19 November 2018
In October, a new analysis  based on the data of the prospective observational Women’s Health Initiative Study was published. The aim of this study was to evaluate relationships between weight change and subsequent breast cancer incidence, given that obesity is an established risk factor for postmenopausal breast cancer, but that the results of weight loss and breast cancer studies are inconsistent. Over 61,000 women with no prior breast cancer and normal mammogram were included and subjected to measurement of body weight, height and body mass index (BMI) at baseline and after 3 years. At screening, 32.4% of women were in the 50–59-year age group (n = 19,884), 44.9% were in the 60–69-year age group (n = 27,584) and 22.6% were in the 70–79-year age group (n = 13,867). Weight change was considered stable if it was < 5%, lost or gained if it was ≥ 5%. Self-reporting was used to determine whether the weight loss was intentional or unintentional. Incident invasive breast cancer diagnosed after the year 3 visit was the primary outcome. Participants were observed from the year 3 visit until breast cancer diagnosis, date of death, loss to follow-up or end of follow-up. In the women who lost weight, most weight loss was maintained through year 6. Weight loss was associated with a 12% risk reduction to develop breast cancer (HR 0.88; p = 0.02), with respect to stable weight. There were no interactions with BMI and with the intentionality of the weight loss. Weight gain, on the other hand, was not associated with breast cancer risk (HR 1.02; 95% CI 0.93–1.11) but was associated with higher triple-negative breast cancer (TNBC) incidence (HR 1.54; 95% CI 1.16–2.05). These results suggest that postmenopausal women who lose weight may reduce their breast cancer risk.
Epidemiological studies have provided convincing evidence that overweight and weight gain in the postmenopause are associated with an increased risk of breast cancer , while there have been contrasting results in studies looking at the benefit related to weight loss [3, 4]. In this recent publication, even modest weight loss of 5%, over a relatively short term, made the difference in terms of breast cancer risk reduction  in a group of postmenopausal, relatively older women, two-thirds of them being older than 60 years of age at baseline. Weight loss did not benefit any particular tumor histology, stage, grade or estrogen/progesterone receptor/HER2 status. Weight gain, with respect to stable weight, did not increase overall risk of breast cancer in this group of women; however, it was associated with a slightly increased incidence in TNBC. Reports in the literature are conflicting regarding the association between obesity and the risk of postmenopausal hormone receptorâ€negative breast cancer [5-7], and a recent meta-analysis revealed no influence of obesity on overall and disease-free survival in women with TNBC .
A very recent Chinese population-based case-control study found that the increased risk of breast cancer was associated with the weight gain in adulthood in postmenopausal women but not in premenopausal women . The risk associated with weight gain since menopause was higher than that from age 18 to menopause. The association tended to be stronger in those with higher waist circumference. These very recent studies taken together [1, 9] seem to indicate that it is the weight gained or lost after the menopause that makes the real difference in terms of breast cancer risk.
It is important to keep in mind that the relationship between obesity and breast cancer risk is quite complex. Increased endogenous estrogen production from aromatization of androgen in peripheral fat tissue  may explain the association between body weight and risk of hormone-dependent breast cancer in the postmenopause. However, estrogens may act independently from estrogen receptor binding. For example, estrogen metabolites can exert genotoxic effects, which contribute to the development of breast cancer . Moreover, the negative effects of adiposity, especially those of visceral fat, are also estrogen-independent . Increased insulin, IGF-1, and leptin signalling in obese women promote mitogenesis and anti-apoptosis in breast cancer cells. Leptin also stimulates the secretion of proinflammatory cytokines from macrophages (IL-6 and tumor necrosis factor-alpha), as well as T cells and mononuclear cells (IL-2 and interferon-gamma) . Together these inflammatory cytokines promote tissue inflammation and activate signaling pathways that promote aggressive tumor behavior . High levels of insulin signaling promote tumor angiogenesis through upregulation of vascular endothelial growth factor and hypoxia inducible factor .
On the other hand, adiponectin activity, which normally inhibits the proliferation of vascular smooth muscle cells, is lower in obese subjects and is associated with increased risk of breast cancer development . Weight loss and control, especially after the menopause, therefore, may counteract breast cancer by targeting multiple pathways and should be encouraged in the battle against this life-threatening disease.
- Chlebowski RT, Luo J, Anderson GL, et al. Weight loss and breast cancer incidence in postmenopausal women. Cancer 2018 Oct 8
- Lauby-Secretan B, Scoccianti C, Loomis D, et al.; International Agency for Research on Cancer Handbook Working Group. Body fatness and cancer--viewpoint of the IARC Working Group. N Engl J Med 2016;375:794-8
- Neuhouser ML, Aragaki AK, Prentice RL, et al. Overweight, obesity, and postmenopausal invasive breast cancer risk. a secondary analysis of the Women’s Health Initiative randomized clinical trials. JAMA Oncol 2015;1:611–21
- Eliassen AH, Colditz GA, Rosner B, et al. Adult weight change and risk of postmenopausal breast cancer. JAMA 2006; 296:193-201
- Ritte R, Lukanova A, Berrino F, et al. Adiposity, hormone replacement therapy use and breast cancer risk by age and hormone receptor status: A large prospective cohort study. Breast Cancer Res 2012;14:R76
- Phipps AI, Chlebowski RT, Prentice R, et al. Body size, physical activity, and risk of triple-negative and estrogen receptor-positive breast cancer. Cancer Epidemiol Biomark Prev 2011;20:454–63
- Pierobon M, Frankenfeld CL. Obesity as a risk factor for tripleâ€negative breast cancers: a systematic review and metaâ€analysis. Breast Cancer Res Treat 2013;137:307â€14
- Mei L, He L, Song Y, et al. Association between obesity with disease-free survival and overall survival in triple-negative breast cancer: A meta-analysis. Medicine (Baltimore) 2018;97:e0719
- Cao S, Zhou J, Zhu Z, et al. Adult weight change and the risk of pre- and postmenopausal breast cancer in the Chinese Wuxi Exposure and Breast Cancer Study. Breast Cancer Res Treat 2018 Oct 27
- Matthews SB, Thompson HJ. The obesity-breast cancer conundrum: an analysis of the issues. Int J Mol Sci 2016;17(6)
- Yager JD, Davidson NE. Estrogen carcinogenesis in breast cancer. N Engl J Med 2006;354:270–82
- Sun H, Zou J, Chen L, et al. Triple-negative breast cancer and its association with obesity. Mol Clin Oncol 2017;7:935-42