BA5 - Identification and Validation of Circulating Biomarkers for the Early Detection of Breast Cancer in Pre-clinical Specimens

This page provides study documentation for BA05.  For description of the specimen results, see Specimen Results Description (open to public). Data sets of the specimen results are included in the existing WHI datasets located on the WHI Data on this site (sign in and a completed Data Distribution Agreement are required; see details on the Data site).

Investigator Names and Contact Information

Christopher I Li, MD, PhD


Our goal is to reduce suffering and death due to breast cancer by discovering and validating plasma biomarkers that can be used to detect breast cancer early, when it is most treatable. Early detection works, as the notable reductions in the mortality rates of breast, cervical, and colorectal cancers are largely attributed to the implementation of successful screening strategies. However, despite improvements in technology and the widespread use of mammography, breast cancer still remains the second leading cause of cancer mortality in women in the United States, and the leading cause of cancer mortality in women worldwide. There are several reasons for this including the sensitivity and specificity of mammography, access to screening services, and the variable utility of mammography to detect different types of tumors. Breast cancer is a markedly heterogeneous disease, and it is well established that mammography is better able to detect certain types of breast cancer (such as invasive ductal carcinomas) than it is other types (such as invasive lobular carcinoma). Thus, there is a great public health need for improvements in our abilities to detect breast cancers of all types earlier.
Proteomics appears to be a promising approach for identifying biomarkers that could be used for the early detection of cancer. While initial reports suggested that Surface Enhanced Laser Desorption Ionization-time of flight (SELDI-TOF) mass spectrometry (MS) could be used for this purpose, poor reproducibility, low sensitivity, and an inability to identify clinically useful biomarkers have dampened enthusiasm considerably. However, proteomic technology has continued to advance rapidly. We propose to use three complementary platforms that overcome the limitations of previous approaches to discover and validate breast cancer early detection markers. Critical to any proteomic study is the availability of a large set of well-characterized specimens. The Women’s Health Initiative (WHI) observational study (OS) offers a unique and unprecedented opportunity to conduct breast cancer protein biomarker discovery and validation projects given that: (1) it is a large well-characterized cohort (93,676 women), and (2) high quality preclinical biologic specimens, collected before cancer diagnosis, are available.
We propose a nested case-control study involving 870 breast cancer cases diagnosed within 6-18 months of a blood draw in the OS and 870 pair matched controls. The study will consist of two phases.
Phase 1 will be devoted to discovering biomarkers that could be used for breast cancer early detection. This discovery will involve using three different proteomic platforms including: Matrix-Assisted Laser Desorption Ionization tandem time of flight MS (MALDI TOF-TOF), antibody microarrays, and an intact protein analysis system (IPAS).
Phase 2 will involve validating biomarkers identified in Phase 1. For MALDI data this will be done by using training and test sets. Selected promising markers identified from the antibody microarray and IPAS platforms will also be validated on individual cases and controls. Given our large sample size, we will also seek to identify and validate markers that are specific for various clinically relevant types of breast cancer (based on estrogen receptor (ER) status, progesterone receptor (PR) status, and histology). Given the known differences between different types of breast cancer, we expect that unique sets of proteins will be predictive of different tumor types.
The specific aims of this proposal are:
1.    To use three proteomic platforms to identify protein biomarkers in preclinical plasma that could potentially be used for the early detection of breast cancer overall as well as for specific types of breast cancer: By identifying informative proteins we will also further our understanding of pathways that may be important in breast carcinogenesis.
2.   To validate the utility of the potential biomarkers identified in this study with respect to their specificity and sensitivity as markers of early detection: Validation of protein biomarkers is critical for determining the potential clinical utility of the biomarkers identified.
3.   To evaluate whether or not adding known risk factors for breast cancer to our biomarker prediction models will optimize the performance and potential clinical utility of the biomarkers we identify: Inclusion of epidemiologic risk factors in prediction models may enhance the utility of early detection strategies based on protein biomarkers.



Some of the publications related to this ancillary study are: 1127, 1782, 1813.

For a complete, up-to-date list of WHI papers related to this ancillary study, please use the searchable Bibliography section of this website. To search for papers by study number, access the Simple Search, and enter the study number in the “Related Studies” field.