Tracking evolution of aromatase inhibitor resistance with circulating tumour DNA analysis in metastatic breast cancer

Fribbens, Charlotte; García-Murillas, Isaac; Beaney, Matthew; Hrebien, Sarah; O’Leary, Ben; Kilburn, Lucy; Howarth, Karen; Epstein, Michael; Green, E.; Rosenfeld, Nitzan; Ring, Alistair; Johnston, Stephen; Turner, Nicholas C.

doi:10.1093/annonc/mdx483

Cited by 129 publications

(102 citation statements)

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“…It has been shown that ESR1 mutant cells retain their dependence on CDK4/6 and cyclin D; thus, CDK4/6 inhibitors seem to be active in ESR1 mutant cells [36]. Since data from patients in the second-line setting (PALOMA-3, Bolero-2, SofEA trials) [20,21,29] provide evidence that fulvestrant is superior to AI in ESR1-mutated patients, it seems that fulvestrant combined with CDK4/6 will be more efficacious in these patients.…”

Section: Discussionmentioning

confidence: 99%

ESR1 mutations are frequent in newly diagnosed metastatic and loco-regional recurrence of endocrine-treated breast cancer and carry worse prognosis

et al. 2020

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Background: Emerging mutations in the ESR1 gene that encodes for the estrogen receptor (ER) are associated with resistance to endocrine therapy. ESR1 mutations rarely exist in primary tumors (~1%) but are relatively common (10-50%) in metastatic, endocrine therapy-resistant cancers and are associated with a shorter progression-free survival. Little is known about the incidence and clinical implication of these mutations in early recurrence events, such as local recurrences or newly diagnosed metastatic disease. Methods:We collected 130 archival tumor samples from 103 breast cancer patients treated with endocrine therapy prior to their local/metastatic recurrence. The cohort consisted of 41 patients having at least 1 sample from local/ loco-regional recurrence and 62 patients with metastatic disease (of whom 41 newly diagnosed and 28 with advanced disease). The 5 most common ESR1 hotspot mutations (D538G, L536R, Y537S/N/C) were analyzed either by targeted sequencing or by droplet digital PCR. Progression-free survival (PFS), disease-free survival (DFS), and distant recurrence-free survival (DRFS) were statistically tested by Kaplan-Meier analysis.Results: The prevalence of ESR1 mutations was 5/41 (12%) in newly diagnosed metastatic patients and 5/28 (18%) for advanced metastases, detected at allele frequency > 1%. All mutations in advanced metastases were detected in patients previously treated with both tamoxifen (TAM) and aromatase inhibitors (AI). However, in newly diagnosed metastatic patients, 4/5 mutations occurred in patients treated with TAM alone. PFS on AI treatment in metastatic patients was significantly shorter for ESR1 mutation carriers (p = 0.017). In the local recurrence cohort, ESR1 mutations were identified in 15/41 (36%) patients but only 4/41 (10%) were detected at allele frequency > 1%. Again, most mutations (3/4) were detected under TAM monotherapy. Notably, 1 patient developed ESR1 mutation while on neoadjuvant endocrine therapy. DFS and DRFS were significantly shorter (p = 0.04 and p = 0.017, respectively) in patients that had ESR1 mutations (> 1%) in their loco-regional recurrence tumor.

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Section: Discussionmentioning

confidence: 99%

ESR1 mutations are frequent in newly diagnosed metastatic and loco-regional recurrence of endocrine-treated breast cancer and carry worse prognosis

et al. 2020

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“…10 Thirty patients exhibited polyclonal Y537S and D538G mutations, and other studies have also confirmed that ESR1 mutations are frequently polyclonal. 9,28,[34][35][36][37] Survival analyses showed that patients with Y537S or D538G mutations exhibited worse overall survival compared with patients who had only WT ER (32.1 vs 20.7 months). Patients with polyclonal Cancer November 1, 2019 ESR1 mutations also exhibited a worse overall survival (15.2 months).…”

Section: Ddpcr Detection Of Esr1 Mutations In Patient Biopsiesmentioning

confidence: 99%

ESR1 mutations in breast cancer

Dustin

Fuqua

2019

Cancer

197

131

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The acquisition of ligand-independent ESR1 mutations during aromatase inhibitor therapy in metastatic estrogen receptor (ER)-positive breast cancer is a common mechanism of hormonal therapy resistance. Preclinical and clinical studies have demonstrated that ESR1 mutations can preexist in primary tumors and can be enriched during metastasis. Furthermore, ESR1 mutations express a unique transcriptional profile that favors tumor progression, suggesting that selected ESR1 mutations may influence metastasis. Several groups have used sensitive detection methods using patient liquid biopsies to track ESR1 or truncal somatic mutations to predict treatment outcome and tumor progression, and some of these techniques may eventually be used to guide sequential treatment options in patients. Further development and standardization of mutation tracking in circulating tumor DNA is ongoing. Clinically, patients with ESR1 mutations derive clinical benefit when treated with fulvestrant and CDK4/6-targeted therapies, but the development of more potent selective ER degraders and/or new targeted biotherapies are needed to overcome the endocrineresistant phenotype of ESR1 mutant-bearing tumors. In this review, we discuss the mechanisms of resistance and dissemination of ESR1 mutations as well as the detection methods for ESR1 mutation tracking, newly discovered potential therapeutic targets, and the clinical implications and treatment options for treating patients with ESR1 mutant-bearing tumors.

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“…Abundant evidence has confirmed that quantification of mutant circulating tumor DNA (ctDNA) is valuable in cancer diagnosis, prognositication, monitoring therapy response, and postoperative recurrence (4)(5)(6). Emerging studies are also reported its application in tracking clonal evolution and elucidating treatment-resistant mechanisms (7,8).…”

Section: Introductionmentioning

confidence: 99%

Monitoring Tumor Burden in Response to FOLFIRINOX Chemotherapy Via Profiling Circulating Cell-Free DNA in Pancreatic Cancer

Tao

Zhang

et al. 2019

Molecular Cancer Therapeutics

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We aimed to explore the application of circulating cell-free DNA (cfDNA) profiling in monitoring tumor burden in patients with pancreatic ductal adenocarcinoma (PDAC). Thirty-eight patients with advanced PDAC receiving first-line FOLFIRINOX chemotherapy were prospectively enrolled. Next-generation sequencing for a panel of 560 genes covering a wide range of cancer-related loci was performed to profile cfDNA. In total, 25 patients (65.8%) had at least one common driver gene alterations (KRAS, TP53, SMAD4, CDKN2A) detected within cfDNA. In contrast, no above tumor-related recurrent mutations were found in plasma from 13 healthy individuals. Concordant alterations in plasma cfDNA and tumor tissue DNA was confirmed in two of three patients with available tissues. Further analysis showed that mutant allele fraction (MAF) for altered loci in cfDNA correlated with tumor stage, metastatic burden, and overall survival. Serial blood samples were collected from 17 patients after chemotherapy. We found that allele fraction for specific altered loci declined in chemotherapy-responding subjects. For cases who were resistant to this therapeutic regimen, increased ctDNA MAF was observed at the time of disease progression. Meanwhile, the dynamics of total cfDNA concentration correlated with tumor burden following chemotherapy. Collectively, we provide evidence that pretreatment ctDNA level correlates with tumor burden in PDAC, and serial cfDNA analysis is a robust tool for monitoring cancer response to chemotherapy.

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Tracking evolution of aromatase inhibitor resistance with circulating tumour DNA analysis in metastatic breast cancer

Abstract: Cancers progressing on the first-line AI show high levels of genetic heterogeneity, with frequent sub-clonal mutations. Sub-clonal KRAS mutations are found at high frequency. The genetic diversity of AI resistant cancers may limit subsequent targeted therapy approaches.

Cited by 129 publications

References 18 publications

ESR1 mutations are frequent in newly diagnosed metastatic and loco-regional recurrence of endocrine-treated breast cancer and carry worse prognosis

ESR1 mutations are frequent in newly diagnosed metastatic and loco-regional recurrence of endocrine-treated breast cancer and carry worse prognosis

ESR1 mutations in breast cancer

Monitoring Tumor Burden in Response to FOLFIRINOX Chemotherapy Via Profiling Circulating Cell-Free DNA in Pancreatic Cancer

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