The Resistance and Immune Response to Palbociclib in Breast Cancer

Prospective Longitudinal Biomarker Study of Acquired Resistance and Immune Response to Palbociclib in Breast Cancer

The investigators propose to conduct a biomarker and molecular profiling study in longitudinally paired tumor biopsies and serum from patients with Hormone Receptor positive (HR+) metastatic Breast Cancer (BC) treated with Palbociclib in combination with endocrine therapies.

Study Overview

• Status: Unknown
• Conditions: Breast Cancer Stage IV
• Intervention / Treatment: Genetic: tissue biopsy, blood sample

Detailed Description

The investigators propose to conduct a biomarker and molecular profiling study in longitudinally paired tumor biopsies and serum from patients with Hormone Receptor positive (HR+) metastatic Breast Cancer (BC) treated with Palbociclib(Palbo) in combination with endocrine therapies.

The investigators plan to obtain tumor biopsy and blood samples, taken at both pre-treatment and post-progression, from 40 patients who develop acquired resistance to Palbo + endocrine combination treatment. All assays will be conducted in parallel on both pre and post-treatment samples to identify differences that may account for acquired resistance. Cyclin E1 and E2 levels will be assessed by IHC on tumor biopsies. Neuregulin-1 levels will be assessed by ELISA assay on serum. Tumor biopsies will be further profiled using whole-exome sequencing (WES) and whole-transcriptome sequencing (RNA-Seq). Matched blood samples will be subject to WES to facilitate somatic mutation detection. Paired tumor biopsies will undergo immunohistochemistry (IHC) analysis of TIL markers to assess Palbo-induced changes. Finally, we will apply the in-house circulating tumor DNA (ctDNA) assay, which employs a custom-designed panel for studying Palbo acquired resistance, towards the analysis of 40 pairs of plasma samples. The custom ctDNA panel will be extended to include additional mutations identified from this study that confer acquired resistance.

To further evaluate the effects of Palbo treatment on intratumoral TILs, the investigators plan to acquire paired tumor biopsy and matched blood samples, at baseline and two time points (6 weeks, 12 weeks) during the course of Palbo treatment, from 20 patients. And they will select metastatic BC patients who exhibit stable diseases (SD) in response to Palbo for tumor biopsies, prior to knowledge of whether post-progression biopsy would be available. Tumor biopsies will be subject to WES, RNA-Seq and IHC analyses. Further, the investigators plan to quantify the abundance of immune cell sub-populations in the matched blood samples using flow cytometry (FACS) to assess Palbo treatment effects on systematic immunity.

While on-treatment samples can be collected after 6 weeks and 12 weeks of initiating Palbo treatment, it takes about 18 months on average for initially treated patients with late stage HR+ breast cancers to develop acquired resistance. Only an estimated 40% of relapsed cases will have successful biopsies due to a lack of consent or difficult-to-operate biopsies such as bone-only metastases. Hence, the investigators plan to bank pre-treatment biopsies and blood samples from about 100 patients by Q2 2018 in order to collect 40 post-progression biopsies as matched pairs within the 2-year time frame. FFPE slides will be made from all tumor biopsies, including the 100 cases at baseline, and subject to H&E staining. The investigators will detect and quantify TILs through machine learning and digital imaging analysis of the H&E data.

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 06351
    • Recruiting
    • Samsung Medical Center
    • Contact: Yeon Hee Park, MD, Ph.D

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: ADULT; OLDER_ADULT; CHILD
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Hormone receptor positive, metastatic breast cancer
• Treated by palbociclib with endocrine therapy

Exclusion Criteria:

• Hormone receptor negative breast cancer
• Treated without palbociclib
• Refuse and withdrawal to this study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Interventional Model: SEQUENTIAL
• Masking: NONE

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarker of palbociclib in metastatic breast cancer	Biomarker of acquired resistance and immune response to palbociclib in metastatic breast cancer from whole exome sequencing, RNASeq, circulating tumor DNA and flow cytometry.	24.8 months (median progression free survival in palbociclib plus letrozole treatment (according to PALOMA-2 trial)

Collaborators and Investigators

• Sponsor: Samsung Medical Center

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 24, 2017
• Primary Completion (ANTICIPATED): October 31, 2020
• Study Completion (ANTICIPATED): October 31, 2022

Study Registration Dates

• First Submitted: December 11, 2017
• First Submitted That Met QC Criteria: January 15, 2018
• First Posted (ACTUAL): January 17, 2018

Study Record Updates

• Last Update Posted (ACTUAL): January 17, 2018
• Last Update Submitted That Met QC Criteria: January 15, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms
• Other Study ID Numbers: 2017-07-049

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No