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Title: Risk estimation of distant metastasis in node-negative, estrogen receptor-positive breast cancer patients using an RT-PCR based prognostic expression signature

Abstract

Background: Given the large number of genes purported to be prognostic for breast cancer, it would be optimal if the genes identified are not confounded by the continuously changing systemic therapies. The aim of this study was to discover and validate a breast cancer prognostic expression signature for distant metastasis in untreated, early stage, lymph node-negative (N-) estrogen receptor-positive (ER+) patients with extensive follow-up times. Methods: 197 genes previously associated with metastasis and ER status were profiled from 142 untreated breast cancer subjects. A "metastasis score" (MS) representing fourteen differentially expressed genes was developed and evaluated for its association with distant-metastasis-free survival (DMFS). Categorical risk classification was established from the continuous MS and further evaluated on an independent set of 279 untreated subjects. A third set of 45 subjects was tested to determine the prognostic performance of the MS in tamoxifen-treated women. Results: A 14-gene signature was found to be significantly associated (p < 0.05) with distant metastasis in a training set and subsequently in an independent validation set. In the validation set, the hazard ratios (HR) of the high risk compared to low risk groups were 4.02 (95% CI 1.91–8.44) for the endpoint of DMFS and 1.97 (95% CImore » 1.28 to 3.04) for overall survival after adjustment for age, tumor size and grade. The low and high MS risk groups had 10-year estimates (95% CI) of 96% (90–99%) and 72% (64–78%) respectively, for DMFS and 91% (84–95%) and 68% (61–75%), respectively for overall survival. Performance characteristics of the signature in the two sets were similar. Ki-67 labeling index (LI) was predictive for recurrent disease in the training set, but lost significance after adjustment for the expression signature. In a study of tamoxifen-treated patients, the HR for DMFS in high compared to low risk groups was 3.61 (95% CI 0.86–15.14). Conclusion: The 14-gene signature is significantly associated with risk of distant metastasis. The signature has a predominance of proliferation genes which have prognostic significance above that of Ki-67 LI and may aid in prioritizing future mechanistic studies and therapeutic interventions.« less

Authors:
 [1];  [2];  [2];  [3];  [2];  [4];  [5];  [2];  [6];  [2];  [3];  [7];  [2];  [8];  [8];  [9];  [10];  [11];  [12];  [13] more »;  [2];  [2];  [9];  [14] « less
+ Show Author Affiliations
  1. King's College, London (United Kingdom). Breakthrough Breast Cancer Research Unit; Guy's Hospital, London (United Kingdom)
  2. Celera, LLC, Alameda, CA (United States)
  3. Guy's and St Thomas' Hospital Breast Research Tissue & Data Bank, London (United Kingdom)
  4. Univ. of California, San Francisco, CA (United States). Comprehensive Cancer Center
  5. Rosetta Inpharmatics, A wholly owned subsidiary of Merck & Co. Inc., Seattle, WA (United States)
  6. Guy's Hospital, London (United Kingdom)
  7. St Thomas' Hospital, London (United Kingdom). Cellular Pathology Dept.
  8. Laboratory Corporation of America, Triangle Park, NC (United States)
  9. Univ. of Hamburg (Germany). Univ. Medical Center. Inst. of Tumor Biology
  10. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Division
  11. California Pacific Medical Center, San Francisco, CA (United States). Dept. of Pathology
  12. Univ. of California, San Francisco, CA (United States). Carol Franc Buck Breast Cancer Center
  13. Stanford Univ., CA (United States). Dept. of Statistics. Dept. of Health Research and Policy
  14. Univ. of California, San Francisco, CA (United States). Comprehensive Cancer Center; California Pacific Medical Center, San Francisco, CA (United States). Dept. of Pathology
Publication Date:
Research Org.:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
OSTI Identifier:
1626529
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
BMC Cancer
Additional Journal Information:
Journal Volume: 8; Journal Issue: 1; Journal ID: ISSN 1471-2407
Publisher:
BioMed Central
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Oncology

Citation Formats

Tutt, Andrew, Wang, Alice, Rowland, Charles, Gillett, Cheryl, Lau, Kit, Chew, Karen, Dai, Hongyue, Kwok, Shirley, Ryder, Kenneth, Shu, Henry, Springall, Robert, Cane, Paul, McCallie, Blair, Kam-Morgan, Lauren, Anderson, Steve, Buerger, Horst, Gray, Joe, Bennington, James, Esserman, Laura, Hastie, Trevor, Broder, Samuel, Sninsky, John, Brandt, Burkhard, and Waldman, Fred. Risk estimation of distant metastasis in node-negative, estrogen receptor-positive breast cancer patients using an RT-PCR based prognostic expression signature. United States: N. p., 2008. Web. doi:10.1186/1471-2407-8-339.
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Tutt, Andrew, Wang, Alice, Rowland, Charles, Gillett, Cheryl, Lau, Kit, Chew, Karen, Dai, Hongyue, Kwok, Shirley, Ryder, Kenneth, Shu, Henry, Springall, Robert, Cane, Paul, McCallie, Blair, Kam-Morgan, Lauren, Anderson, Steve, Buerger, Horst, Gray, Joe, Bennington, James, Esserman, Laura, Hastie, Trevor, Broder, Samuel, Sninsky, John, Brandt, Burkhard, & Waldman, Fred. Risk estimation of distant metastasis in node-negative, estrogen receptor-positive breast cancer patients using an RT-PCR based prognostic expression signature. United States. https://doi.org/10.1186/1471-2407-8-339
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Tutt, Andrew, Wang, Alice, Rowland, Charles, Gillett, Cheryl, Lau, Kit, Chew, Karen, Dai, Hongyue, Kwok, Shirley, Ryder, Kenneth, Shu, Henry, Springall, Robert, Cane, Paul, McCallie, Blair, Kam-Morgan, Lauren, Anderson, Steve, Buerger, Horst, Gray, Joe, Bennington, James, Esserman, Laura, Hastie, Trevor, Broder, Samuel, Sninsky, John, Brandt, Burkhard, and Waldman, Fred. Fri . "Risk estimation of distant metastasis in node-negative, estrogen receptor-positive breast cancer patients using an RT-PCR based prognostic expression signature". United States. https://doi.org/10.1186/1471-2407-8-339. https://www.osti.gov/servlets/purl/1626529.
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@article{osti_1626529,
title = {Risk estimation of distant metastasis in node-negative, estrogen receptor-positive breast cancer patients using an RT-PCR based prognostic expression signature},
author = {Tutt, Andrew and Wang, Alice and Rowland, Charles and Gillett, Cheryl and Lau, Kit and Chew, Karen and Dai, Hongyue and Kwok, Shirley and Ryder, Kenneth and Shu, Henry and Springall, Robert and Cane, Paul and McCallie, Blair and Kam-Morgan, Lauren and Anderson, Steve and Buerger, Horst and Gray, Joe and Bennington, James and Esserman, Laura and Hastie, Trevor and Broder, Samuel and Sninsky, John and Brandt, Burkhard and Waldman, Fred},
abstractNote = {Background: Given the large number of genes purported to be prognostic for breast cancer, it would be optimal if the genes identified are not confounded by the continuously changing systemic therapies. The aim of this study was to discover and validate a breast cancer prognostic expression signature for distant metastasis in untreated, early stage, lymph node-negative (N-) estrogen receptor-positive (ER+) patients with extensive follow-up times. Methods: 197 genes previously associated with metastasis and ER status were profiled from 142 untreated breast cancer subjects. A "metastasis score" (MS) representing fourteen differentially expressed genes was developed and evaluated for its association with distant-metastasis-free survival (DMFS). Categorical risk classification was established from the continuous MS and further evaluated on an independent set of 279 untreated subjects. A third set of 45 subjects was tested to determine the prognostic performance of the MS in tamoxifen-treated women. Results: A 14-gene signature was found to be significantly associated (p < 0.05) with distant metastasis in a training set and subsequently in an independent validation set. In the validation set, the hazard ratios (HR) of the high risk compared to low risk groups were 4.02 (95% CI 1.91–8.44) for the endpoint of DMFS and 1.97 (95% CI 1.28 to 3.04) for overall survival after adjustment for age, tumor size and grade. The low and high MS risk groups had 10-year estimates (95% CI) of 96% (90–99%) and 72% (64–78%) respectively, for DMFS and 91% (84–95%) and 68% (61–75%), respectively for overall survival. Performance characteristics of the signature in the two sets were similar. Ki-67 labeling index (LI) was predictive for recurrent disease in the training set, but lost significance after adjustment for the expression signature. In a study of tamoxifen-treated patients, the HR for DMFS in high compared to low risk groups was 3.61 (95% CI 0.86–15.14). Conclusion: The 14-gene signature is significantly associated with risk of distant metastasis. The signature has a predominance of proliferation genes which have prognostic significance above that of Ki-67 LI and may aid in prioritizing future mechanistic studies and therapeutic interventions.},
doi = {10.1186/1471-2407-8-339},
journal = {BMC Cancer},
number = 1,
volume = 8,
place = {United States},
year = {Fri Nov 21 00:00:00 EST 2008},
month = {Fri Nov 21 00:00:00 EST 2008}
}
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https://doi.org/10.1186/1471-2407-8-339
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