A Four Gene Signature of Chromosome Instability (CIN4) Predicts for Benefit from Taxanes in the NCIC-CTG MA21 Clinical Trial

Overview

Journal Oncotarget

Specialty Oncology

Date 2016 Apr 9

PMID 27056899

Citations 2

Authors

Melanie Spears

Nicola Lyttle

Alister DCosta

Bingshu E Chen

Cindy Q Yao

Paul C Boutros

Margot Burnell

Mark N Levine

Patti OBrien

Lois Shepherd

John M S Bartlett

Affiliations

Soon will be listed here.

Abstract

Recent evidence demonstrated CIN4 as a predictive marker of anthracycline benefit in early breast cancer. An analysis of the NCIC CTG MA.21 clinical trial was performed to test the role of existing CIN gene expression signatures as prognostic and predictive markers in the context of taxane based chemotherapy.RNA was extracted from patients in cyclophosphamide, epirubicin and flurouracil (CEF) and epirubicin, cyclophosphamide and paclitaxel (EC/T) arms of the NCIC CTG MA.21 trial and analysed using NanoString technology.After multivariate analysis both high CIN25 and CIN70 score was significantly associated with an increased in RFS (HR 1.76, 95%CI 1.07-2.86, p=0.0018 and HR 1.59, 95%CI 1.12-2.25, p=0.0096 respectively). Patients whose tumours had low CIN4 gene expression scores were associated with an increase in RFS (HR: 0.64, 95% CI 0.39-1.03, p=0.06) when treated with EC/T compared to patients treated with CEF.In conclusion we have demonstrated CIN25 and CIN70 as prognostic markers in breast cancer and that CIN4 is a potential predictive maker of benefit from taxane treatment.

Citing Articles

Centromere 17 copy number gain reflects chromosomal instability in breast cancer.

Lee K, Kim H, Jang M, Lee S, Ahn S, Park S Sci Rep. 2019; 9(1):17968.

PMID: 31784614 PMC: 6884473. DOI: 10.1038/s41598-019-54471-w.

Clinical Implications of Chromosomal Instability (CIN) and Kinetochore Abnormalities in Breast Cancers.

Voutsadakis I Mol Diagn Ther. 2019; 23(6):707-721.

PMID: 31372940 DOI: 10.1007/s40291-019-00420-2.

References

Carter S, Eklund A, Kohane I, Harris L, Szallasi Z . A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers. Nat Genet. 2006; 38(9):1043-8. DOI: 10.1038/ng1861. View

Noguchi S . Predictive factors for response to docetaxel in human breast cancers. Cancer Sci. 2006; 97(9):813-20. PMC: 11158941. DOI: 10.1111/j.1349-7006.2006.00265.x. View

Swain S, Whaley F, Ewer M . Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer. 2003; 97(11):2869-79. DOI: 10.1002/cncr.11407. View

Peto R, Davies C, Godwin J, Gray R, Pan H, Clarke M . Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet. 2011; 379(9814):432-44. PMC: 3273723. DOI: 10.1016/S0140-6736(11)61625-5. View

Parker J, Mullins M, Cheang M, Leung S, Voduc D, Vickery T . Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol. 2009; 27(8):1160-7. PMC: 2667820. DOI: 10.1200/JCO.2008.18.1370. View

Torikoshi Y, Gohda K, Davis M, Fraser Symmans W, Pusztai L, Kazansky A . Novel functional assay for spindle-assembly checkpoint by cyclin-dependent kinase activity to predict taxane chemosensitivity in breast tumor patient. J Cancer. 2013; 4(9):697-702. PMC: 3842438. DOI: 10.7150/jca.6248. View

Habermann J, Doering J, Hautaniemi S, Roblick U, Bundgen N, Nicorici D . The gene expression signature of genomic instability in breast cancer is an independent predictor of clinical outcome. Int J Cancer. 2008; 124(7):1552-64. PMC: 2707256. DOI: 10.1002/ijc.24017. View

Ellis P, Barrett-Lee P, Johnson L, Cameron D, Wardley A, OReilly S . Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet. 2009; 373(9676):1681-92. PMC: 2687939. DOI: 10.1016/S0140-6736(09)60740-6. View

J van t Veer L, Dai H, van de Vijver M, He Y, Hart A, Mao M . Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002; 415(6871):530-6. DOI: 10.1038/415530a. View

10.

Waggott D, Chu K, Yin S, Wouters B, Liu F, Boutros P . NanoStringNorm: an extensible R package for the pre-processing of NanoString mRNA and miRNA data. Bioinformatics. 2012; 28(11):1546-8. PMC: 3356845. DOI: 10.1093/bioinformatics/bts188. View

11.

Spears M, Yousif F, Lyttle N, Boutros P, Munro A, Twelves C . A four gene signature predicts benefit from anthracyclines: evidence from the BR9601 and MA.5 clinical trials. Oncotarget. 2015; 6(31):31693-701. PMC: 4741633. DOI: 10.18632/oncotarget.5562. View

12.

Mercuro G, Cadeddu C, Piras A, Dessi M, Madeddu C, Deidda M . Early epirubicin-induced myocardial dysfunction revealed by serial tissue Doppler echocardiography: correlation with inflammatory and oxidative stress markers. Oncologist. 2007; 12(9):1124-33. DOI: 10.1634/theoncologist.12-9-1124. View

13.

Pritchard K, Messersmith H, Elavathil L, Trudeau M, OMalley F, Dhesy-Thind B . HER-2 and topoisomerase II as predictors of response to chemotherapy. J Clin Oncol. 2008; 26(5):736-44. DOI: 10.1200/JCO.2007.15.4716. View

14.

Birkbak N, Eklund A, Li Q, McClelland S, Endesfelder D, Tan P . Paradoxical relationship between chromosomal instability and survival outcome in cancer. Cancer Res. 2011; 71(10):3447-52. PMC: 3096721. DOI: 10.1158/0008-5472.CAN-10-3667. View

15.

Bartlett J, AHern R, Piper T, Ellis I, Dowsett M, Mallon E . Phosphorylation of AKT pathway proteins is not predictive of benefit of taxane therapy in early breast cancer. Breast Cancer Res Treat. 2013; 138(3):773-81. DOI: 10.1007/s10549-013-2489-y. View

16.

Martin M, Romero A, Cheang M, Lopez Garcia-Asenjo J, Garcia-Saenz J, Oliva B . Genomic predictors of response to doxorubicin versus docetaxel in primary breast cancer. Breast Cancer Res Treat. 2011; 128(1):127-36. DOI: 10.1007/s10549-011-1461-y. View

17.

Jones L, Haykowsky M, Swartz J, Douglas P, Mackey J . Early breast cancer therapy and cardiovascular injury. J Am Coll Cardiol. 2007; 50(15):1435-41. DOI: 10.1016/j.jacc.2007.06.037. View

18.

Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M . A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004; 351(27):2817-26. DOI: 10.1056/NEJMoa041588. View

19.

Swanton C, Nicke B, Schuett M, Eklund A, Ng C, Li Q . Chromosomal instability determines taxane response. Proc Natl Acad Sci U S A. 2009; 106(21):8671-6. PMC: 2688979. DOI: 10.1073/pnas.0811835106. View

20.

Bartlett J, Nielsen T, Gao D, Gelmon K, Quintayo M, Starczynski J . TLE3 is not a predictive biomarker for taxane sensitivity in the NCIC CTG MA.21 clinical trial. Br J Cancer. 2015; 113(5):722-8. PMC: 4559832. DOI: 10.1038/bjc.2015.271. View