Predictive Biomarkers of Response to Checkpoint Inhibitors in Triple Negative Breast Cancer: a Multiomics Platform

Official title

Identification of Predictive Biomarkers of Response to Chemotherapy and Immune Checkpoint Inhibitors in Early Triple Negative Breast Cancer: an Integrative Multiomics Platform

Overview

Patients with stage II-III Triple negative breast cancer (TNBC) candidates to receive neoadjuvant chemotherapy (NACT) +/- immune checkpoint inhibitor (ICI) will be included. Several samples from different tissues will be analyzed through different omics to establish predictive biomarkers of response to the treatment. Multiple algorithms will then be used to look for an integrative predictive algorithm that incorporates multi-parameter inputs in order to develop a clinical tool to assist clinicians in the process of treatment decision-making in TNBC.

Detailed description

The combination of pembrolizumab, an immune checkpoint inhibitor (ICI), with neoadjuvant chemotherapy (NACT) increases pathologic complete response (pCR) and event-free survival (EFS) in patients with early triple negative breast cancer (eTNBC). However, not all patients equally benefit from a treatment that may have relevant adverse events (AEs).

Objectives: (1) To establish predictive biomarkers of response to NACT + ICI in eTNBC by correlating data coming from different layers of omics performed in different tissues, together with imaging, with pCR, EFS, and overall survival (OS). (2) To integrate data generated from (1), and clinical data, and explore multivariate predictive models of response to NACT + ICI.

Methods: Patients with stage II-III TNBC candidates to receive NACT +/- ICI will be included. Collected samples and type of analysis: (1) Tumor tissue (baseline and from residual disease after NACT): whole genome sequencing (WGS) and RNA-Seq will be performed (Hartwig sequencing platform and analytical pipeline), tissue immune phenotyping (PD-L1, T and B infiltrating lymphocytes, among others), and microbiome analysis (16S rRNA); (2) Blood (before and during NACT): circulating tumor DNA (ctDNA) analysis (targeted gene panel and shallow WGS), T-cell receptor beta (TCR-β) repertoire sequencing and analysis (ImmunoSeq hsTCRβ kit and immunoSEQ), and peripheral blood mononuclear cells (PBMCs) phenotyping; (3) Stools and saliva (before and during NACT): microbiome analysis (16S rRNA); (4) Breast MRI imaging (before and after NACT): radiomics analysis. Multiple algorithms including Multiple Kernel Learning, Multi-Omics Factor Analysis (MOFA) and Method for the Functional Integration of Spatial and Temporal Omics data (MEFISTO) will then be used to look for an integrative predictive algorithm that incorporates multi-parameter inputs. The aim is to provide more personalized treatment efficacy and risk for relapse estimates.

Expected outcome: To develop a clinical tool to assist clinicians in the process of treatment decision-making in eTNBC, in order to maximize patient's benefit and quality of life, while minimizing AEs and financial burden to the health system.

Interventions

• Diagnostic test Whole Genome Sequencing
  Whole genome sequencing (WGS) will be performed in tumor tissue from baseline and from residual disease after neoadjuvant chemotherapy (NACT), if present.
• Diagnostic test RNA-Sequencing
  RNA-Sequencing will be performed in tumor tissue from baseline and from residual disease after NACT (if present).
• Diagnostic test Microbiome analysis
  Microbiome analysis will be performed in stools and saliva before, during NACT and at the end of adjuvant systemic therapy if adjuvant systemic therapy is clinically indicated.
• Diagnostic test ctDNA analysis
  ctDNA analysis will be performed in plasma before and during NACT.
• Diagnostic test TCR-β repertoire sequencing
  TCR-β repertoire sequencing will be performed in plasma before and during NACT.
• Diagnostic test PBMCs phenotyping
  PBMCs phenotyping will be performed in plasma before and during NACT.
• Drug Pembrolizumab
  Pembrolizumab will be given in combination with standard NACT.
• Drug Chemotherapy
  Standard NACT will be given.

Primary outcome measures

• Pathologic complete response (pCR) rate at definitive surgery [Time frame: after neoadjuvant treatment and surgery, up to approximately 27-30 weeks]
• Event-free survival (EFS) [Time frame: Up to approximately 60 months]
• Overall survival (OS) [Time frame: Up to approximately 60 months]
• Identification of biomarkers to predict clinical outcomes (pCR at definitive surgery, EFS, OS). [Time frame: After all data are analyzed, up to approximately 60 months]

Eligibility criteria

Inclusion criteria

• Histologically documented TNBC (negative human epidermal growth factor receptor 2 \[HER2\], estrogen receptor \[ER\], and progesterone receptor \[PgR\] status)
• Stage 2 - 3 defined by the American Joint Committee of Cancer (AJCC) staging criteria 8th edition for breast cancer as assessed by the investigator based on radiological and/or clinical assessment
• Patient is a candidate to receive NACT with or without ICI as assessed by the investigator
• Patient is ≥ 18 years old at the time of consent to participate in this trial

Exclusion criteria

• Metastatic disease on imaging (stage 4)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Spain · 1 center

• Vall d'Hebron Institute of Oncology — Barcelona

Identifiers

NCT: NCT05916755 · PR(AG)165-2021

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗