Liquid biopsy detects ESR1 mutations that cause AI failure

Here's related research on ESR1 mutations detected by Liquid Biopsy in those taking AI's for HR+ advanced BC, as reported at the 38th San Antonio Breast Cancer Symposium (SABCS) today.

This is relevant to determine which MBC patients might respond better to "mTOR targeted therapy".

Liquid biopsy can detect Estrogen Receptor Mutations - May guide therapy soon

December 2015: SAN ANTONIO -- A "liquid biopsy" using blood plasma was able to detect estrogen receptor 1 (ESR1) mutations that affected the outcome of treatment in a large randomized drug trial, a researcher said.
An analysis of blood samples from metastatic breast cancer patients found that nearly 30% carried mutations that increased the risk of relapse and shortened their lives, according to Sarat Chandarlapaty, MD, PhD, of Memorial Sloan Kettering Cancer Center.

But the two mutations responded differently to treatment with the mTOR inhibitor everolimus (Afinitor).
"This is a really nice study that shows the prevalence of ERS1 mutations and that you can detect them with a blood test," commented Lisa Carey, MD, of the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, who was not part of the study.
Such a simple technique would be "very important for understanding tumor evolution, biology and resistance going forward."
And in the near future, such tests might be useful to guide therapy, Carey said: "I think this is coming within the next year or two."
Estrogen and the estrogen receptor 1 (ESR1) are an important part of normal breast biology, Chandarlapaty said, so it's not surprising that the hormone and its receptor play key roles in up to 89% of all breast cancers.
One unintended effect of blocking estrogen as a cancer treatment -- for instance, with AI's -- is to spur development of estrogen receptors that don't need estrogen to be active and promote tissue growth.
The two most common mutations that permit estrogen-independence are dubbed D538G and Y537S, he noted, and he and colleagues asked how common they were and what effects they had, especially in the face of treatment.
To find out, they turned to the BOLERO-2 clinical trial, which enrolled 724 women with ER+ breast cancer that had metastasized on treatment with a nonsteroidal aromatase inhibitor (NSAI).
The trial treated participants with the AI, exemestane (Aromasin) plus or minus everolimus (Afinitor) and found a significant benefit for the mTOR inhibitor -- about a doubling of median progression-free survival -- that led to approval for this indication.
Using blood samples taken when the women entered the study, Chandarlapaty and colleagues showed that 28.8% had at least one of the mutations, 15.3% had D538G, 7.8% had Y537S, and 5.5% had both.
Interestingly, a subset of patients had paired samples -- blood taken at the start of BOLERO-2 and tissue from the original tumor. In the tissue samples, the mutants were rare -- occurring in 1.3% -- while they were found in 28.4% of the blood samples.
Chandarlapaty said the discrepancy might have several explanations:
- The blood samples were taken after metastasis, and mutations are more frequent in metastatic lesions.
- The tissue samples were taken before any treatment, which might have selected for mutant receptors.
- And the blood samples can be thought of as the "summation" of many different metastatic lesions.

The researchers found that in the study as a whole, the presence of the mutations had an important effect on overall survival, which was 32.1 months for patients with neither variant. But it was 26 months with D537G, 20 months with Y537S, and 15.2 months with both.
The overall effect of adding everolimus was to double progression free-survival, from 3.9 months to 8.5 months for patients with neither variant, Chandarlapaty said. And a similar boost -- although at a lower level -- occurred for patients with D538G or both mutations: 2.7 months to 5.8 months and 2.78 months to 5.42 months, respectively.
Surprisingly, however, having the Y537S mutation meant the drug offered no benefit at all -- progression-free survival was 4.1 months with everolimus and 4.2 months without. The result was unexpected and needs further validation, Chandarlapaty said.

More can be read in this article called: Blood-Based Test Identifies which MBC Patients May Respond to mTOR Targeted Therapy

More "ESR1" news released recently.

According to this recent Abstract in JAMA Oncology, mutations in the estrogen receptor (ESR1) are associated with worse outcomes.
The specific ESR1 mutations are: Y537S and D538G.

Here's the Abstract: Prevalence of ESR1 Mutations in Cell-Free DNA and Outcomes in Metastatic Breast CancerA Secondary Analysis of the BOLERO-2 Clinical Trial

ABSTRACT
Importance: Estrogen receptor α (ESR1) mutations found in metastatic breast cancer (MBC) promote ligand-independent receptor activation and resistance to estrogen-deprivation therapy in laboratory models. The prevalence of these mutations and their potential impact on clinical outcomes has not been established.

Objective: To determine the prevalence of ESR1 mutations (Y537S and D538G) in estrogen receptor (ER)-positive MBC and determine whether mutation is associated with inferior outcomes.

Design, Setting, and Participants: From December 16, 2014, to August 26, 2015, we analyzed cell-free DNA (cfDNA) from baseline plasma samples from participants in the BOLERO-2 double-blind phase 3 study that randomized patients from 189 centers in 24 countries with MBC to exemestane plus placebo or exemestane plus everolimus. The study enrolled postmenopausal women with a diagnosis of MBC and prior exposure to an aromatase inhibitor. Baseline plasma samples were available from 541 of 724 patients (74.7%). We assessed the effect of mutation on overall survival of the population and the effect of mutation on progression-free survival (PFS) by treatment arm.

Interventions: Patients were randomized to treatment with exemestane (25 mg oral daily) together with everolimus (10 mg oral daily) or with placebo.

Main Outcomes and Measures: The 2 most frequent mutations in ESR1 (Y537S and D538G) were analyzed from cfDNA using droplet digital polymerase chain reaction and samples scored as wild-type, D538G, Y537S, or double mutant. Cox-proportional hazards model was used to assess PFS in patient subgroups defined by mutations, and the effect of each mutation on overall survival.

Results: Of 541 evaluable patients, 156 (28.8%) had ESR1 mutation D538G (21.1%) and/or Y537S (13.3%), and 30 had both. These mutations were associated with shorter overall survival (wild-type, 32.1 months [95% CI, 28.09-36.40 months]; D538G, 25.99 months [95% CI, 19.19-32.36 months]; Y537S, 19.98 months [13.01-29.31 months]; both mutations, 15.15 months [95% CI, 10.87-27.43 months]). The D538G group (hazard ratio, 0.34 [95% CI, 0.02-0.57]) derived a similar PFS benefit as wild type from addition of everolimus to exemestane.

Conclusions and Relevance: ESR1 mutations are prevalent in ER+ aromatase inhibitor-treated MBC.
Both Y537S and D538G mutations are associated with more aggressive disease biology.

Study Finds ESR1 Mutations Drive Metastasis in ER+ Breast Cancer
http://www.cancernetwork.com/videos-breast-cancer/study-finds-esr1-mutations-drive-metastasis-er-positive-breast-cancer

In this short 2 minute video, Suzanne A. W. Fuqua, PhD, of the Baylor College of Medicine, discusses a new study that found that in addition to conferring resistance to hormone therapies, estrogen receptor (ESR1) mutations can cause cancer cells to metastasize.

The researchers generated ESR1 Y537S homozygous mutations using CRISPR technology and found that the mutation drove distant metastasis in estrogen receptor (ER)-positive breast cancer cell xenografts. Using the METABRIC database, the researchers also found that this gene expression signature predicted poor disease-free survival and distant lung metastasis in ER-positive patients.

Fuqua presented results of the study at last months 2016 San Antonio Breast Cancer Symposium (SABCS).