Determinants of Acquired Endocrine Resistance in Metastatic Breast Cancer: A Pilot Study (ENDO-RESIST)

This is a single-center prospective study involving analysis of circulating tumor DNA (ctDNA) and the gut microbiome in patients with metastatic breast cancer on standard of care endocrine therapy with an aromatase inhibitor in combination with an inhibitor of the cyclin-dependent kinases 4 and 6 (CDK 4/6). Up to 20 patients with Estrogen Receptor positive (ER+), Human Epidermal Growth Factor Receptor 2 negative (HER2-) metastatic breast cancer and Eastern Cooperative Oncology Group (ECOG) performance status 0-1 will be enrolled. This study involves the collection and analysis of patient samples and does not involve therapeutic intervention.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Breast Cancer

Detailed Description

Endocrine therapies have been associated with an overall survival benefit in breast cancer and are the preferred initial treatment approach in patients with ER+, HER2- metastatic breast cancer. Unfortunately, resistance to endocrine therapies eventually develops in the metastatic setting and metastatic breast cancer remains an incurable disease. Endocrine resistance may develop as a result of alterations in estrogen signaling and metabolism pathways, which may be modulated by gut bacteria. In addition, genomic profiling of archival tissues and circulating tumor DNA (ctDNA) in ER+ breast cancer has identified multiple somatic molecular alterations that may mediate response to endocrine therapies.

This study is designed to identify markers of endocrine resistance in ctDNA and the gut microbiome in patients with ER+ HER2- metastatic breast cancer.

• Study Type: Observational
• Enrollment (Anticipated): 20

Contacts and Locations

• Study Contact: Name: Rossanna C. Pezo, MD/PhD; Phone Number: 416-480-4757; Email: rossanna.pezo@sunnybrook.ca

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Recruiting
      • Sunnybrook Health Sciences Centre
      • Contact: Rossanna C. Pezo, MD/PhD; Phone Number: 416-480-4757; Email: rossanna.pezo@sunnybrook.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients with ER positive and HER2 negative metastatic breast cancer planned to initiate on standard of care treatment with an aromatase inhibitor and a CDK 4/6 inhibitor

Description

Inclusion Criteria:

• Sign written and voluntary informed consent
• Histological confirmation of advanced ER positive and HER2 negative breast cancer.
• Adult patients at least 18 years of age
• ECOG performance status equal to 0 or 1
• Able to provide written informed consent
• Must be willing to provide blood for ctDNA analysis on study enrollment and at specified study time points
• Must be willing and able to perform stool sample collection
• Patients must be suitable, as per their treating physician, for initiation of first line endocrine therapy with an aromatase inhibitor and a CDK 4/6 inhibitor for metastatic disease

Exclusion Criteria:

• Prior treatment with CDK 4/6 inhibitors in the neoadjuvant or adjuvant setting
• Use of targeted therapies other than endocrine therapies alone in the neoadjuvant or adjuvant setting
• Relapse on prior endocrine therapy or within 6 months of discontinuation of prior adjuvant endocrine therapy
• History of inflammatory bowel disease, chronic diarrhea or malabsorption syndromes and significant prior bowel resection as judged by the study investigator
• Use of immunosuppressants including steroids within the previous 4 weeks of planned Cycle 1 Day 1 treatment

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to treatment failure	Time from first treatment on study (standard of care aromatase inhibitor and a CDK 4/6 inhibitor) until the date of treatment discontinuation	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation between specific mutations in ctDNA and in archival tissue samples (where available from prior testing) with time to treatment failure	Identification of mutations in archival tissue samples (where available from prior testing) and sequencing of ctDNA using next generation sequencing panel	12 months
Diversity and composition of the gut microbiome in patients with ER+ HER2- metastatic breast cancer	Analysis of the gut microbiome via 16S rRNA sequencing and metagenomic sequencing of fecal samples at baseline and at development of progressive disease	12 months
Dietary factors and composition of the gut microbiome	Assessment of food intake via dietary questionnaire and correlation with diversity and composition of the gut microbiome	14 days
Overall survival	Time from start of treatment until death	2 years

Collaborators and Investigators

• Sponsor: Sunnybrook Health Sciences Centre
• Investigators: Principal Investigator: Rossanna C. Pezo, MD/PhD, Sunnybrook Health Sciences Centre

Study record dates

Study Major Dates

• Study Start (Actual): February 4, 2019
• Primary Completion (Anticipated): December 31, 2022
• Study Completion (Anticipated): December 31, 2022

Study Registration Dates

• First Submitted: October 1, 2020
• First Submitted That Met QC Criteria: October 1, 2020
• First Posted (Actual): October 8, 2020

Study Record Updates

• Last Update Posted (Actual): May 5, 2022
• Last Update Submitted That Met QC Criteria: May 4, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: gut microbiome; endocrine resistance; CDK4/6 inhibitors
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms
• Other Study ID Numbers: ENDO-RESIST

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No