Background:Obese postmenopausal women are at higher breast cancer risk potentially

driven by hyperinsulinemia. However, reports of insulin level associations with breast cancer

incidence and survival are inconsistent. Therefore, we examined associations among insulin

resistance by homeostasis model assessment-insulin resistance (HOMA-IR) index and

incident breast cancer, deaths from breast cancer, and deaths after breast cancer in

postmenopausal women participating in the Women's Health Initiative (WHI).

Patients and Methods:From the 161,808 postmenopausal women, aged 50-79 years,

enrolled at 40 US clinical centers from 1993 through1998 in WHI clinical trials or the

observational study, 22,837 with available fasting serum insulin and glucose by the same

methodology and no prior breast cancer represent the current study population. The

exposure was insulin resistance (HOMA-IR index) as [fasting insulin (qIU/ml) times fasting

glucose (mg/dL) / 22.5. Survival by cause was determined by central medical record or

death certificate review, enhanced by National Death Index queries. Breast cancers, initially

ascertained by serial survey, were confirmed by medical record review. Associations

between HOMA-IR quartiles and breast cancer outcomes were examined using Cox multi-

variate proportional hazards models with results reported as hazard ratios (HR) and 95%

confidence intervals.

Results: At entry, women in the highest HOMA-IR quartile were more likely to be Black,

have lower education level, have higher body mass index (BMI), higher waist circumference

≥ 88 cm and lower physical activity levels, but have lower calculated five-year breast cancer

risk. After 18.1 years median follow-up from randomization with 1,148 incident breast

cancers, breast cancer incidence was higher in women in the highest, compared to the

lowest, HOMA-IR index quartile (HR 1.39 95% CI 1.14 -1.69, P = 0.0012). Of the women

with incident breast cancer, 353 (31%) have died, with cause of death available on 334

(95% of cases) where breast cancer was the most common cause of death (33%); followed

by cardiovascular disease (24%); and other cancers (13%). With median post-breast cancer

diagnosis follow-up of 10.5 years, breast cancer mortality was examined from breast cancer

diagnosis. No association was found between death from breast cancer and HOMA-IR.

However, women with breast cancer in the highest HOMA-IR quartile, compared to women

in the lowest, were significantly more likely to experience death after breast cancer from

any cause (HR 1.45 95% CI 1.00 - 2.09, P = 0.0488) and were at somewhat higher risk of

death from cardiovascular disease (HR 1.51 95% CI 0.67 - 3.41) and other causes (HR 1.93

95% CI 0.87-4.27).

Conclusion:In postmenopausal women, higher insulin resistance is associated with higher

breast cancer incidence and more deaths after breast cancer, likely due to insulin influence

on several causes of death. However, deaths from breast cancer, even in this older

postmenopausal population, remains a major factor limiting survival which needs to be

addressed. The findings suggest insulin resistance represented a potential intervention

target for postmenopausal women with early stage

breast cancer.

Citation Format: Chlebowski RT, Pan K, Mortimer J, Cespedes Feliciano EM, Gunter MJ, Hurria A, Rohan T, Vitolins MZ, Adams-Campbell L, Ho G, Cheng T-YD, Nelson R. Insulin resistance and breast cancer incidence and mortality in postmenopausal women [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-08-10.