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.
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
Metastatic disease on imaging (stage 4)
Patients with stage II-III TNBC candidates to receive NACT +/- ICI will be included
Cohort
Prospective
Whole Genome Sequencing
Diagnostic testWhole genome sequencing (WGS) will be performed in tumor tissue from baseline and from residual disease after neoadjuvant chemotherapy (NACT), if present.
RNA-Sequencing
Diagnostic testRNA-Sequencing will be performed in tumor tissue from baseline and from residual disease after NACT (if present).
Microbiome analysis
Diagnostic testMicrobiome 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.
ctDNA analysis
Diagnostic testctDNA analysis will be performed in plasma before and during NACT.
TCR-β repertoire sequencing
Diagnostic testTCR-β repertoire sequencing will be performed in plasma before and during NACT.
PBMCs phenotyping
Diagnostic testPBMCs phenotyping will be performed in plasma before and during NACT.
Pembrolizumab
DrugPembrolizumab will be given in combination with standard NACT.
Chemotherapy
DrugStandard NACT will be given.
Pathologic complete response (pCR) rate at definitive surgery
The rate (given as a percentage) of patients with a pCR at definitive surgery using the definition of ypT0/Tis ypN0 (i.e., no invasive residual in breast or nodes; noninvasive breast residuals allowed) from the American Joint Committee on Cancer (AJCC) staging criteria
Event-free survival (EFS)
EFS is defined as the time from the start of neoadjuvant treatment to any of the following events: progression of disease that precludes surgery, local or distant recurrence, second primary malignancy (breast or other cancers) or death due to any cause
Overall survival (OS)
OS is defined as the time from starting neoadjuvant treatment until death due to any cause
Identification of biomarkers to predict clinical outcomes (pCR at definitive surgery, EFS, OS).
The clinical data (pCR at definitive surgery, EFS, OS) will be integrated with the results from the multiomics platform and multivariate predictive models of response to neoadjuvant chemotherapy (NACT) + immune checkpoint inhibitor (ICI) will be explored. Precisely, the multiomics platform will analyze: 1. RNA-Sequencing of the initial tumor and residual disease (if present) 2. microbiome analysis of the saliva and feces, 3. circulating tumor DNA (ctDNA) analysis (targeted gene panel and shallow WGS), 4. Tissue immune phenotyping, 5. T-cell receptor beta (TCR-β) repertoire sequencing and analysis using ImmunoSeq hsTCRβ kit and immunoSEQ, 6. Breast MRI imaging (before and after NACT), 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.
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