In this large pooling analysis of 14,948 breast cancer survivors, the association between pre-diagnosis BMI and breast cancer outcomes, specifically overall death and non-breast cancer death, was U-shaped with both underweight and morbidly obese women being at higher risk. Compared to normal-weight women, morbidly obese women were on average at two-fold greater risk of all mortality outcomes. In general, the estimates did not differ by menopausal status, hormone receptor status, comorbidity history, smoking history, and receipt of chemotherapy. Across all analyses, overweight women (25.0-29.9 kg/m2) had similar risk of outcomes compared to normal-weight women. No significant associations were found for risk of recurrence. These results suggest that the association of obesity with poorer outcomes after breast cancer observed in previous studies may be driven predominantly by the relationship between morbid obesity (≥40 kg/m2) and mortality.
It has been previously suggested that the association of body size with breast cancer outcomes may be U- or J-shaped [11
], particularly in ethnically diverse study populations [3
]. In two recent studies, being underweight/low-normal weight (<18.5 kg/m2
or <22.5 kg/m2
) and obese (≥30 kg/m2
) were both associated with increased risks of breast cancer recurrence and mortality compared to normal-weight ranges (18.5-24.9 kg/m2
and 22.5-24.9 kg/m2
) while no elevated risk was observed in the overweight range (25.0-29.9 kg/m2
). Similarly, in two large studies of 1.1 million Asians and nearly 900,000 Whites, U shaped associations of BMI with decreased all-cause mortality were observed in the ranges of 22.6-27.5 kg/m2
and 22.5-25.0 kg/m2
, respectively [26
]. These BMI ranges lend support to our observation that normal or high-normal BMI before diagnosis might represent an ideal weight for healthy outcomes.
Several plausible biological mechanisms have been proposed to support the prognostic effects of obesity in breast cancer patients, yet they are primarily relevant to breast cancer-related outcomes. Studies have found that obese (compared to non-obese) postmenopausal women have higher circulating bioavailable estrogen that could fuel tumor regrowth and progression [28
]. Obesity might also increase insulin and insulin–like growth factors (IGF-I, IGF-II), which are involved in the regulation of normal and malignant growth of epithelial breast cells [31
] and have been associated with greater distant recurrence and death in women with early stage breast cancer [12
]. Moreover, adipose tissue serves as an important endocrine organ by secreting obesity-related regulatory proteins (adipokines such as leptin and adiponectin) [34
] and triggering obesity-related inflammatory cytokines (interleukins, C-reactive protein, and serum amyloid A) [37
] that play a key role in proliferation, apoptosis, and/or migration of breast tumor cells. Both adipokines [40
] and inflammatory cytokines [43
] have been associated with breast cancer prognosis.
It is unclear why we observed a possible risk threshold by level of obesity, especially since level of obesity was not associated with tumor stage or hormone receptor status. However, we hypothesize that larger amounts of adipose tissue in the morbidly obese compared to the moderately obese might place a woman at even greater risk of poor outcomes via a constant imbalance in obesity-related regulatory proteins and inflammatory cytokines.
From the treatment perspective, obese women may be underdosed for chemotherapy due to toxicity-related concerns, resulting in reduced therapeutic response and worse outcomes [47
]. However, when we stratified the obese women in our cohort by receipt of chemotherapy, no prognostic risk differences were observed by chemotherapy status. There is also emerging evidence that obesity can negatively impact the standard dose effectiveness of aromatase inhibitors (AIs), leading to poorer prognosis and survival [50
]. Nevertheless, we were unable to explore this potential pharmacotherapy issue among obese women due to only 8% of women being treated with AIs (8%).
The biological plausibility for underweight and prognosis has been less explored compared to the effects of obesity. Underweight could be an indicator of pre-existing comorbid conditions that have already placed these women at greater risk of poor outcomes. However, all our analyses were adjusted for comorbidity status, and when we stratified the cohort by presence and absence of comorbid conditions, risk estimates among underweight women did not differ by subgroup. Residual confounding by other unmeasured comorbidity is also possible since we only had pooled data on four common conditions (diabetes, hypertension, MI, and stroke). Smoking could also be an indicator of comorbidity as the NHS previously reported that underweight, middle-aged women without breast cancer who never smoked had no elevated risk of mortality [52
]. However, when we stratified by smoking status in our analyses, the increased risk remained among the underweight non-smokers. A possible reason as to why no differential risk by smoking history was observed is that in our pooled cohort, three-quarters (76.2%) of the underweight women had never smoked and were from the SBCSS. Finally, underweight could be a marker for poor health and undernutrition. It has been suggested that inhibition or promotion of tumor progression may be controlled by immune cells [53
]. In patients with chronic undernutrition and micronutrient deficiency, cytokine reactions and the subsequent activation of the immune system are compromised, which may influence tumor development [55
Strengths of this pooled study include being the largest to date of prospective breast cancer survivors, thus enabling our ability to explore finer BMI categories, particularly in the higher obesity range. To our knowledge, the role of extreme obesity (≥35 kg/m2) on outcomes after breast cancer has not been explored. We were able to adjust for most potentially important prognostic and treatment-related factors, including smoking, hormone receptor status, comorbidity, treatment, and menopausal status. Finally, pooling provided improved power to conduct stratified analyses by these key characteristics and to address reverse causality among the underweight women.
Limitations should also be considered. Pre-diagnosis weight was self-reported in all studies, yet measured weight is preferable to minimize recall bias and exposure misclassification. However, substantial agreement between self-reported weight and measured weight has been shown with the caveat that underreporting may be more common in well-educated white populations compared with minority populations [57
]. Furthermore, self-reported weight was found to produce accurate disease risk estimates if adjusted for key sociodemographics [58
]. Also, waist-hip-ratio, another measure of obesity, before diagnosis/at diagnosis was not uniformly available from all studies. Finally, we could not examine nutritional status (diet and supplements) at diagnosis since not all cohorts collected this information.
In conclusion, BMI prior to breast cancer diagnosis was associated with reduced survival among both underweight and morbidly obese women in this study of nearly 15,000 breast cancer survivors. Compared to women of normal-weight, overweight and moderately obese women had no increased mortality risk. These results underscore the strong prognostic influence of pre-diagnosis BMI on breast cancer outcomes and suggest that degree of obesity confers differential risk on survival.