Breast Cancer is Increased in Women with Primary Ovarian Insufficiency.

Context: DNA damage/repair gene variants are associated with both primary ovarian insufficiency (POI) and cancer risk.

Objective: We hypothesized that a subset of women with POI and family members would have increased risk for cancer.

Design: Case-control population-based study using records from 1995-2022.

Setting: Two major Utah academic healthcare systems serving 85% of the state.

Subjects: Women with POI (n=613) were identified using ICD codes and reviewed for accuracy. Relatives were linked using the Utah Population Database.

Intervention: Cancer diagnoses were identified using the Utah Cancer Registry.

Main Outcome Measures: The relative risk of cancer in women with POI and relatives was estimated by comparison to population rates. Whole genome sequencing was performed on a subset of women.

Results: Breast cancer was increased in women with POI (OR [95%CI] 2.20 [1.30, 3.47]; p=0.0023) and there was a nominally significant increase in ovarian cancer. Probands with POI were 36.5±4.3 years and 59.5±12.7 years when diagnosed with POI and cancer, respectively. Causal and candidate gene variants for cancer and POI were identified.Among second-degree relatives of these women, there was an increased risk of breast (1.28 [1.08, 1.52]; p=0.0078) and colon cancer (1.50 [1.14, 1.94]; p=0.0036). Prostate cancer was increased in first- (1.64 [1.18, 2.23]; p=0.0026), second- (1.54 [1.32, 1.79]; p<0.001), and third-degree relatives (1.33 [1.20, 1.48]; p<0.001).

Conclusions: Data suggest common genetic risk for POI and reproductive cancers. Tools are needed to predict cancer risk in women with POI and potentially to counsel about risks of hormone replacement therapy.