In the United States, approximately half of all breast cancer patients are diagnosed with estrogen receptor- positive (ER+) lymph node negative (LN-) primary tumors. Two adjuvant systemic treatment options exist for such patients and include hormonal therapy alone or hormonal therapy and chemotherapy. Choosing the appropriate adjuvant regimen for ER+LN- breast cancer patients remains a significant challenge. We have developed a novel real-time PCR assay, HOXB13:IL17BR-MGI, which is a robust, independent prognostic and predictive biomarker of both tamoxifen and aromatase inhibitor hormonal therapy. This biomarker identifies a subgroup of early stage ER+ breast cancer patients with very poor outcome despite endocrine therapy. The long-term goals of this project are: 1) to assess the chemotherapy treatment-predictive utility of the HOXB13:IL17BR-MGI biomarker in ER-positive lymph node negative breast cancer patients;2) to compare the prognostic performance of the HOXB13:IL17BR-MGI biomarker to OncotypeDx;and 3) to assess the prognostic and predictive performance of the HOXB13:IL17BR-MGI biomarker in ER-positive breast cancer patients treated with adjuvant aromatase inhibitor therapy. Specifically, in Aim 1, we will assess the ability of the HOXB13:IL17BR-MGI biomarker to predict chemotherapy benefit in tumor samples from the International Breast Cancer Study Group Trial IX breast cancer cohort.
In Aim 2, we will compare the prognostic performance of the HOXB13:IL17BR-MGI biomarker with that of the Oncotype DX assay in a cohort of 800 patients who have undergone Oncotype DX testing, and we will assess whether the HOXB13:IL17BR-MGI biomarker provides additional prognostic information to the OncoDX-RS assay. Finally, in Aim 3, we propose to assess prognostic and predictive biomarker performance in samples from the NCIC CTG- and NCI-sponsored MA.17 adjuvant aromatase inhibitor therapy trial. Accomplishment of these goals will improve the identification of ER+LN- breast cancer patients who will benefit from hormonal therapy alone and those who will benefit from the addition of adjuvant chemotherapy, and may provide for novel therapeutic strategies for women with tamoxifen-resistant disease.
The purpose of the work outlined in this proposal is to investigate whether the HOXB13:IL17BR-MGI gene expression signature is predictive of chemotherapy benefit and to compare its prognostic performance with the assay Oncotype DX in early-stage breast cancer patients. Furthermore, we will assess the prognostic performance of this gene expression biomarker in the setting of adjuvant aromatase therapy in ER-positive breast cancer patients. The HOXB13:IL17BR-MGI gene expression signature offers distinctive advantages over current biomarkers, and validation of its prognostic and predictive performance could translate to significant changes in current diagnostic and therapeutic approaches for women with breast cancer.
|Olsen, Lars; Campos, Benito; Winther, Ole et al. (2014) Tumor antigens as proteogenomic biomarkers in invasive ductal carcinomas. BMC Med Genomics 7 Suppl 3:S2|
|Price, Jessica C; Pollock, Lana M; Rudd, Meghan L et al. (2014) Sequencing of candidate chromosome instability genes in endometrial cancers reveals somatic mutations in ESCO1, CHTF18, and MRE11A. PLoS One 8:e63313|
|Shen, Keyue; Luk, Samantha; Hicks, Daniel F et al. (2014) Resolving cancer-stroma interfacial signalling and interventions with micropatterned tumour-stromal assays. Nat Commun 5:5662|
|Rudd, Meghan L; Mohamed, Hassan; Price, Jessica C et al. (2014) Mutational analysis of the tyrosine kinome in serous and clear cell endometrial cancer uncovers rare somatic mutations in TNK2 and DDR1. BMC Cancer 14:884|
|Sgroi, Dennis C; Carney, Erin; Zarrella, Elizabeth et al. (2013) Prediction of late disease recurrence and extended adjuvant letrozole benefit by the HOXB13/IL17BR biomarker. J Natl Cancer Inst 105:1036-42|
|Habel, Laurel A; Sakoda, Lori C; Achacoso, Ninah et al. (2013) HOXB13:IL17BR and molecular grade index and risk of breast cancer death among patients with lymph node-negative invasive disease. Breast Cancer Res 15:R24|
|Sgroi, Dennis C; Sestak, Ivana; Cuzick, Jack et al. (2013) Prediction of late distant recurrence in patients with oestrogen-receptor-positive breast cancer: a prospective comparison of the breast-cancer index (BCI) assay, 21-gene recurrence score, and IHC4 in the TransATAC study population. Lancet Oncol 14:1067-76|
|Le Gallo, Matthieu; O'Hara, Andrea J; Rudd, Meghan L et al. (2012) Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes. Nat Genet 44:1310-5|
|Imielinski, Marcin; Cha, Sangwon; Rejtar, Tomas et al. (2012) Integrated proteomic, transcriptomic, and biological network analysis of breast carcinoma reveals molecular features of tumorigenesis and clinical relapse. Mol Cell Proteomics 11:M111.014910|
|Bell, Daphne W; Sikdar, Nilabja; Lee, Kyoo-Young et al. (2011) Predisposition to cancer caused by genetic and functional defects of mammalian Atad5. PLoS Genet 7:e1002245|
Showing the most recent 10 out of 30 publications