Kinetics, prognostic and predictive values of ESR1 circulating mutations in metastatic breast cancer patients progressing on aromatase inhibitor

Abstract

PurposeTo assess the prognostic and predictive value of circulating ESR1 mutation and its kinetics before and after progression on aromatase inhibitor (AI) treatment.Patients and methodsESR1 circulating D538G and Y537S/N/C mutations were retrospectively analyzed by digital droplet PCR after first-line AI failure in patients treated consecutively from 2010 to 2012 for hormone receptor-positive metastatic breast cancer. Progression-free survival (PFS) and overall survival (OS) were analyzed according to circulating mutational status and subsequent lines of treatment. The kinetics of ESR1 mutation before (3 and 6 months) and after (3 months) AI progression were determined in the available archive plasmas.ResultsCirculating ESR1 mutations were found at AI progression in 44/144 patients included (30.6%). Median follow-up from AI initiation was 40 months (range 4-94). The median OS was decreased in patients with circulating ESR1 mutation than in patients without mutation (15.5 versus 23.8 months, P=0.0006). The median PFS was also significantly decreased in patients with ESR1 mutation than in patients without mutation (5.9 vs 7 months, P=0.002). After AI failure, there was no difference in outcome for patients receiving chemotherapy (n = 58) versus non-AI endocrine therapy (n=51) in patients with and without ESR1 mutation. ESR1 circulating mutations were detectable in 75% of all cases before AI progression, whereas the kinetics 3 months after progression did not correlate with outcome.ConclusionESR1 circulating mutations are independent risk factors for poor outcome after AI failure, and are frequently detectable before clinical progression. Interventional studies based on ESR1 circulating status are warranted.

ESR1 mutations in breast cancer

“…Fifteen years after this seminal discovery, many laboratories have now confirmed the presence of ESR1 mutations in MBC biopsy samples using deep sequencing, and collectively these studies have identified a hotspot for ESR1 mutations within the LBD region using various DNA sequencing methods. 9,10,12,15,16,[26][27][28] Early studies using next generation sequencing (NGS) as the detection method for ESR1 mutations found that mutations were relatively rare in clinical samples. However, the development of droplet digital PCR (ddPCR) technology has allowed for more sensitive and reliable detection of these mutations.…”

Single-cell Transcriptomics reveals multi-step adaptations to endocrine therapy

“…However, this same model is mostly inconsistent with the decade-long latency observed in luminal BCa. In addition, despite recent studies showed that the majority of the genetic lesions in BCa are accumulated during the early phases of tumour development 5,13 , they failed to identify any major driver associated to metastasis and resistance, with the exception of a minor fraction of cases showing either ESR1 mutations or CYP19A1 amplification [14][15][16][17] . Yet, the transcriptomes of the resistant cells are profoundly heterogeneous and different from those of the primary tumour [18][19][20] , suggesting a contribution of non-genetic mechanisms 21 .…”

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

“…The first question was to understand the input cfDNA quantity and quality and how it affected allele burden quantification. While several previous studies 10,38 used total amount (ng) of cfDNA as a measurement of input; for ddPCR assay, it is important to know how many copies of genomic equivalence (GE) were used as input which then sets the sample driven LOD. For example, if only 50 genomes worth of cfDNA was used as input, then even with the most sensitive assay that would detect a single mutant genome out of 50 genomes, the theoretical LOD would be 1/50 or 2%.…”

“…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.…”