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Summary

The role of obesity and weight change in breast-cancer development is complex and incompletely understood. Recently, Ellingjord-Dale et al. [1] recently reported the results of a study that investigated the effects of long-term weight change and the risk of breast-cancer risk taking into account body mass index (BMI) at 20 years of age, menopausal status, hormone replacement therapy (HRT) and hormone-receptor status. The authors used data related to weight collected at three different time points from women who participated in the European Prospective Investigation into Cancer and Nutrition (EPIC) study in order to analyze the association between weight change since age 20 up to mid-adulthood and risk of breast cancer. A total of 150,257 women (median age 51 years at cohort entry) were followed for a mean 14 years (standard deviation = 3.9) during which 6,532 breast-cancer cases occurred. In comparison to those with stable weight (± 2.5 kg), long-term weight gain of more than 10 kg was positively associated with postmenopausal breast-cancer risk in women who were lean at age 20 [hazard ratio (HR) = 1.42; 95% CI 1.22–1.65], were ever HRT users (HR = 1.23; 95% CI 1.04–1.44), never HRT users (HR = 1.40; 95% CI 1.16–1.68) and in estrogen and progesterone receptor positive (ER+PR+) breast cancer cases (HR = 1.46; 95% CI 1.15–1.85). The authors conclude that long-term weight gain was positively associated with postmenopausal breast cancer in women who were lean at age 20, both in HRT ever users and non-users, and hormone-receptor-positive breast cancer.

Commentary

In this study, the authors have evaluated the association between long-term weight change and the risk of breast cancer by investigating whether BMI at the age of 20 years or the use of HRT in menopause, modified this association. The results have shown that long-term weight gain was not associated with an increase in premenopausal breast cancer, but was positively associated with overall breast cancer risk in postmenopausal women who were thin at 20 years of age. Interestingly, this association was stronger in non-HRT users who were thin at age 20 than in HRT users. Another important fact is that weight gain was associated with a higher risk of ER+ and ER+PR+ breast cancer than with respect to the other types of cancer.

This study has the consistency of being a very long-term analysis and of the enormous number of cases. As we have mentioned, in this study no increased risk of breast cancer was found in premenopausal women. A possible explanation for the difference from the findings in postmenopausal women could have to do with the different metabolic behavior of menopausal weight gain (abdominal fat) than fat deposition in younger women (peripheral fat). The results found for the relationship between weight gain and the risk of breast cancer are in line with other studies. Obesity has a very important effect on breast cancer. It is estimated that up to 33% of all breast cancers are due to obesity [2]. However, it is important to distinguish this increased risk according to menopausal status. For every 5 kg/m2 increase in BMI, the hazard risk ratio (HR) for breast cancer in postmenopausal women increases by 1.05 (95% CI 1.03 to 1.07). However, in premenopausal women, the HR is 0.89 (95% CI 0.86 to 0.92) [3]. This lower risk of breast cancer in premenopausal women is even lower in Caucasian and African women, and much higher in Asian women [4].

Although menopause per se is not associated with weight gain, it can lead to an increase in body fat and its redistribution from the periphery to the trunk. It has been found that the distribution of fat in postmenopausal women receiving HRT is very similar to that of premenopausal women [5]. The mechanism by which obesity increases the risk of breast cancer may be due to the carcinogenic effect of visceral fat [2]. This effect can be influenced by endogenous sex hormones, hyperinsulinemia, IGF-1, hyperglycemia, adipokines, chronic inflammation, and even the microbiome [6]. Regarding sex hormones, it is known that the level of estrogen is higher in obese women, both pre- and postmenopausal, levels that exert mitogenic and mutagenic activity, and promoting proliferation and genetic instability of both normal and tumor cells [7]. Hyperinsulinemia and hyperglycemia, present in most people with obesity, can promote carcinogenesis [8]. In obese women, visceral fat and elevated leptin and estrogen levels have been associated with increased levels of pro-inflammatory molecules (IL-1β, IL-6, TNFα, prostaglandin E2), which promote carcinogenesis [9 ]. Finally, the alteration of the microbiota, due to excess calorie consumption, could induce the transformation of compounds from the diet into obesogenic and diabetogenic molecules, which would also play an important role in carcinogenesis [10]. Voluntary weight loss has been shown to decrease the risk of breast cancer. Thus, a 30% weight loss through bariatric surgery can reduce the risk of breast cancer by 80% [11].

The study has the typical limitations of an observational cohort study, highlighting that there are no data on abdominal circumference, which is possibly a better predictor of breast cancer risk. Moreover, weight was self-reported. The authors also note as a limitation that data on menopausal status at breast cancer diagnosis were not available and therefore age at diagnosis was used as a proxy. Despite this, since the median age of menopause presentation for European women is 51 years, we estimate that with such a large number of patients the deviation from reality would be very small.

From my point of view, this study reminds us how important it is to insist on healthy lifestyle habits, to maintain a normal weight that avoids increasing risks, in this case breast cancer. On the other hand, they point out that this increased risk is completely independent of whether HRT is being taken or not.

Santiago Palacios, MD
Instituto Palacios, Salud y Medicina de la Mujer
Madrid Spain

References

  1. Ellingjord-Dale M, Christakoudi S, Weiderpass E, et al. Long-term weight change and risk of breast cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Int J Epidemiol. 2022;50(6):1914-1926.
    https://pubmed.ncbi.nlm.nih.gov/34999853/
  2. Sung H, Siegel RL, Torre LA, et al. Global patterns in excess body weight and the associated cancer burden. CA Cancer J Clin. 2019;69(2):88-112.
    https://pubmed.ncbi.nlm.nih.gov/30548482/
  3. Bhaskaran K, Douglas I, Forbes H, dos-SantosSilva I, Leon DA, Smeeth L. Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5.24 million UK adults. Lancet. 2014;384(9945):755-65.
    https://pubmed.ncbi.nlm.nih.gov/25129328/
  4. Amadou A, Ferrari P, Muwonge R, et al. Overweight, obesity and risk of premenopausal breast cancer according to ethnicity: a systematic review and dose-response meta-analysis. Obes Rev. 2013;14(8):665-78.
    https://pubmed.ncbi.nlm.nih.gov/23615120/
  5. Genazzani AR, Gambacciani M. Effect of climacteric transition and hormone replacement therapy on body weight and body fat distribution. Gynecol Endocrinol. 2006;22(3):145-50.
    https://pubmed.ncbi.nlm.nih.gov/16835076/
  6. Benedetto C, Salvagno F, Canuto EM, Gennarelli G. Obesity and female malignancies. Best Pract Res Clin Obstet Gynaecol. 2015;29(4):528-40.
    https://pubmed.ncbi.nlm.nih.gov/25779915/
  7. Renehan AG, Zwahlen M, Egger M. Adiposity and cancer risk: new mechanistic insights from epidemiology. Nat Rev Cancer. 2015;15(8):484- 98.
    https://pubmed.ncbi.nlm.nih.gov/26205341/
  8. Giovannucci E, Harlan DM, Archer MC, et al. Diabetes and cancer: a consensus report. Diabetes Care. 2010;33(7):1674-85.
    https://pubmed.ncbi.nlm.nih.gov/20587728/
  9. Oh SW, Park CY, Lee ES, et al. Adipokines, insulin resistance, metabolic syndrome, and breast cancer recurrence: a cohort study. Breast Cancer Res. 2011;13(2):R34.
    https://pubmed.ncbi.nlm.nih.gov/21450081/
  10. Rogers CJ, Prabhu KS, Vijay-Kumar M. The microbiome and obesity-an established risk for certain types of cancer. Cancer J. 2014;20(3):176- 80.
    https://pubmed.ncbi.nlm.nih.gov/24855004/
  11. Christou NV, Lieberman M, Sampalis F, Sampalis JS. Bariatric surgery reduces cancer risk in morbidly obese patients. Surg Obes Relat Dis. 2008;4(6):691-5.
    https://pubmed.ncbi.nlm.nih.gov/19026373/

 


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