Serum Biomarkers to Characterize the Effects of Therapy on Ovarian Reserve in Premenopausal Women With Early-stage Breast Cancer or BRCA Mutations

For Cohort of Premenopausal Women with Early Stage Breast Cancer

Prior therapy for breast cancer or any other cancer, such as chemotherapy, hormonal therapy or immunotherapy.

Ovarian resection, unilateral or bilateral oophorectomy, hysterectomy or radiation to pelvic region.

Plans for risk-reducing bilateral oophorectomy within one year of completion of chemotherapy.

Prior known infertility; infertility is defined as one year of inability to conceive despite unprotected intercourse and/or the need to use medication (e.g clomiphene) or assisted reproductive technology (e.g. intrauterine insemination or in vitro fertilization) to attempt pregnancy.

Family history of a first-degree relative with non-surgical menopause \< age 40

Current pregnancy.

For Unaffected High Risk Premenopausal Women with BRCA mutation

1. Participant has therapy for breast cancer or any other cancer, such as chemotherapy, hormonal therapy or immunotherapy.

2. Participant has ovarian resection, unilateral or bilateral oophorectomy, radiation to pelvic region.

3. Participant has Plans for risk-reducing bilateral oophorectomy within one year of completion of chemotherapy.

4. Participant has prior known infertility; infertility is defined as one year of inability to conceive despite unprotected intercourse and/or the need to use medication (e.g., clomiphene) or assisted reproductive technology (e.g., intrauterine insemination or in vitro fertilization) to attempt pregnancy.

5. Participant has a family history of a first-degree relative with non-surgical menopause \< age 40.

6. Participant is currently pregnant. For affected BRCA1 and BRCA2 mutation carriers, affected women with non-BRCA mutations, and BC patients with no mutations (control)

1\. Subjects who did not undergo mutation testing, as well as those who tested positive for more than one family (BRCA1, BRCA2, non-BRCA) of ATM-Pathway gene mutations, will be excluded.

2\. Women aged \>42 years will be excluded as they carry a very high probability of chemotherapy-induced OI49. It is important to select an age range where immediate OI is less likely to occur because if most women become menopausal post-chemotherapy, the comparison of ovarian reserve decline will not be feasible. 3. In our prior grant period, we showed that the AC-based and CMF regimens similarly compromise ovarian reserve (Fig. 1)9 Currently, the AC-based chemotherapy is utilized in \>90% breast ca cases, and CMF protocol is rarely administered9. For this reason and to enhance uniformity, rare non-AC-based protocols will be excluded. 4. A previous study showed that smoking and BRCA mutations may have additive negative effects on the age of menopause27, consequently, we will exclude current smokers (smoked 100 cigarettes lifetime and currently smokes, per CDC). Based on our past studies6,9, the smoking incidence is low in our study population (\<20%) and should not significantly limit accrual.

5\. BMI: In our recent publication9 (Fig. 1), the mean BMI was 24.22 ±0.4 (median 23.2; range 17-42); hence the extreme BMI values are rare in our population. Nevertheless, those with BMI of \<18.5 and \>40 will be excluded.

What this study is about