Overview

The purpose of this study is to learn more about the effects of your BRCA mutation on the ovaries. The BRCA gene can make it hard to conceive a child in the future. It may also bring on early menopause. The researchers will check blood levels of hormones that the ovaries produce. The hormones that researchers will check are anti-Mullerian hormone (AMH), estradiol and follicle stimulating hormone (FSH). The researchers will do this before, during, and after cancer treatment. The researchers will also ask you to fill out questionnaires about your menstrual cycle (your periods) and information about your health and pregnancies. This may help us learn which women will be more likely to have early menopause.

Eligibility

Inclusion Criteria:

For Premenopausal Women with Early Stage Breast Cancer

1. Participant is between 18-44 years old.
2. Participant is premenopausal.
3. Participant is female.
4. Participant has a known breast cancer diagnosis of AJCC Stage 0-III breast cancer, regardless of hormone-receptor status or HER2-overexpression, before the start of planned adjuvant or neoadjuvant chemotherapy and/or hormonal therapy.
5. The chemotherapy regimen must be either CMF, anthracycline-containing, or taxane-containing. If hormonal therapy is planned, the regimen must be limited to tamoxifen All biologics are allowed in addition to the above therapies.
6. The participant has regular menstrual cycles; note: patients can have no more than 1 irregular cycle (too early or too late) within the past year and/or at least 10 spontaneous cycles within the past year. Exceptions are made for patients who have been pregnant in the last 12 months and patients with IUDs or a LARC.

Subject Inclusion:

For Unaffected High Risk Premenopausal Women with BRCA mutations

1. The participant is between 25 and 45 years of age.
2. The participant is female.
3. The patient has a known BRCA mutation.
4. Have regular menstrual (21-35 days); patients can have no more than 1 irregular cycle (too early or too late) within the past year or were pregnant in the past 12 months, and/or at least 10 spontaneous cycles within the past year. Exceptions are made for patients who have been pregnant in the last 12 months and patients with IUDs or a LARC.

Subject Inclusion:

For affected BRCA1 and BRCA2 mutation carriers, affected women with non-BRCA mutations, and BC patients with no mutations (control)

1 . Premenopausal women age 21-45 with stage 0-3 breast cancer. 2. No prior ovarian surgery or ovarian disease. 3. No prior chemotherapy. 4. Regular menstrual periods (21-35 days), no PCOS. 5. No hormonal contraception within the prior 4 weeks. 6. Mutation testing decision based on NCCN Guidelines V1.2021: according to these Guidelines, both centers test all pre-menopausal women with breast cancer for BRCA and non-BRCA mutations which are the subject of this proposal.

7\. Receiving an anthracycline (typically doxorubicin/Adriamycin) and Cy (AC)-based chemotherapy protocol.

Exclusion Criteria:

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.

Subject Exclusion Criteria:

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.