# Discovery and validation of early molecular breast cancer risk markers in benign breast disease

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $522,498

## Abstract

PROJECT SUMMARY
1.6 million women undergo breast biopsy for benign breast disease (BBD) annually in the United States. 90%
of these show no evidence of cellular atypia, and are at only modestly increased risk for breast cancer, but this
group represents the great majority who develop cancer among women with BBD, since women with
identifiable risk factors, such as atypia or strongly positive family history are a small minority. BBD lesions in
women who later progress to cancer very likely display molecular changes which predate overt cancer by
years. An assay detecting such changes will provide a critical improvement in our ability accurately identify
high risk women for preventive interventions (particularly if it distinguishes risk of estrogen receptor (ER)
positive vs. negative breast cancer), and allow better targeting advanced surveillance strategies to women who
will benefit the most. Aberrant promoter methylation has been documented very early in cancer progression.
We have successfully adapted genome-wide array-based tools interrogating the methylome to formalin-fixed
tissue samples, creating an opportunity to study archival samples with known long-term outcomes.
For the past 15 years, we have built an integrated clinical-pathological relational database of all electronic data
of over 75,000 breast patients at this institution since 1985. We identified women with non-atypical BBD who
subsequently developed breast cancer (cases), and matched them to women with BBD who remained cancer-
free (controls) with documented follow-up of a minimum of 10 years. In a pilot study, we demonstrated that
molecular signatures in archival BBD tissue matched signatures present in subsequent invasive breast cancer
(IBC); furthermore, these signatures were distinct from those in control BBD patients with no evidence of
subsequent IBC, and differed in ER+ vs ER- cases.
We now propose to combine our scientific and clinical resources to enable the discovery and validation of risk
markers derived from BBD. We have identified over 500 cases with BBD predating IBC and paired IBC
samples with known ER status with available archival tissue blocks. We will perform a case-control study of the
methylomes of archival non-atypical non-familial BBD from 185 cases as well as their subsequent IBC, and 75
control samples, matched by follow-up, age and presence of hyperplasia. We will also capture known risk
factors for IBC, mammographic density and body mass index, assess involution of terminal duct lobular units
(TDLU), and characterize the status of key hormone receptors by semiquantitative immunohistochemistry.
Our hypothesis is that molecular changes are present in BBD prior to the development of IBC, and are distinct
in women who subsequently develop ER + versus ER- IBC. Our overarching goal is the identification of
molecular changes in breast tissue that will allow the accurate risk stratification of all women undergoing breast
biopsy showing no atypia. In the future, su...

## Key facts

- **NIH application ID:** 9991785
- **Project number:** 5R01CA222779-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** CHRISTOPHER B UMBRICHT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $522,498
- **Award type:** 5
- **Project period:** 2018-09-17 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991785

## Citation

> US National Institutes of Health, RePORTER application 9991785, Discovery and validation of early molecular breast cancer risk markers in benign breast disease (5R01CA222779-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9991785. Licensed CC0.

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