Project 3: Identification of Prognostic Factors for Triple Negative Breast Cancer
- Xia Ou Shu, MD, PhD Project Leader
Triple-negative breast cancers (TNBCs), characterized by tumors that do not express the estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2) genes, account for 11-20% of all breast cancers. TNBCs have aggressive clinical behaviors, for which there are currently no effective targeted therapies. Although the majority of TNBCs possess a basal phenotype and show varying degrees of basal marker expression, global gene expression profiling studies suggest that TNBCs can be further classified into distinct molecular classes that may differ in terms of prognosis and thus benefit from targeted therapy.
Since 2002, we have been funded by the Department of Defense Breast Cancer Research Program (DAMD17-02-1-0607) and National Cancer Institute (R01 CA118229) to conduct a longitudinal population-based study, the Shanghai Breast Cancer Survival Study (SBCSS). The primary objective of the SBCSS is to identify genetic and lifestyle predictors of breast cancer outcomes, including recurrence, quality of life, and mortality. A total of 5,042 women who were diagnosed with primary breast cancer and aged 25-75 years were recruited into the study 6 months after cancer diagnosis with an overall participation rate of 81%. Tumor slides were collected from 4,410 patients; 12% were diagnosed with TNBC. Follow-up of the cohort for outcomes has been conducted through a combination of in-person surveys (at 18, 36, and 60 months post-diagnosis) and record linkage with the vital statistics registry. During the same time period, we have been conducting two epidemiological studies in the United States aimed at elucidating risk factors for breast cancer occurrence and outcomes: the Southern Community Cohort Study (SCCS) and the Nashville Breast Health Study (NBHS). The SCCS (R01 CA092447) is a large, prospective cohort study of approximately 86,000 adults, two-thirds of whom are African American, and is projected to accrue over 1,500 breast cancer cases, including over 200 TNBC cases, by the year 2015. The NBHS (R01 CA100374) is a case-control study that has enrolled over 2,700 breast cancer cases and collected tumor tissue specimens for 1,500, 196 of which are TNBC.
Using these three large, established resources, we propose to conduct the first phase of a two-phase study to systematically investigate gene expression profiles and genetic structure alterations (e.g., mutations, insertions, deletions, and splicing variations) in TNBCs and their associations with outcomes (i.e., mortality and recurrence). The specific aims for the first phase of the study, based predominantly within the SBCSS, are:
- To conduct RNA sequencing on stored tumor tissue from 100 TNBC patients recruited in the SBCSS. This will include 50 patients who died within 5 years of cancer diagnosis and 50 surviving, recurrence-free cases matched to the deceased cases on age and disease stage.
- To identify gene expression profiles and individual gene expression levels that are predictive of TNBC outcomes.
- To identify genetic structure alterations in TNBC for future studies of cancer biology, genetics, and outcomes.
- To validate the promising markers derived from Aim 2 in an independent set of 400 TNBC patients from the SBCSS with stored tumor tissue using NanoString Technologies' nCounter Gene Expression Assays.
- To extend collection of paraffin-embedded tumor tissue from TNBC patients in the SCCS, and to extend mortality follow up of TNBC patients within the NBHS, to help prepare for replication of findings in a future phase II study to be proposed for the renewal of the breast SPORE grant.
We expect that this research may greatly enhance our understanding of the molecular heterogeneity of TNBC and the underlying biological pathways that lead to disease progression, with the study among Chinese women setting the stage for a parallel study among US women. The study results could be directly translated into clinical practice and lead to the development of novel therapeutic targets and therapies for these aggressive tumors.