The analysis of the PADA-1 study shows the kinetics and determinants of ESR1 mutations in HR+/HER2 metastatics breast cancer

An analysis from the PADA-1 study (NCT03079011), in which the kinetics and determinants are examined by ESR1 Mutations that were detected in the blood of patients with hormone receptor-positive her2-negative metastatic breast cancer showed that the incidence of these changes was uneven over time.¹

Findings in the 2025 Esmo Breast Congress showed that the incidence of ESR1 ESR1 Mutation.

A multivariate analysis in which factors are examined modulated the relative incidence of ESR1 Mutations showed that estrogen recepotr expression per immunohistochemistry (odds ratio [OR]1.12; 95% CI, 1.01-1.26), the presence of bones and another place of metastasis (OR, 2,08; 95% CI, 1.30-3.38), the presence of bone-negative metastases (OR, 2.67; 95% CI, 1.52-4.76) and increased lactate hydrogenase mirrors (1.10-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-20-20-20-2. ESR1 Mutations compared to progressive illness without ESR1 Mutations.

“Catching of ESR1 Mutations before a progressive illness were easier [patients with] Bone metastases and low proliferation, ”said the study author François-Clément Bidard, MD, PhD, in a presentation of the data.“ These results can provide information on how to adapt ESR1 Mutation monitoring in the first line.

Bidard is a professor of medicine in the Department of Medical Oncology to Institut Curie and UVSQ/Université Paris-Saclay; Coordinator of breast cancer research at the Curie Institute; and the deputy chair of the French breast cancer research group UCBG.

Previous findings of Pada-1

PADA-1 was a proof-of-concept study in which a change in therapies for patients with hormone receptor positive/her2-negative breast cancer were evaluated, which received their first aromata chimmer (AI) in combination with PalboCiclib (ibrance). Patients who had a newly recognized or increased level of ESR1 Mutations in the blood in the absence of the synchronous disease were then randomly assigned in order to stay on the same therapy in combination with Palbociclib or to switch to fulvestrant (faslodex).

The results showed that with an average follow -up period of 35.3 months (interquartile areas [IQR]29.2-41.4) From the registration and 26.0 months (IQR, 13.8-34.3) from randomization, patients who switched to fulvestrant plus palboociclib (n = 88), a median progression (9.1 to 11.6). receive an AI plus palboociclib (n = 84; layered HR, 0.61; 95% CI, 0.43-0.86; P = .0040).

“This was the first proof that supported ESR1 Mutation monitoring during the first line, ”said Bidard during the presentation.

While step 1 of the study before the randomization, 1017 patients were inscribed in combination with a AI.¹ In this phase, ESR1 Mutations were found in 283 patients before the disease progressed, and 395 patients had progressed the disease without evidence of one ESR1 Mutation. As soon as the target number of patients has been reached for randomization, ESR1 Mutation tests were discontinued for step 1; At this point, 339 patients still received Palboociclib Plus a AI or were canceled from the study.

When taking into account patients who had ESR1 Proven mutations and those who had a progress in the absence of a disease progress ESR1 Mutation that ESR1 The mutation detection rate was 41.9% (n = 283/678).

The populations of patients with ESR1 proven mutations and people with progressive illness without ESR1 Mutations were included in the analysis of the cumulative and current incidence of ESR1 Mutations.

Further ESR1 Analysis from step 2

Among the 283 patients who had one ESR1 Mutation demonstrated, 71 ultimately had a synchronous progressive illness and left the study; The remaining 212 patients without synchronous progressive disease were entitled to randomly assignment.

The researchers used a further multivariate analysis to evaluate factors that could contribute to a higher incidence of synchronous progressive diseases with one ESR1 Mutation against the lack of a progressive illness in the presence of one ESR1 Mutation. The results showed that the tumor degree of 3 compared to 1 (OR 2.56; 95% CI, 0.90-8.4) and a metastasis-free interval of more than 3 years (OR, 6.61; 95% CI, 2.3-20.8). Age (OR, 0.77; 95% CI, 0.60-0.90), bone plus another metastasis (OR, 0.34; 95% CI, 0.16-0.75) and bone-negative metastasis (OR, 0.21; 95% CI, 0.08-0.55) were not with an increased incidence Increased incidence with an increased incidence with an increased incidence with an increased incidence with an increased incidence with increased incidence with increased incidence). ESR1 Mutations without progressive illness.

Future instructions

According to PADA-1, Phase 3 Sernean-6 study (NCT04964934) evaluated a similar strategy in which patients with hormone receptor positive/her2-negative advanced breast cancer that has been proven ESR1 The mutation before the progression of the clinical disease changed either from an AI plus a CDK4/6 inhibitor to oral selective estrogen receptor in combination with the same CDK4/6 inhibitor or remained on the same AI plus CDK4/6 -Inhibitor regime.

Above all, Serena-6 filled its primary endpointWith camizestrant plus a CDK4/6 inhibitor that creates a statistically significant and clinically significant improvement in PFS compared to an AI plus a CDK4/6 inhibitor.³

“Pada-1 was a proof-of-concept attempt. [At the 2025 ASCO Annual Meeting]We will have the results of Serena-6, ”concluded Bidard.¹

References

1. Cabel L., Bachelot T., Hardy-Bessard AC, et al. Kinetics and determinants of BESR1 under AI and PalboCiclib in patients with HR+/HER2-MBC in the PADA-1 study. Presented at: 2025 ESMO breast cancer congress. 14.-17. May 2025; Munich, Germany. Summary 1o.
2. Bidard FC, Hardy-Bessard AC, Dalenc f, et al. Switch to Fulvestrant and PalboCiclib compared to no change in the advanced breast cancer with increasing ESR1 mutation during the aromata seed and the PalboCiclib therapy (PADA-1): a randomized, open, multical, multal phase-3 study. Lancet Oncol. 2022; 23 (11): 1367-1377. DOI: 10.1016/S1470-2045 (22) 00555-1
3. Camizestrant showed a highly statistically significant and clinically sensible improvement in progression-free survival in advanced HR-positive breast cancer in the first line with an up-and-coming ESR1 tumor in the Serena-6-Phase III study. Press release. Astrazeneca. February 26, 2025. Access on May 15, 2025.