Breast cancer is the most commonly diagnosed cancer among women (1), with luminal tumors accounting for 70% of all cases (2). Obesity has been widely recognized as a risk factor for postmenopausal breast cancer but rather protective for premenopausal women from developing breast cancer (3–5). Meanwhile, obesity is associated with impaired survival, regardless of menopausal status (3, 4). Substantial evidence has suggested that obese women with early stage disease have an increased risk of recurrence (6–9) and reduced survival (6–12) compared to normal-weight women with early-stage disease. Studies have also identified obesity as a risk factor for contralateral breast cancer, as well as second primary cancers (13, 14). Furthermore, the association between obesity and outcomes of breast cancer varied by tumor estrogen receptor (ER) status (15). The prospective POSH study, which enrolled 2,956 patients aged ≤40 at breast cancer diagnosis, revealed that obesity is an independent prognostic factor for ER-positive but not ER-negative breast cancer (15). Regarding molecular subtypes, the association between obesity and prognosis was still in controversy (15–17). Increasing body mass index (BMI) was found to be associated with inferior outcomes in luminal/human epidermal growth factor receptor 2 (HER2)-negative disease but not other subtypes (7, 16, 18).

Obesity has been associated with increased local and circulating estrogen production due to high expression of the aromatase in the breast and peripheral fat (19, 20). Aromatase inhibitors (AIs) can inhibit the conversion of androgens to estrogens in adipose tissue, indicating AIs may be less effective in obese postmenopausal patients (21). Retrospective analysis from ATAC and ABCSG-12 trials found that obese patients treated with anastrozole had worse prognosis than those without obesity. This was not the case in the tamoxifen treatment group (22, 23).

Therefore, the objectives of our study are to explore whether obesity is prognostic and predictive in Chinese breast cancer survivors. We also searched for potential clinicopathological features, for instance, a luminal subtype that might influence the impact of obesity on survival and performance of endocrine therapy in breast cancer patients.

Our current study included 2,875 Chinese luminal breast cancer patients. We have found that obesity was related to the patient’s comorbidity and PR status. We also concluded that obese patients with luminal A breast cancer have significantly shorter OS and RFS. This relation was not significant in luminal B breast cancer. Our study is one of the few to investigate the impact of obesity on prognosis of breast cancer patients according to luminal subtypes in the Chinese population, which may provide an insight into how obesity adversely influences clinical outcomes.

Nearly one-tenth of our study population were obese, which was relatively lower than the Western population (30). In our study, we found that obese patients tended to be elder and more likely to have a medical history of comorbidities compared to non-obese patients, which is consistent with previous studies (6–8, 17, 31). Interestingly, our cohort found that obese patients had a slightly higher proportion of PR-positive tumors compared to non-obese patients, which was similar to the findings of Ladoire et al. (31). A preclinical study with obese rats with breast cancer induced by high-fat diet and 1-methyl-1-nitrosourea demonstrated that obesity enhanced the tumor expression of PR. Obesity-induced PR expression in tumors was thought to be an adaption to extreme metabolic changes and loss of sex hormone production during menopause (32). Additionally, previous studies reported that obesity was related with more advanced and biologically adverse tumors, such as larger tumor size, more lymph node involvement, higher proportion of ER-negative, triple negative tumors, grade III, or high Ki-67 index, and this could not be reproduced in our study (16, 33, 34), which may be explained by our study only including the luminal population. Molecular subtypes were similarly distributed in obese and non-obese patients in our study. Whereas in the PAM50 testing dated from the CALGB 9741 study, obese breast cancer patients had a significantly larger share of luminal B breast cancers (35), possibly explained by ethnic background difference or different molecular subtype detecting methods. In terms of adjuvant systemic therapy, obese patients were less likely to receive chemotherapy, which may be contributed to the elder age and the relatively worse baseline performance status (36, 37). Moreover, obese patients would also be more likely to receive insufficient dosage of treatment according to actual body surface area, which would also impact the patient’s disease outcome (38).

With a growing body of evidence exploring the correlation between obesity and clinical outcomes, controversy still exists on the relation between obesity and prognosis in specific molecular subtypes of breast cancer (7, 17, 19, 39). In our current study, we did not find the prognostic value of obesity in the overall luminal/HER2-negative population or in the subgroup of luminal B tumors. Meanwhile, we demonstrated a significant inverse relationship between BMI and disease outcomes in patients with luminal A breast cancer, which was in accordance with previously published literature based on PAM50 subtypes (40, 41). In an analysis based on the LACE and Pathways studies, obesity was adversely correlated with outcomes only among those with luminal A cancers, basically driven by class II/III obesity (BMI ≥ 35 kg/m²) (40). Similarly, Kwan et al. also found that the association between BMI and disease outcome was the strongest for luminal A tumors (41). Though obesity has been shown to be related with less favorable characteristics (9, 42, 43), the statistical significance of survival outcome still existed in luminal A patients after adjusting for other clinicopathological factors. Possible explanations for such difference between luminal A and luminal B tumors might be as follows. Firstly, increased endogenous estrogen with obesity would fuel the growth of ER-positive tumors but the effect would be less obvious for luminal B tumors which were also hormone receptor-positive but to a lesser extent (40). In addition, luminal B disease had a more aggressive nature compared to luminal A disease with increased proliferation and less hormone receptor expression, which would overlap and mask the effect of obesity. In addition, we showed in the univariate model that nodal status was associated with RFS in Luminal A patients (Supplementary Table S3). However, node status was no longer significantly related to prognosis in Luminal A patients in the multivariate model (Table 4), possibly due to the effect of chemotherapy, which suggests that standard adjuvant chemotherapy brings substantial benefit for node positive Luminal patients.

It is widely recognized that obesity has great influence on the endocrine system both in pre- and post-menopausal breast cancer patients (20, 21). Retrospective analysis from the ATAC trial found that tamoxifen was equally effective across all BMI levels, while anastrozole was significantly less effective in obese patients compared to normal weight patients (23). Similarly, results from the ABCSG-12 trial, exclusively including premenopausal patients treated with OFS, showed a worse disease outcome for obese patients treated with AI but not for tamoxifen cohorts (24). Speculation has arisen whether the constant dosage of anastrozole is sufficient for the obese to suppress the estrogen to a relatively low extent. Anastrozole was found to be inferior to tamoxifen for overweight or obese premenopausal patients in the ABCSG-12 trial and equal to tamoxifen for obese postmenopausal patients in the ATAC trial (23, 24). Other large phase III trials did not find any influence of obesity on letrozole (34) or exemestane (44) performance, possibly due to the different potencies of estrogen level suppression ability (45). In our study, we did not observe an effect of obesity on AI or tamoxifen treatment. Studies of large sample size are needed and essential to compare the efficacy of different types of AI for obese patients.

There are certainly several limitations in this study. Firstly, it is a retrospective study from a single institution with possible selection bias. Secondly, we did not take the effect of weight change after diagnosis into account for the lack of relevant information. Weight gain following breast cancer diagnosis has been reported to be associated with worse survival (46, 47). In addition, we did not include the lifestyle covariates like physical activity and diet preference into survival analysis, which have been related with breast cancer outcomes (48–50). Finally, it is important to carry out a comprehensive analysis of additional metabolic parameters other than obesity, for instance, metabolic syndrome, insulin, c-peptide, blood glucose, etc. on patients’ outcomes (51–53), so as to provide a more precise view regarding patient metabolism and cancer survival.

In conclusion, the adverse impact of obesity on luminal-like patients’ survival announced in previous studies could not be reproduced with our cohort of the Chinese luminal-like population. Our study found that obesity was associated with slightly more PR positive tumor and worse clinical outcomes in luminal A subtype but not for luminal B tumor. In patients treated with adjuvant endocrine therapy, obesity had no significant impact on patients’ outcome, regardless of endocrine treatment regimen received, which deserves further clinical evaluation.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by independent Ethical Committees of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. The patients/participants provided their written informed consent to participate in this study.

Data collection and analysis were performed by SZ. YT, SZ, and WC wrote the first draft of the manuscript. XC made substantial contributions to the conception of the work and revised the manuscript. KS substantively revised the manuscript. All authors have contributed to read and approved the final manuscript for submission.

The authors appreciate the financial supports by the National Natural Science Foundation of China (Grant Number: 81772797, 82072897), Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (20172007); and Shanghai Sailing Program (21YF1427400). All these financial sponsors had no role in the study design, collection, analysis or interpretation of data.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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