Circulating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial

Abstract

Elevated CTC at baseline was a strong prognostic factor in this cohort. Early on-treatment changes were observed in CTC-ER and ctDNA, but not in overall CTC number. Integrating multiple biomarkers in prospective trials may improve outcome prediction and ET resistance mechanisms' identification over a single biomarker.

The Emerging Role of ESR1 Mutations in Luminal Breast Cancer as a Prognostic and Predictive Biomarker of Response to Endocrine Therapy

“…The primary endpoint was to find the maximum tolerated dose, and to assess safety and drug activity in patients with and without ESR1 mutations. Early modifications in circulating tumor cells (CTCs) and ctDNA of patients recruited to that trial have recently been reported, assessing the significance that these changes may have in relation to the pharmacodynamics and efficacy of AZD9496 [68]. Patients who had ≥5 CTCs per 7.5 mL of whole blood at baseline had worse PFS than those with <5 CTCs per 7.5 mL (p = 0.0003).…”

Coupling multiplex pre-amplification and droplet digital PCR for longitudinal monitoring ofESR1andPIK3CAmutations from plasma cell-free DNA

“…The motivation to design and validate such a panel was to develop a sensitive, reproducible and costeffective way to longitudinally track clinically relevant ESR1 and PIK3CA mutations in MBC using a user-friendly and de-centralized workflow. The potential of tracking PI3K and ESR1 mutation dynamics in plasma as biomarkers to predict clinical response to endocrine therapy has been the focus of many clinical studies, such as BOLERO-2 phase 3 study 7,39 , Paloma-3 Phase III Study 4 , and the AZD9496 Phase I study 5 , and development of custom panels like the one described here is critical to obtain reliable cfDNA mutation assessment while using as little material as possible.…”

“…Despite the initial effectiveness of anti-endocrine therapies, a vast majority of patients develop resistance. Although several mechanisms of resistance have been elucidated, it was only recently noted that recurrent mutations in ESR1 are enriched in ~20-40% of patients with MBC treated with an AI [3][4][5][6][7][8][9][10] . The fact that frequencies of ESR1 mutations are extremely low in primary breast tumors and enriched in metastatic tumors, supports the potential functional role of these mutations in acquired resistance to anti-endocrine therapies.…”

“…In contrast, patients whose best response was stable disease or progressed disease displayed changes that were more variable 12 . In a recent phase I trial of AZD9496 oral selective ER degrader, patients without ESR1 ligand binding domain mutations (ESR1-LBDm) at baseline, or with a decline of mutations larger than 50% at C1D15, had a trend toward longer progression free survival (PFS), as compared to those who had less than 50% reduction of ESR1-LBDm cfDNA at C1D15 5 . Additionally, in the PALOMA-3 phase III study, longitudinal changes in ESR1 and PIK3CA mutations in cfDNA were assessed for correlation with early efficacy of a CDK4/6 inhibitor.…”

Estrogen Receptor Covalent Antagonists: The Best Is Yet to Come

“…In clinical studies, ERa mutations are rarely found in primary tumors; however, they are enriched in tumor biopsies collected from patients who progressed on the SOC endocrine therapies, supporting the idea that ERa mutations are a common mechanism of resistance across endocrine therapies (10,11). Advances in noninvasive alternatives to tumor biopsies, such as droplet digital PCR (ddPCR) analysis of circulating free DNA (10,(12)(13)(14)(15)(16)(17)(18)(19), have increased the detection rate of recurrent ESR1 mutations. Multiple studies using this approach have reported ESR1 mutations in approximately 25% to 40% of patients with ERa-positive metastatic breast cancer (MBC) previously treated with AI therapies (Table 1).…”