Genetic Analysis in Blood and Tumor Samples From Patients With Advanced or Metastatic Estrogen Receptor Positive and HER2 Negative Breast Cancer Receiving Palbociclib and Endocrine Therapy

Recurrent Breast Carcinoma Clinical Trial

Official title: Prospective Study to Evaluate the Role of Tumor Sequencing in Women Receiving Palbociclib for Advanced Hormone Receptor (HR)-Positive, Breast Cancer (PROMISE)

Status Active, not recruiting

Clinical Trial Summary

This research trial studies genetic profiles in blood and tumor samples from patients with estrogen receptor positive and HER2 negative breast cancer that has spread to other places in the body who are receiving palbociclib and endocrine therapy. Examining the genetic changes associated with the cancer and comparing the genetic material from the cancer tissue with the genetic material found in the blood may help doctors to develop customized treatment for breast cancer.

Clinical Trial Description

PRIMARY OBJECTIVES:

I. To identify novel genomic variants and pathways associated with baseline, as well as the change in serum thymidine kinase (TK1) levels (measured pre-registration, after two cycles, and at disease progression) among women with advanced hormone receptor (HR) positive breast cancer treated with palbociclib and endocrine therapy (ET).

SECONDARY OBJECTIVES:

I. To generate patient derived xenograft (PDX)s and organoids from tumor biopsies obtained at pre-registration, at 2 months, and at disease progression, to test novel endocrine therapy combinations. (PDX Aim) II. To test whether PDX engraftment is associated with progression free survival. (PDX Aim) Sequencing Aims III. to describe changes in the genomic landscape of HR-positive HER2-negative advanced breast cancer by comparing sequencing data (deoxyribonucleic acid [DNA] and ribonucleic acid [RNA]) from preregistration archival breast primary tumors (when available), with tumor biopsies obtained preregistration, after two months on study, and at disease progression on palbociclib and ET.

IV. To evaluate whether genomic variants and pathways (measured using DNA and RNA sequencing at pre-registration and after two months of treatment) are associated with 1) PFS; 2) baseline and changes in serum TK1. (Sequencing Aim) V. To tabulate the number of patients who have targetable mutations found in the preregistration tumor biopsy and to record their subsequent treatment regimen following progression on palbociclib and ET. (Sequencing Aim) VI. To compare and contrast the actionable genomic alterations found in cfDNA or CTC derived DNA that are not found in tumor tissue. (Sequencing Aim) VII. To assess whether genetic alterations known to be associated with endocrine monotherapy resistance are seen in circulating tumor- DNA (ctDNA) and circulating tumor cell (CTC) derived DNA. (Sequencing Aim) VIII.To determine whether use of a 3D micro cancer model, combined with sequencing data from tumor biopsies, ctDNA and PDXs collected at the time of disease progression, can be used to personalize future treatment options for PROMISE participants. (Sequencing Aim) IX. To compare the changes in Ki67 levels (by immunohistochemistry [IHC]) and serum TK1 levels after 2 months of treatment. (Proliferative biomarker aim) X. To assess whether the change in Ki67 and serum TK1 levels after 2 months of treatment with palbociclib and ET is associated with progression free survival (PFS) outcomes. (Proliferative biomarker aim) XI. To assess whether high baseline serum TK1 levels (> 200 Du/L) are associated with PFS outcomes. (Proliferative biomarker aim) XII. To assess whether an increase in TK1 between 2 months and 12 months is associated with PFS. (Proliferative biomarker aim) XIII. To assess the change in EMT marker expression (e.g. Vimentin, SLUG and E-cadherin) and serum TK1 after two months of treatment with palbociclib and ET. (EMT aim) XIV. To determine the association between the expression of EMT markers and Ki67 levels after two months of treatment with palbociclib and ET. (EMT aim) XV. To determine the association between the expression of EMT markers after two months of treatment with palbociclib and ET, and PFS outcomes. (EMT aim) XVI. To assess whether there is a change in the level of tumor infiltrating lymphocytes (TILs) observed in archival tumor, at pre-registration, at 2 months, and at disease progression on palbociclib and ET. (Immune aim) XVII. To assess the change in TILs (including CD8, PD-L1, and FOXP3) after 2 months of treatment with palbociclib and ET. (Immune aim) XVIII. To assess the association between TILs and serum TK1 levels at preregistration, at 2 months, and at disease progression on palbociclib and ET. (Immune aim) XIX. To characterize and evaluate changes in the immune landscape of HR+ HER2 -MBC using serial biopsies obtained pre-registration, at 2 months, and at disease progression (as well as archived primary tumor when available) using digital spatial profiling (DSP) (NanoString GeoMx platform) . (Immune aim) XX. To assess, by use of mass cytometry (CyTOF), whether i) peripheral blood immune markers obtained pretreatment are associated with either TK1 or PFS and ii) whether the changes in peripheral blood immune markers after 2 cycles of treatment are associated with changes in serum TK1 levels. (Immune aim) XXI. To discover putative mechanistic connections underlying bacteria-drug interactions in all patients. (Microbiome aim) XXII. To identify the biomolecular features within the gut (stool) microbiome and its association with the pharmacokinetics and pharmacodynamics of letrozole and palbociclib. (Microbiome aim) XXIII. To discover novel predictive biomarkers of resistance to CDK4/6i and ET and/or to find biomarkers that add additional predictive power to other promising biomarkers such as TK1 by performing the following: (Metabolic, proteomic and lipidomic aim) XXIV. A metabolomics analysis (>5,000 metabolites sampled through untargeted mass spectrometry at Metabolon) of paired serum samples obtained pre-registration and after 2 months on palbociclib and ET.

XXIVa. An Olink-based cytokines panel (Explore panel of 1,536 proteins) of paired serum samples obtained pre-registration and after 2 months on palbociclib and ET.

XXIVb. A lipidomics analysis (platform TBC) of paired serum samples obtained pre-registration and after 2 months on palbociclib and ET.

XXV. To correlate the changes in the metabolites, cytokines and lipids to the preregistration genomic tumor characteristics, serial Ki67 levels and PFS outcomes. (Metabolic, proteomic and lipidomic aim) XXVI. To assess the change in serum TK1 levels after 2 months, and at disease progression, on palbociclib and ET, and its association with the preregistration CD44high/CD24/low/ERlow cancer stem cell-like phenotype, including the following: total and phosphorylated AURKA, breast cancer stemness biomarkers (CD44, CD24, ALDH1) EMT transcription factors (SMAD5, SOX2), cyclin E, cyclin A and phosphorylated Retinoblastoma (Rb). (Other aim) XXVII. To examine shifts in the populations of epithelial like CTCs and stem cell like CTCs during the course of endocrine therapy with palbociclib. (Other aim) XXVIII. To assess CTC expression of ER, HER2, and other markers of endocrine resistance. (Other aim)

OUTLINE:

Patents undergo collection of blood and stool samples at baseline, 7 days after letrozole monotherapy treatment, and at completion of each cycle, urine samples at baseline and completion of each cycle, and saliva samples at baseline. Patients also undergo collection of blood and urine samples at disease progression. Biopsy samples are analyzed for genetic profile via genome sequencing and ribonucleic acid (RNA) sequencing. Biopsy samples are also used for the generation of xenograft mice model.

After completion of study, patients are followed up every 6 months for 7 years. ;

Related Conditions & MeSH terms

• Advanced Breast Carcinoma
• Breast Neoplasms
• Carcinoma
• Locally Advanced Breast Carcinoma
• Metastatic Breast Carcinoma
• Recurrent Breast Carcinoma
• Stage III Breast Cancer AJCC v7
• Stage IIIA Breast Cancer AJCC v7
• Stage IIIB Breast Cancer AJCC v7
• Stage IIIC Breast Cancer AJCC v7
• Stage IV Breast Cancer AJCC v6 and v7

• NCT number: NCT03281902
• Study type: Observational
• Source: Mayo Clinic
• Status: Active, not recruiting
• Start date: November 13, 2017
• Completion date: December 1, 2024