7326 Breast and Ovarian Cancer are Increased in Women with Primary Ovarian Insufficiency and Early Menopause and Cancer is Increased in Family Members

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Abstract Disclosure: K.L. Allen-Brady: None. L. Verrilli: None. M. Alvord: None. M. Kern: None. N. Camp: None. K. Kelley: Consulting Fee; Self; Immunogen. J. Letourneau: None. L. Cannon-Albright: None. E.B. Johnstone: Stock Owner; Self; Abbott Laboratories, Abbvie. C.K. Welt: None. Introduction: Next generation sequencing in women with primary ovarian insufficiency (POI) identified deleterious variants in DNA damage repair and transcription fidelity genes. Based on underlying genetics, we hypothesized that a subset of women with POI may also be predisposed to reproductive or hormonally influenced cancers and that family members may be at risk. Methods: Women with POI (≤40 years) and early menopause >40 and <45 years) were identified using ICD9 and 10 codes in electronic medical records (1995-2021) from two major healthcare systems in Utah and reviewed for accuracy. Women with POI and their relatives were linked to genealogy information using the Utah Population Database (UPDB) and to cancer diagnoses (breast, ovarian, endometrial, colon, testicular and prostate) using the Utah Cancer Registry. The relative risk (RR) of cancer in women with POI and in relatives was estimated by comparison to population rates matched by age, sex, and birthplace. We also identified POI pedigrees with an excess number of observed cancer cases compared to the expected number in population controls. Results: We identified 613 women with POI and 165 women with early menopause. Of these, 416 women with POI had at least three generations of genealogical data with 2,405 first-degree relatives, 6,798 second-degree relatives and 17,666 third-degree relatives. Breast cancer was significantly increased in women with POI (OR [95%CI] 1.89 [1.20, 2.84]; p=0.0056) and there was a borderline increase in ovarian cancer. Probands were 36.5±4.3 years when diagnosed with POI and 59.5±12.7 years (range 43-80 years) at the time of breast cancer diagnosis and only 2 women took hormone replacement therapy after age 50 years. When women with early menopause were added, breast cancer risk remained increased and ovarian cancer was also nominally significant (3.38 [1.15, 8.65]; p=0.032). There was no increased risk of endometrial cancer and there were no cases of colon cancer. Among second-degree relatives of women with POI and 3 generations of family members, there was a significantly increased risk of breast (1.28 [1.08, 1.71]; 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). There were 27 POI pedigrees that were high risk for these reproductive or hormonally influenced cancer diagnoses. Conclusions: Our data suggest common risk factors for POI and reproductive or hormonally influenced cancers. Therefore, clinicians need tools to predict cancer risk and comorbid disease in women with POI and early menopause to adequately counsel about future health risk. This understanding may change recommendations for hormone replacement based on the underlying genetic cause of POI for an individual. Presentation: 6/3/2024

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