Amy Tiersten, MD

Carlos L. Arteaga, MD

Amy Tiersten, MD, Professor of Medicine, Hematology, and Medical Oncology, Icahn School of Medicine at Mount Sinai, and Carlos L. Arteaga, MD, Director of the Simmons Comprehensive Cancer Center and Associate Dean of Oncology at The University of Texas Southwestern Medical Center, Dallas, welcomed the findings of PADA-1¹ as useful to physicians and meaningful for patients. They also emphasized that the findings were made via blood-based sampling rather than tissue biopsy.

“If anything, this study emboldens us to use circulating tumor DNA [ctDNA] more and to move forward in diagnosing these mutations, which can inform our treatments,” Dr. Arteaga commented.

Dr. Tiersten called the PADA-1 trial “a tremendously exciting study,” being the first in breast cancer to document a benefit for switching therapy based on genomic findings, prior to clinical progression. Patients with emerging acquired ESR1 mutations (which confer resistance to aromatase inhibitors) found on ctDNA who were switched from an aromatase inhibitor plus a cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitor to fulvestrant with continuation of the CDK4/6 inhibitor had doubling in median progression-free survival, from 5.7 to 11.9 months. This contrasts with the median progression-free survival of 3.5 months when patients switched after disease progression was clinically identified.

“The implication here is that early detection of resistant disease and switching therapy based on this finding actually makes a difference, something that has never been shown before,” Dr. Tiersten said. Ongoing trials investigating this finding “will hopefully lend support to this approach,” she added.

From Laboratory to Clinic

Dr. Arteaga, who moderated a press briefing where the results were presented, called PADA-1 “an excellent trial that validates the discovery in the laboratory a few years ago that estrogen-receptor mutations do not depend on the estrogen hormone.”

He continued: “The aromatase-inhibitor arm of the study was clearly inferior to the fulvestrant-containing arm, but those tumors that are now driven by estrogen-receptor mutations independent of the estrogen hormone continue to depend on and use the estrogen receptor, which is the target of fulvestrant. Even in these patients, we need to continue to inhibit the estrogen receptor with a strategy other than estrogen suppression with aromatase inhibitors, in this case, a direct estrogen-receptor antagonist in combination with CDK4 inhibitors.”

As Dr. Arteaga pointed out, many clinicians in the United States are already performing liquid biopsies, with assays equivalent to the one used in this study. “One of the lessons here is that we can use blood, without always needing invasive tissue biopsies of metastasis, to look for ESR1 mutations,” he explained. “I think we now have enough evidence that we can use plasma ctDNA at least to detect ESR1 mutations …. Dr. Bidard uses a very sensitive digital droplet polymerase chain reaction assay, but he made the point, and I agree that it is equivalent to plasma ctDNA next-generation sequencing.” 

DISCLOSURE: Dr. Tiersten has received research funding from Lilly, Pfizer, and Novartis. Dr. Arteaga has served in a leadership role for the AACR; holds minor stock options in Provista Diagnostics; serves or has served as a scientific advisor to Daiichi Sankyo, AstraZeneca, Immunomedics, Lilly, Merck, Novartis, OrigiMed, Sanofi, and Taiho Oncology; receives research funding from Lilly, Pfizer, and Takeda; and serves on the scientific advisory board of the Susan G. Komen for the Cure Foundation.

REFERENCE

1. Bidard FC, Hardy-Bessard AC, Bachelot T, et al: Fulvestrant-palbociclib vs continuing AI-palbociclib upon detection of circulating ESR1 mutation in HR+ HER2– metastatic breast cancer patients: Results of PADA-1, a -UCBG-GINECO randomized phase 3 trial. 2021 San Antonio Breast Cancer Symposium. Abstract GS3-05. Presented December 9, 2021.