30 May ASCO20: Prognostic Impact of ESR1 mutations in ER+ HER2- Metastatic Breast Cancer
MedicalResearch.com Interview with:
Francois-Clement Bidard, MD PhD
Head of Breast Cancer Group, Institut Curie
Professor of Med. Oncology, UVSQ/Paris
MedicalResearch.com: What is the background for this study?
Response: A timely question is how to optimize the endocrine therapy of ER+ HER2- metastatic breast cancers? Aromatase inhibitors (AI) are currently the standard of care in first line, in combination with CDK4/6 inhibitors. Mutations in the estrogen receptor gene (ESR1) can be detected in up to 40% of AI-resistant metastatic breast cancers, but no data was available in the current first line setting (AI combined to CDK4/6 inhibitor).
This exploratory study of the first line PADA-1 study reports on the detection rate of ESR1 mutations in cell-free DNA from an “AI-sensitive” population (with no metastatic relapse during adjuvant AI therapy), before the start of therapy (at inclusion). As expected, we found a low prevalence of 3.2% in the general population (N=1,017 patients included). The prevalence of ESR1 mutations among subgroups appeared primarily driven by the type of adjuvant endocrine therapy: patients with prior exposure to adjuvant therapy with AI displayed the highest prevalence of ESR1 mutations (7.1%), followed by patients with no prior adjuvant endocrine therapy (mostly de novo stage IV; ESR1 mutation prevalence: 2.4%). Patients who received adjuvant endocrine therapy with no AI (e.g. tamoxifen only) had the lowest ESR1 mutation prevalence (1.2%).
MedicalResearch.com: What are the main findings?
Response: We found that patients with ESR1 mutations at baseline had a significantly shorter median PFS under AI and palbociclib (11 vs 26.7 mo; HR=2.3[1.5;3.6]). Among the ESR1-positive patients at baseline, we showed that two-thirds had an early clearance of ctDNA (no ESR1 mutation detected after 1 month on AI and palbociclib). These patients had a much longer PFS than those who still displayed detectable ESR1 mutations at 1 month.
MedicalResearch.com: What should readers take away from your report?
Response: ESR1 mutations were known to be positively selected during AI therapy at metastatic stage; the PADA-1 data show that they are also selected during adjuvant AI therapy and can be detected prior at metastatic relapse, prior to any treatment.
Our data confirm that ESR1 mutations are associated with a worse prognosis under AI-based therapy, yet both the median PFS achieved in the ESR1-mutant subgroup (11 months) and ctDNA clearance observed in many patients suggest that the combination of AI and palbociclib retain some activity in that population.
These findings may partly explain the results of the PARSIFAL trial (also disclosed at ASCO 20), which had very similar inclusion criteria and showed no superiority of fulvestrant over AI when combined with Palbociclib in an AI-sensitive population.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: The key question is how and when to use fulvestrant or the many Selective Estrogen Receptor Degraders (SERDs) currently in development. We know that, when patients treated with fulvestrant as single agent in the late lines have very short PFS – even in presence of ESR1 mutations (EFECT trial, PlasmaMATCH study). In the first line setting, in combination with CDK4/6 inhibitors, the PARSIFAL study just taught us that fulvestrant is no better than AI in an all-comers AI-sensitive population. Our hypothesis in the PADA-1 trial (which results will be known in 2021) is that the use of fulvestrant should be triggered by the emergence of an ESR1-mutated subclone during the first line AI-based therapy. This will likely pave the way for the future development of new oral SERDs.
MedicalResearch.com: Is there anything else you would like to add?
Response: PADA-1 is funded by a research grant to UCBG. Personal disclosures of Prof Bidard include travel support, advisory and speaker fees from Pfizer; advisory fees from Radius Pharma; travel support, advisory and speaker fees from Novartis; advisory fees from Lilly.Citation:
DOI: 10.1200/JCO.2020.38.15_suppl.1010 Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020) 1010-1010.
Published online May 25, 2020.
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