# Evolution and clinical impact of clonal hematopoiesis of indeterminate potential in breast tumor microenvironment

> **NIH NIH R01** · RBHS -CANCER INSTITUTE OF NEW JERSEY · 2021 · $642,910

## Abstract

PROJECT SUMMARY/ABSTRACT
 Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related expansion of hematopoietic stem
cells that harbor somatic alterations without presenting other hematologic abnormalities. CHIP has been
detected in normal peripheral blood of cancer patients with solid tumors and has been suggested to have a
permissive role in therapy-related secondary myeloid disease development. Our recent analysis of clinical
sequencing of 113,079 solid tumor specimens demonstrated that CHIP clones are also present in the solid
tumor microenvironment due to admixed mutated hematopoietic elements; however, enrichment of admixed
CHIP, its evolution under therapy, and its clinical impact on solid tumor treatment are poorly understood.
 In this proposal, we will characterize CHIP in the context of breast invasive carcinoma, which is treated with
chemotherapeutics in both adjuvant and neoadjuvant settings and has been shown to have prognostic
interactions with infiltrating hematopoietic cells in its microenvironment. We hypothesize that CHIP exhibits a
distinct genomic landscape when enriched in breast tumor microenvironment, evolves under breast tumor
treatment, and is correlated with the development of therapy-induced hematological toxicity. To test these
hypotheses, we will assemble a cohort of 1,200 newly diagnosed breast cancer patients, collect
comprehensive clinical data as well as sequential pre- and post-treatment peripheral blood and breast tumor
samples, and profile CHIP at high resolution in three aims. First, we will determine the mutational spectrum of
admixed CHIP before breast tumor treatment. Using high-depth sequencing of peripheral blood and breast
tumor samples, we will detect CHIP mutations at >0.1% allele frequency and correlate the prevalence of
admixed CHIP with the level of infiltrating lymphocytes and other hematopoietic markers. Using single-cell
genomic analysis, we will resolve the number of exclusive CHIP clones. Second, we will profile CHIP after
chemotherapy in peripheral blood – and breast tumor samples in neoadjuvant settings – to study its evolution
by assessing mutation-specific fitness and therapeutic bottleneck size, using hormonal therapy as control. We
will also investigate the effect of granulocyte-colony stimulation on CHIP's clonal dynamics. Longitudinal
peripheral blood sampling will elucidate the long-term evolution of CHIP 1-2 years after the end of breast
tumor's treatment. Third, we will develop a statistical regression model to determine the distinct CHIP clones
that may be correlated with clinical response and development of therapy-induced hematological toxicity.
 This study is novel in its utilization of systematically collected clinical and high-resolution molecular data,
and it will provide insight on CHIP's clonal evolution under breast tumor treatment. Moreover, it will illustrate
the significance of molecularly defined clonal analysis of hematopoietic populations as a fundamenta...

## Key facts

- **NIH application ID:** 10144002
- **Project number:** 5R01CA233662-03
- **Recipient organization:** RBHS -CANCER INSTITUTE OF NEW JERSEY
- **Principal Investigator:** Hossein Khiabanian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $642,910
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10144002

## Citation

> US National Institutes of Health, RePORTER application 10144002, Evolution and clinical impact of clonal hematopoiesis of indeterminate potential in breast tumor microenvironment (5R01CA233662-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10144002. Licensed CC0.

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