Journal Article
. 2012 May;5().
doi: 10.1186/1755-8794-5-16.

A target based approach identifies genomic predictors of breast cancer patient response to chemotherapy

Robin M Hallett 1 Gregory Pond  John A Hassell  
Affiliations
  • PMID: 22578285
  •     52 References
  •     10 citations

Abstract

Background: The efficacy of chemotherapy regimens in breast cancer patients is variable and unpredictable. Whether individual patients either achieve long-term remission or suffer recurrence after therapy may be dictated by intrinsic properties of their breast tumors including genetic lesions and consequent aberrant transcriptional programs. Global gene expression profiling provides a powerful tool to identify such tumor-intrinsic transcriptional programs, whose analyses provide insight into the underlying biology of individual patient tumors. For example, multi-gene expression signatures have been identified that can predict the likelihood of disease reccurrence, and thus guide patient prognosis. Whereas such prognostic signatures are being introduced in the clinical setting, similar signatures that predict sensitivity or resistance to chemotherapy are not currently clinically available.

Methods: We used gene expression profiling to identify genes that were co-expressed with genes whose transcripts encode the protein targets of commonly used chemotherapeutic agents.

Results: Here, we present target based expression indices that predict breast tumor response to anthracycline and taxane based chemotherapy. Indeed, these signatures were independently predictive of chemotherapy response after adjusting for standard clinic-pathological variables such as age, grade, and estrogen receptor status in a cohort of 488 breast cancer patients treated with adriamycin and taxotere/taxol.

Conclusions: Importantly, our findings suggest the practicality of developing target based indices that predict response to therapeutics, as well as highlight the possibility of using gene signatures to guide the use of chemotherapy during treatment of breast cancer patients.

Low E2F1 transcript levels are a strong determinant of favorable breast cancer outcome.
Vincent Vuaroqueaux, Patrick Urban, +8 authors, Serenella Eppenberger-Castori.
Breast Cancer Res, 2007 May 31; 9(3). PMID: 17535433    Free PMC article.
Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific beta-tubulin isotypes.
M Kavallaris, D Y Kuo, +4 authors, S B Horwitz.
J Clin Invest, 1997 Sep 01; 100(5). PMID: 9276747    Free PMC article.
Highly Cited.
Topoisomerase IIalpha gene amplification predicts favorable treatment response to tailored and dose-escalated anthracycline-based adjuvant chemotherapy in HER-2/neu-amplified breast cancer: Scandinavian Breast Group Trial 9401.
Scandinavian Breast Group Trial 9401, Minna Tanner, +7 authors, Jonas Bergh.
J Clin Oncol, 2006 May 10; 24(16). PMID: 16682728
Alterations in the TOP2A and HER2 genes: association with adjuvant anthracycline sensitivity in human breast cancers.
Dennis J Slamon, Michael F Press.
J Natl Cancer Inst, 2009 Apr 30; 101(9). PMID: 19401550
An algorithm to discover gene signatures with predictive potential.
Robin M Hallett, Anna Dvorkin, Christine M Gabardo, John A Hassell.
J Exp Clin Cancer Res, 2010 Sep 04; 29. PMID: 20813028    Free PMC article.
Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer.
Charles L Vogel, Melody A Cobleigh, +10 authors, Michael Press.
J Clin Oncol, 2002 Feb 01; 20(3). PMID: 11821453
Highly Cited.
Taxanes: microtubule and centrosome targets, and cell cycle dependent mechanisms of action.
M Abal, J M Andreu, I Barasoain.
Curr Cancer Drug Targets, 2003 May 29; 3(3). PMID: 12769688
Review.
Tumor topoisomerase II alpha status and response to anthracycline-based neoadjuvant chemotherapy in breast cancer.
Alíz Nikolényi, Farkas Sükösd, +8 authors, Zsuzsanna Kahán.
Oncology, 2011 Jul 08; 80(3-4). PMID: 21734419
Overexpression of class III beta-tubulin predicts good response to taxane-based chemotherapy in ovarian clear cell adenocarcinoma.
Daisuke Aoki, Yoshinao Oda, +10 authors, Michihiko Kuwano.
Clin Cancer Res, 2009 Feb 21; 15(4). PMID: 19228748
Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer:National Surgical Adjuvant Breast and Bowel Project Protocol B-27.
Harry D Bear, Stewart Anderson, +11 authors, Norman Wolmark.
J Clin Oncol, 2006 Apr 12; 24(13). PMID: 16606972
Highly Cited.
Multifactorial approach to predicting resistance to anthracyclines.
Christine Desmedt, Angelo Di Leo, +25 authors, Christos Sotiriou.
J Clin Oncol, 2011 Mar 23; 29(12). PMID: 21422418
Gene expression profiling predicts clinical outcome of breast cancer.
Laura J van 't Veer, Hongyue Dai, +13 authors, Stephen H Friend.
Nature, 2002 Feb 02; 415(6871). PMID: 11823860
Highly Cited.
A national cancer clinical trials system for the 21st century: reinvigorating the NCI Cooperative Group Program.
John F Scoggins, Scott D Ramsey.
J Natl Cancer Inst, 2010 Aug 05; 102(17). PMID: 20682918    Free PMC article.
Chromatin remodeling and SWI/SNF2 factors in human disease.
Juraj Kokavec, Jarmila Podskocova, Jiri Zavadil, Tomas Stopka.
Front Biosci, 2008 May 30; 13. PMID: 18508648
Review.
Distinct roles for E2F proteins in cell growth control and apoptosis.
J DeGregori, G Leone, +2 authors, J R Nevins.
Proc Natl Acad Sci U S A, 1997 Jul 08; 94(14). PMID: 9207076    Free PMC article.
Highly Cited.
A gene signature for predicting outcome in patients with basal-like breast cancer.
Robin M Hallett, Anna Dvorkin-Gheva, Anita Bane, John A Hassell.
Sci Rep, 2012 Feb 23; 2. PMID: 22355741    Free PMC article.
Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18.
N Wolmark, J Wang, +2 authors, B Fisher.
J Natl Cancer Inst Monogr, 2002 Jan 05; (30). PMID: 11773300
Highly Cited.
A cell proliferation signature is a marker of extremely poor outcome in a subpopulation of breast cancer patients.
Hongyue Dai, Laura van't Veer, +9 authors, Stephen Friend.
Cancer Res, 2005 May 19; 65(10). PMID: 15899795
Chromatin remodeling and human disease.
Cheng Huang, Emily A Sloan, Cornelius F Boerkoel.
Curr Opin Genet Dev, 2003 Jun 06; 13(3). PMID: 12787786
Review.
Meta-analysis of gene expression profiles in breast cancer: toward a unified understanding of breast cancer subtyping and prognosis signatures.
Pratyaksha Wirapati, Christos Sotiriou, +10 authors, Mauro Delorenzi.
Breast Cancer Res, 2008 Jul 30; 10(4). PMID: 18662380    Free PMC article.
Highly Cited.
Cellular targets for activation by the E2F1 transcription factor include DNA synthesis- and G1/S-regulatory genes.
J DeGregori, T Kowalik, J R Nevins.
Mol Cell Biol, 1995 Aug 01; 15(8). PMID: 7623816    Free PMC article.
Highly Cited.
Taxol: an antimitotic agent with a new mechanism of action.
J J Manfredi, S B Horwitz.
Pharmacol Ther, 1984 Jan 01; 25(1). PMID: 6149569
Highly Cited. Review.
Taxol binds to polymerized tubulin in vitro.
J Parness, S B Horwitz.
J Cell Biol, 1981 Nov 01; 91(2 Pt 1). PMID: 6118377    Free PMC article.
Highly Cited.
Distinct and Overlapping Roles for E2F Family Members in Transcription, Proliferation and Apoptosis.
James DeGregori, David G Johnson.
Curr Mol Med, 2006 Nov 15; 6(7). PMID: 17100600
Highly Cited. Review.
Lapatinib.
Beverly Moy, Peter Kirkpatrick, Santwana Kar, Paul Goss.
Nat Rev Drug Discov, 2007 Jul 20; 6(6). PMID: 17633789
Assessment of an RNA interference screen-derived mitotic and ceramide pathway metagene as a predictor of response to neoadjuvant paclitaxel for primary triple-negative breast cancer: a retrospective analysis of five clinical trials.
Nicolai Juul, Zoltan Szallasi, +12 authors, Charles Swanton.
Lancet Oncol, 2010 Mar 02; 11(4). PMID: 20189874
Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer.
Cornelia Liedtke, Chafika Mazouni, +10 authors, Lajos Pusztai.
J Clin Oncol, 2008 Feb 06; 26(8). PMID: 18250347
Highly Cited.
A genomic predictor of response and survival following taxane-anthracycline chemotherapy for invasive breast cancer.
Christos Hatzis, Lajos Pusztai, +27 authors, W Fraser Symmans.
JAMA, 2011 May 12; 305(18). PMID: 21558518    Free PMC article.
Highly Cited.
Drebrin, a development-associated brain protein from rat embryo, causes the dissociation of tropomyosin from actin filaments.
R Ishikawa, K Hayashi, +4 authors, K Kohama.
J Biol Chem, 1994 Nov 25; 269(47). PMID: 7961990
Pharmacogenomic predictor of sensitivity to preoperative chemotherapy with paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide in breast cancer.
Kenneth R Hess, Keith Anderson, +14 authors, Lajos Pusztai.
J Clin Oncol, 2006 Aug 10; 24(26). PMID: 16896004
Highly Cited.
Role of the human RAD51 protein in homologous recombination and double-stranded-break repair.
P Baumann, S C West.
Trends Biochem Sci, 1998 Aug 11; 23(7). PMID: 9697414
Highly Cited. Review.
TPX2, A novel xenopus MAP involved in spindle pole organization.
T Wittmann, M Wilm, E Karsenti, I Vernos.
J Cell Biol, 2000 Jun 28; 149(7). PMID: 10871281    Free PMC article.
Highly Cited.
Dose-dense doxorubicin and cyclophosphamide followed by weekly paclitaxel with trastuzumab and lapatinib in HER2/neu-overexpressed/amplified breast cancer is not feasible because of excessive diarrhea.
Chau Dang, Nancy Lin, +10 authors, Clifford Hudis.
J Clin Oncol, 2010 May 19; 28(18). PMID: 20479410    Free PMC article.
Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer.
Soonmyung Paik, Gong Tang, +11 authors, Norman Wolmark.
J Clin Oncol, 2006 May 25; 24(23). PMID: 16720680
Highly Cited.
Cell cycle correlated genes dictate the prognostic power of breast cancer gene lists.
Jonathan D Mosley, Ruth A Keri.
BMC Med Genomics, 2008 Apr 29; 1. PMID: 18439262    Free PMC article.
A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.
Soonmyung Paik, Steven Shak, +12 authors, Norman Wolmark.
N Engl J Med, 2004 Dec 14; 351(27). PMID: 15591335
Highly Cited.
Introduction to the E2F family: protein structure and gene regulation.
J E Slansky, P J Farnham.
Curr Top Microbiol Immunol, 1996 Jan 01; 208. PMID: 8575210
Review.
Most random gene expression signatures are significantly associated with breast cancer outcome.
David Venet, Jacques E Dumont, Vincent Detours.
PLoS Comput Biol, 2011 Oct 27; 7(10). PMID: 22028643    Free PMC article.
Highly Cited.
E2F1 and KIAA0191 expression predicts breast cancer patient survival.
Robin M Hallett, John A Hassell.
BMC Res Notes, 2011 Apr 02; 4. PMID: 21453498    Free PMC article.
A multigene predictor of metastatic outcome in early stage hormone receptor-negative and triple-negative breast cancer.
Christina Yau, Laura Esserman, +3 authors, Christopher C Benz.
Breast Cancer Res, 2010 Oct 16; 12(5). PMID: 20946665    Free PMC article.
Class III beta-tubulin overexpression is a prominent mechanism of paclitaxel resistance in ovarian cancer patients.
Simona Mozzetti, Cristiano Ferlini, +8 authors, Giovanni Scambia.
Clin Cancer Res, 2005 Jan 27; 11(1). PMID: 15671559
Highly Cited.
Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis.
Christos Sotiriou, Pratyaksha Wirapati, +17 authors, Mauro Delorenzi.
J Natl Cancer Inst, 2006 Feb 16; 98(4). PMID: 16478745
Highly Cited.
Exo1 roles for repair of DNA double-strand breaks and meiotic crossing over in Saccharomyces cerevisiae.
H Tsubouchi, H Ogawa.
Mol Biol Cell, 2000 Jul 11; 11(7). PMID: 10888664    Free PMC article.
Highly Cited.
A gene-expression signature as a predictor of survival in breast cancer.
Marc J van de Vijver, Yudong D He, +18 authors, René Bernards.
N Engl J Med, 2002 Dec 20; 347(25). PMID: 12490681
Highly Cited.
Cytoskeleton and paclitaxel sensitivity in breast cancer: the role of beta-tubulins.
Stefania Tommasi, Anita Mangia, +11 authors, Angelo Paradiso.
Int J Cancer, 2007 Feb 08; 120(10). PMID: 17285590
Taxol binds to cellular microtubules.
J J Manfredi, J Parness, S B Horwitz.
J Cell Biol, 1982 Sep 01; 94(3). PMID: 6127342    Free PMC article.
Highly Cited.
Prospective comparison of clinical and genomic multivariate predictors of response to neoadjuvant chemotherapy in breast cancer.
Jae K Lee, Charles Coutant, +6 authors, Lajos Pusztai.
Clin Cancer Res, 2010 Jan 14; 16(2). PMID: 20068086    Free PMC article.
Breast cancer molecular subtypes respond differently to preoperative chemotherapy.
Roman Rouzier, Charles M Perou, +13 authors, Lajos Pusztai.
Clin Cancer Res, 2005 Aug 24; 11(16). PMID: 16115903
Highly Cited.
Biological processes associated with breast cancer clinical outcome depend on the molecular subtypes.
Christine Desmedt, Benjamin Haibe-Kains, +6 authors, Christos Sotiriou.
Clin Cancer Res, 2008 Aug 14; 14(16). PMID: 18698033
Highly Cited.
Topoisomerase levels determine chemotherapy response in vitro and in vivo.
Darren J Burgess, Jason Doles, +6 authors, Michael T Hemann.
Proc Natl Acad Sci U S A, 2008 Jun 25; 105(26). PMID: 18574145    Free PMC article.
Highly Cited.
Molecular classification of cancer: class discovery and class prediction by gene expression monitoring.
T R Golub, D K Slonim, +9 authors, E S Lander.
Science, 1999 Oct 16; 286(5439). PMID: 10521349
Highly Cited.
Exploration, normalization, and summaries of high density oligonucleotide array probe level data.
Rafael A Irizarry, Bridget Hobbs, +4 authors, Terence P Speed.
Biostatistics, 2003 Aug 20; 4(2). PMID: 12925520
Highly Cited.
Exploratory study on the correlation between 14 lung cancer-related gene expression and specific clinical characteristics of NSCLC patients.
Yi Han, Guo Li, +17 authors, Zhidong Liu.
Mol Clin Oncol, 2014 Mar 22; 1(5). PMID: 24649266    Free PMC article.
Mammary glands exhibit molecular laterality and undergo left-right asymmetric ductal epithelial growth in MMTV-cNeu mice.
J P Robichaux, R M Hallett, +2 authors, A F Ramsdell.
Oncogene, 2014 Jun 10; 34(15). PMID: 24909172    Free PMC article.
A program to identify prognostic and predictive gene signatures.
Sam D Chorlton, Robin M Hallett, John A Hassell.
BMC Res Notes, 2014 Aug 20; 7. PMID: 25135081    Free PMC article.
Immune cell transcript modules reveal leukocyte heterogeneity in synovial biopsies of seronegative spondylarthropathy patients.
Robin M Hallett, Tracy Chew.
BMC Musculoskelet Disord, 2014 Dec 21; 15. PMID: 25526985    Free PMC article.
Treatment-induced cell cycle kinetics dictate tumor response to chemotherapy.
Robin M Hallett, Cheng Huang, +5 authors, Jonathan S Draper.
Oncotarget, 2015 Mar 10; 6(9). PMID: 25749523    Free PMC article.
Identification and evaluation of network modules for the prognosis of basal-like breast cancer.
Robin M Hallett, Jessica G Cockburn, +3 authors, Anita Bane.
Oncotarget, 2015 May 21; 6(19). PMID: 25991675    Free PMC article.
Transcript signatures that predict outcome and identify targetable pathways in MYCN-amplified neuroblastoma.
Robin M Hallett, Alex B K Seong, David R Kaplan, Meredith S Irwin.
Mol Oncol, 2016 Sep 08; 10(9). PMID: 27599694    Free PMC article.
Next-Generation Sequencing May Discriminate Extreme Long-term versus Short-term Survival in Patients with Metastatic Small Cell Lung Cancer (SCLC).
Zoltan Lohinai, Zsolt Megyesfalvi, Balazs Dome, Glen J Weiss.
Transl Oncol, 2019 Sep 03; 12(12). PMID: 31476386    Free PMC article.
BMI1 is a therapeutic target in recurrent medulloblastoma.
David Bakhshinyan, Chitra Venugopal, +35 authors, Sheila K Singh.
Oncogene, 2018 Oct 24; 38(10). PMID: 30348991
Wnt activation as a therapeutic strategy in medulloblastoma.
Branavan Manoranjan, Chitra Venugopal, +20 authors, Sheila K Singh.
Nat Commun, 2020 Aug 30; 11(1). PMID: 32859895    Free PMC article.