweight in BC subtypes were included. The pooled hazard ratio was computed and weighted using generic inverse variance and random effects models.

Results: Twenty-seven studies were included. Obese compared with nonobese women had worse DFS in all subtypes: the hazard ratios were 1.26 (95% confidence interval [CI] = 1.13 to 1.41, P < .001) for HR+HER2− BC, 1.16 (95% CI = 1.06 to 1.26, P < .001) for HER2+ BC, and 1.17 (95% CI = 1.06 to 1.29, P = .001) for TNBC. OS was also worse in obese vs nonobese women (HR+HER2− BC HR = 1.39, 95% CI = 1.20 to 1.62, P < .001; HER2+ BC HR = 1.18, 95% CI = 1.05 to 1.33, P = .006; and TNBC HR = 1.32, 95% CI = 1.13 to 1.53, P < .001). As opposed to obesity, overweight was not associated with either DFS or OS in HER2+ BC (HR = 1.02, 95% CI = 0.81 to 1.28, P = .85; and HR = 0.96, 95% CI = 0.76 to 1.21, P = .99, respectively) or TNBC (HR = 1.04, 95% CI = 0.93 to 1.18, P = .49; and HR = 1.08, 95% CI = 0.81 to 1.44, P = .17), respectively. In HR+HER2− BC, being overweight was associated with worse OS (HR = 1.14, 95% CI = 1.07 to 1.22, P < .001).

Conclusions: Obesity was associated with modestly worse DFS and OS in all BC subtypes.

Introduction

Obesity is recognized as being associated with poor prognosis in several cancers, including breast cancer (BC).[1,2] Key prior meta-analyses of obesity and localized BC outcome have focused on all BCs[1] (hazard ratio [HR] for mortality in obese vs nonobese = 1.41, 95% confidence interval [CI] = 1.29 to 1.53) disease-free survival (DFS) or BC subdivided by hormone receptor status only.[2] For example, in a literature-based meta-analysis, the hazard ratio for overall mortality in obese vs nonobese was 1.31 (95% CI = 1.17 to 1.46) for hormone receptor positive (HR+) and 1.18 (95% CI = 1.06 to 1.31) for hormone receptor negative (HR−) BC (Pdifference = .31).[2] In a more recent meta-analysis that focused on triple-negative BC (TNBC), obesity was not associated with DFS or overall survival (OS) (HR = 0.93 and 1.07, respectively); however, inclusion of studies was incomplete and numbers of patients in the included studies were small.[3]

Differences in obesity associations among studies may reflect patient selection, a factor that is particularly important in the comparison of observational and interventional studies. Even when body mass index (BMI) is similar, metabolically healthier patients (ie, those without diabetes or cardiovascular disease) may be more likely to be enrolled into intervention trials, particularly those that include cardiotoxic treatments. These metabolically healthy patients are less likely than metabolically unhealthy patients to have obesity-associated attributes such as hyperinsulinemia, dysglycemia, dyslipidemia, and inflammation that may mediate associations of obesity with poor BC outcomes, even when BMIs are similar, and they have lower rates of non-BC deaths, leading to different associations of obesity with outcomes.

Previous comprehensive meta-analyses have not comprehensively examined obesity associations across BC subtypes, nor have they focused on BCs diagnosed since the introduction of routine HER2 testing. Although there is a growing consensus that obesity is associated with poor outcomes in HR+ BC, there is less evidence in those HR+ BCs that are also shown to be HER2−. There has also been limited and inconsistent evidence regarding the association of obesity with BC outcome in more aggressive BC subtypes such as TNBC and HER2 positive (HER2+).[4–6] For example, despite the suboptimal meta-analysis in TNBC discussed above, Turkoz et al.[4] reported worse DFS for obese vs nonobese patients in the HER2+ and TNBC subgroups (HR = 1.51, 95% CI = 1.1 to 2.1; and HR = 1.41, 95% CI = 1.0 to 2.0, respectively), whereas Sparano et al.[5] did not find statistically significant associations of obesity with DFS in these 2 populations (HR = 1.06, 95% CI = 0.82 to 1.38; and HR = 1.03, 95% CI = 0.81 to 1.30, respectively). Some of the differences across studies may reflect patient selection as discussed above; they may also reflect advances in adjuvant treatment in HER2+ and TNBC that may result in different associations of BMI with outcomes than was seen in earlier cohorts receiving less intensive therapy.

Given the limitations of prior meta-analyses and the continuing appearance of studies examining the association of obesity with BC outcomes, we conducted a literature-based meta-analysis with the goal of clarifying the association of body size with outcomes in nonmetastatic BC across the spectrum of immunohistochemically defined BC subtypes (HR+HER2−, HER2+, and TNBC) in women receiving modern adjuvant therapies.

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