For the therapies that are used in postmenopausal women with HR+ breast cancer to be effective in premenopausal women, one needs to shut off the ovarian production of estrogen. That can be done through oophorectomy, with gonadotropin-releasing hormone (GnRH) agonists, or with radiation to the ovaries (which is now rarely used). The most common approach for shutting off the ovarian production of estrogen is with the use of GnRH agonists, although patients who may need to have long-term ovarian function suppression often elect to have an oophorectomy, especially if they are responding well to antiestrogen therapy. Once you give the first injection of a GnRH agonist, it takes approximately 2 to 3 weeks for ovarian estradiol levels to be suppressed to postmenopausal levels, although you must keep in mind that sometimes the patient experiences a surge in estrogen. And once estrogen levels are suppressed, the current approach to first- and second-line treatment is essentially the same in both pre- and postmenopausal women with metastatic estrogen receptor–positive/human epidermal growth factor receptor 2–negative (HER2-) breast cancer.

Multiple studies have demonstrated that the addition of CDK4/6 inhibitors improve clinical outcomes when added to first- or second-line endocrine therapy, including aromatase inhibitors or fulvestrant in the first line, or fulvestrant in the second line. Most of these studies included largely postmenopausal women. 

The only trial evaluating CDK4/6 inhibitors exclusively in premenopausal women was the MONALEESA-7 trial, a first-line phase 3 trial that compared the addition of the CDK4/6 inhibitor ribociclib to the endocrine therapy including ovarian function suppression with goserelin plus the selective estrogen receptor modulator tamoxifen or a nonsteroidal aromatase inhibitor (ie, letrozole or anastrozole) vs endocrine therapy alone. At the initial analysis, the addition of ribociclib was associated with significantly longer progression-free survival (PFS) compared with placebo, but it demonstrated no benefit in overall survival (OS). In a recent exploratory analysis after a median follow-up of 53.5 months, Lu et al found that the addition of ribociclib to the endocrine therapy group was associated with prolonged OS compared with endocrine therapy alone (58.7 months vs 48 months, respectively), and this benefit extended to those under 40 years of age. 

Other randomized clinical trials, such as the phase 3 PALOMA-3 and MONARCH 2 trials, evaluated CDK4/6 inhibitors for the second-line treatment of advanced HR+/HER2- breast cancer and included small proportions of premenopausal women. PALOMA-3 evaluated the combination of palbociclib plus fulvestrant in women with advanced HR+/HER2- breast cancer after prior progression on endocrine therapy. An initial subgroup analysis showed that PFS and objective response rates improved with the addition of palbociclib over endocrine monotherapy; however, Turner et al more recently found no benefit in OS among pre- or perimenopausal women. MONARCH 2 evaluated the addition of abemaciclib to fulvestrant in patients with endocrine resistant disease, and findings in the premenopausal subgroup of this study were consistent with those in the intent-to-treat population, showing benefits in both PFS and OS with the combination of abemaciclib plus fulvestrant with ovarian suppression.