Dr Callahan on the Efficacy of ctDNA-Based Therapy Switch in ER+ Advanced Breast Cancer

“There was an analysis of PFS2, which was difficult to interpret. But [the PFS2 data] provide some rationale to make [treatment] changes based on molecular findings or blood tests.”

Rena D. Callahan, MD, a breast medical oncologist at UCLA Health and an associate clinical professor of medicine at the David Geffen School of Medicine at UCLA, discussed the potential clinical implications of the phase 3 SERENA-6 trial (NCT04964934), which investigated the addition of camizestrant to a first-line aromatase inhibitor in patients with estrogen receptor (ER)–positive advanced breast cancer who had an emergent ESR1 mutation in circulating tumor DNA (ctDNA).

Callahan characterized these trial findings as a potentially paradigm-shifting development in the field of ER-positive breast oncology. Callahan noted that traditional medical education and patient consultations have long prioritized radiographic imaging as the standard for determining disease progression and making subsequent treatment decisions. Under this established clinical framework, therapy is generally not altered until a scan provides definitive evidence of disease advancement; however, Callahan explained that the SERENA-6 trial data challenge this conventional approach by using molecular markers to guide clinical intervention.

According to Callahan, the trial identifies molecular progression through the detection of ctDNA associated with ESR1 mutations. This molecular evidence serves as a precursor to physical progression, prompting an earlier switch in therapy than would occur under standard imaging protocols. Callahan highlighted that patients who underwent a treatment change based on these molecular findings experienced a longer median progression-free survival (PFS) compared with those whose treatment remained unchanged.

Although the PFS data are encouraging, Callahan addressed the remaining uncertainties regarding long-term patient outcomes, specifically noting that it is not yet clear whether the SERENA-6 strategy will result in improved overall survival. She also pointed out the complexities involved in interpreting the time to second progression (PFS2) data. Callahan explained that the PFS2 findings were difficult to evaluate because the treatment arms were not symmetrical, with one group receiving 3 different treatments and the other receiving 2. Despite these analytical challenges, Callahan concluded that the current data provides a legitimate clinical rationale for integrating molecular findings and blood tests into the decision-making process for treatment changes.