Vasomotor symptoms (VMS) are among the most clinically consequential adverse events of endocrine therapy in patients with hormone receptor–positive breast cancer, affecting the majority of treated patients and contributing to suboptimal treatment adherence. In this video series, Carmine Valenza, MD, MPH, PhD(c), reviews the neurobiology underlying VMS, explaining how estrogen deprivation leads to hyperactivation of hypothalamic KNDy neurons and how dual NK1/NK3 receptor antagonism with elinzanetant (Lynkuet) targets this pathway through a nonhormonal mechanism considered safe for use in patients with breast cancer.
Vasomotor symptoms affect more than 50% of patients receiving endocrine therapy for hormone receptor–positive breast cancer and can reach 90% in younger patients on ovarian function suppression, with more than 20% of affected patients discontinuing treatment—a factor directly linked to increased recurrence risk and reduced survival.
Hyperactivation of hypothalamic KNDy neurons—which express kisspeptin, neurokinin B, and dynorphin—drives VMS during estrogen deprivation, providing the mechanistic basis for dual NK1/NK3 receptor antagonism as a nonhormonal strategy that may also improve sleep quality.
In the phase 3 OASIS-4 trial (NCT05587296), elinzanetant (Lynkuet) produced clinically meaningful reductions in moderate-to-severe vasomotor symptoms frequency—beginning as early as week 1—compared with placebo, with improvements extending across all menopause-related quality-of-life domains.
An analysis from OASIS-4 demonstrated that elinzanetant (Lynkuet) consistently improved sleep disturbance and menopause-related quality of life across all endocrine therapy subgroups—with patients transitioning from moderate to normal sleep disturbance range by week 12—and that these benefits were sustained through 52 weeks.
Effective management of VMS in patients with breast cancer requires individualized assessment and shared decision-making, with elinzanetant (Lynkuet) emerging as the preferred pharmacologic option for patients with moderate-to-severe symptoms given its early onset of action, NCCN-preferred status, and the most robust evidence base in this population.
Key unanswered questions in the management of VMS in patients with breast cancer include the long-term oncologic impact of NK receptor antagonists, the broader role of patient-reported outcomes in guiding therapy selection, and the need for prospective observational studies to evaluate real-world outcomes.
