Fertility and Overtreatment of Premenopausal Breast Cancer

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One key concern about chemotherapy in premenopausal women is its impact on fertility. Chemotherapy can cause premature ovarian failure and infertility, and a future desire for fertility should be discussed with every premenopausal patient. Fertility preservation (FP) should be offered to anyone who is interested in becoming pregnant after chemotherapy for breast cancer.

Ovarian stimulation followed by egg retrieval and oocyte, or embryo cryopreservation can be performed quickly and safely before starting chemotherapy, in as little as 2-3 weeks. Several studies have shown that FP does not have a negative impact on breast cancer outcomes, regardless of HR-positive status.

Marklund et al published a prospective cohort study which evaluated 1275 women with breast cancer in Sweden who underwent FP and compared them to a cohort of age-matched controls with breast cancer who did not undergo FP.¹ The 5-year relapse-free survival was 89% for those who underwent hormonal stimulation of the ovaries and 82% for those who did not undergo FP. From this data, patients can be reassured that neither the hormonal stimulation nor the delay in starting chemotherapy while completing FP will negatively impact their breast cancer outcomes.

Because of the fertility concerns mentioned, determining which premenopausal women can safely omit chemotherapy is of the utmost importance. This is one of the more controversial topics in breast cancer care today. The RxPONDER trial (NCT01272037) mentioned earlier evaluated women with HR-positive/HER2-negative early breast cancer with 1-3 positive lymph nodes and a RS of 25 or less.² Subgroup analysis of premenopausal women showed that all node positive premenopausal women derive a benefit from the addition of chemotherapy to endocrine therapy (5-year iDFS 93.9% vs 89.0% HR 0.60; P =0.002).

Similar benefits were noted in premenopausal women in the TAILORx trial (NCT00310180) with RS 21-25 or clinical high risk and RS 16-20.³ The controversy around this data centers on whether this benefit is the result of direct cytotoxicity of the chemotherapy or just a very toxic means of ovarian function suppression. If it is the latter, then there may be many premenopausal women who are being over-treated with potential long-term impacts on fertility.

To answer this question, the ongoing NRG BR009 (OFSET) clinical trial (NCT05879926) will enroll the above-mentioned patients (premenopausal HR+/HER2- patients who are node positive with RS 0-25, node negative with RS 21-25, or node negative with RS 16-20 and high clinical risk).⁴ Patients will be randomized to chemotherapy, OFS, and aromatase inhibitor (AI) vs OFS and AI alone. It will be a number of years before we have results from this trial, so in the interim we will need to have nuanced conversations with our patients regarding these uncertainties to help them to make informed decisions regarding their treatment.

Another success for young women with breast cancer interested in future childbearing came with the results of the POSITIVE trial.⁵ In this trial, 516 women with early breast cancer who were interested in becoming pregnant and had been on endocrine therapy for 18-30 months interrupted their endocrine therapy for up to 2 years in an effort to become pregnant. Among these women, 63.8% had at least one live birth. The 3-year incidence of breast cancer events was 8.9% among trial participants vs 9.2% among women from a historical control cohort.

These are exciting results for young women with breast cancer, but some important caveats must be considered. The follow-up on this trial remains relatively short given the late recurrences that can occur in this subtype of breast cancer. It is also important to note that 93% of patients in this trial had stage 1 or 2 breast cancer, so these results may be difficult to generalize to our stage 3 patients who are at higher risk of relapse.

Safe and temporary interruption of therapy to have a family is an important example of de-escalation that allows patients to achieve a balance between their treatment goals and other life goals.

_REFERENCES:

_{1. Markland A, Lekberg T, Hedayati E, et al. Relapse rates and disease-specific mortality following procedures for fertility preservation at time of breast cancer diagnosis. JAMA Oncol. 2022;8(10):1438-1446. doi:10.1001/jamaoncol.2022.3677}

_{2. Kalinsky K, Barlow WE, Gralow JR, et al. 21-Gene assay to inform chemotherapy benefit in node-positive breast cancer. N Engl J Med. 2021; 385:2336-2347. doi: 10.1056/NEJMoa2108873}

_{3. Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018; 379:111-121. doi: 10.1056/NEJMoa1804710}

_{4. Evaluating the addition of adjuvant chemotherapy to ovarian function suppression plus endocrine therapy in premenopausal patients with pN0-1, ER-positive/​HER2-negative breast cancer and an oncotype recurrence score less than or equal to 25 (OFSET). ClinicalTrials.gov. Updated September 5, 2023. Accessed September 7, 2023.}

_{5. Patridge AH, Niman SM, Ruggeri M, et al. Interrupting endocrine therapy to attempt pregnancy after breast cancer. N Engl J Med. 2023; 388:1645-1656. doi: 10.1056/NEJMoa2212856}