Metabolic Syndrome, Obesity Contribute to Breast Cancer Mortality in Postmenopausal Women

Metabolic syndrome (MetS) scores and obesity status have independent but differential adverse associations with breast cancer receptor subtypes and breast cancer mortality, according to new findings published in Cancer.¹

The Women’s Health Initiative (WHI) led a clinical trial, including 40 US clinical centers, with enrollment from 1993 through 1998. Participants were enrolled if they were postmenopausal women, between the ages of 50 to 79 years, without prior history of breast cancer.

Study methods randomized women to 1 or more hormone therapy clinical trials. There were 16,608 women with an intact uterus who were randomized to daily conjugated equine estrogen (CEE) combined with medroxyprogesterone acetate (2.5 mg/day) or placebo. Another group consisted of 10,739 women with a prior hysterectomy, randomized to daily CEE (0.625 mg/day) or placebo. Some participants were randomized to a low-fat dietary modification trial or usual diet comparison.

Components used to measure MetS scores included waist circumference, blood pressure, cholesterol history, and diabetes history. Clinical outcomes observed invasive breast cancer incidence, breast cancer mortality, deaths after breast cancer, and results by estrogen receptor (ER) and progesterone receptor (PR) status.

Out of 68,132 patients, the study population consisted of 63,330 participants with both body mass index (BMI) and MetS score determination at enrollment. Most commonly, older, less educated, Black women had higher MetS scores. In addition, higher MetS scores were seen in participants who were considered obese or had prior history of a hysterectomy or bilateral oophorectomy and if they were less likely to exercise or use hormone therapy.

Breast cancer incidence was followed up for over 18.6 years.¹ Out of the 4562 incidences of breast cancer, 2073 resulted in death after breast cancer and 659 women had breast cancer mortality.

An analysis was adjusted for BMI category and discovered breast cancer incidence was not higher with a higher MetS score (3-4 vs 0; P = .42). Following BMI adjustment, associations between MetS score and poor prognosis, ER-positive, and PR-negative cancers (P = .03) were detected. Adjusting for BMI, higherMetS score was also linked to more deaths after breast cancer (P < .001). There were no statistically significant links between MetS score and HER2 status (P = .63).

When the MetS score was adjusted, overweight and obese women displayed higher breast cancer incidence compared with normal weight women (P_trend = .001). Furthermore, ER-positive and PR-positive breast cancers had hazard ratio (HR) increases as their BMI increased. Comparatively, ER-positive and PR-negative breast cancer findings were invalid throughout obesity categories where the HR of 1.03 was the highest in the category.

Death rates after breast cancer were higher in women who were overweight or considered obese (P < .001) but breast cancer mortality was only significantly higher in women with grade 2 or 3 obesity (BMI ≥ 35 kg/m²; P < .001).

Obesity is often recognized among 3 separate categories based on BMI, a screening tool for overweight and obesity.² Class 1 has a BMI between 30 and 35, class 2 has a BMI of 35 to 40, and class 3 has a BMI of 40 or higher, sometimes considered severe.

Waist circumference was associated with breast cancer mortality, death after breast cancer, and with ER-positive and PR-negative incidence throughout the MetS score subgroups. Diabetes was linked to death after breast cancer (P < .001), ER-positive, and PR-positive cancers (P = .002).

Interestingly, mammography rates decreased as MetS scores increased. While the breast cancer mortality reports lacked significance, they were consistent with the overall study population.

Understanding how obesity increases mortality risk in breast cancer patients can help tackle existing health care disparities for obese populations. Negative stereotypes often unfairly blame obese individuals for their weight, associating them with laziness and a lack of willpower.³ However, the reality is that socioeconomic factors, like limited access to healthy food options, create significant challenges for weight management. To improve health outcomes for both individuals with obesity and patients with breast cancer, especially those facing socioeconomic challenges, access to health care must be expanded while ensuring inclusive care for all populations.

Study limitations consist of the neglect in comprehensive breast cancer therapy information as well as the reliance on questionnaire findings for diabetes and cholesterol, preventing direct comparisons to MetS studies with laboratory determinations.¹ In addition to weight, MetS scores also have separate negative effects on the types of breast cancer and survival rates.

The study suggests that while obesity and metabolic syndrome both increase breast cancer mortality risk, they do so in distinct ways. Metabolic syndrome is linked to a higher risk of ER-positive and PR-negative breast cancers, while obesity is associated with increased risk across all ER/PR categories. These findings highlight the importance of a nuanced approach to understanding breast cancer risk in patients with weight concerns. Further research is needed to explore the underlying biological mechanisms and identify interventions to improve health outcomes for all patients.

References

1. Chlebowski RT, Aragaki AK, Pan K, et al. Breast cancer incidence and mortality by metabolic syndrome and obesity: the Women’s Health Initiative. Cancer. 2024;1-10. doi:10.1002/cncr.35318

2. Defining adult overweight and obesity. CDC. June 3, 2022. Accessed May 12, 2024. https://www.cdc.gov/obesity/basics/adult-defining.html#:~:text=Class%201%3A%20BMI%20of%2030

3. Washington TB, Johnson VR, Kendrick K, et al. Disparities in access and quality of obesity care. Gastroenterol Clin North Am. 2023;52(2):429-441. doi:10.1016/j.gtc.2023.02.003