IST Neoadjuvant Abraxane in Newly Diagnosed Breast Cancer

Summary

The aim of this project is to evaluate tailored primary systemic therapy with sequential nab paclitaxel and epirubicin and cyclophosphamide in early breast cancer. This study will be an open label phase II clinical trial. The hypothesis is that tailored neoadjuvant chemotherapy with sequential nab paclitaxel and epirubicin and cyclophosphamide is feasible and achieves high response rates. It is proposed that 60 patients will be enrolled in this study including 40 patients which are likely to have chemotherapy sensitive tumors and 20 patients who have ER positive tumors and are more likely to respond to hormonal treatment as an exploratory cohort. The target population is women with early breast cancer who are eligible for primary systemic therapy. The overall response rate in the breast will be measured. Secondary endpoints will include response rates in axillary lymph nodes, safety and tolerability and the rate of breast conservation. Participants will have a blood test to determine a specific genotype status that may help in predicting sensitivity to chemotherapy. This genotype test result is exploratory and will not influence selection of therapy for participants. Patients will also be given the option of having he their tumour tissues used in laboratory studies involving isolating cancer initiating cells from the tumor to subsequently generate breast cancer models in the laboratory and using aptamers (chemical antibodies) to target tumours.

Timeline

Start

2013-04

Primary completion

2015-09

Completion

2020-06

Publications

• Background Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med. 2010 Nov 11;363(20):1938-48. doi: 10.1056/NEJMra1001389.
• Background Kaufmann M, Hortobagyi GN, Goldhirsch A, Scholl S, Makris A, Valagussa P, Blohmer JU, Eiermann W, Jackesz R, Jonat W, Lebeau A, Loibl S, Miller W, Seeber S, Semiglazov V, Smith R, Souchon R, Stearns V, Untch M, von Minckwitz G. Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: an update. J Clin Oncol. 2006 Apr 20;24(12):1940-9. doi: 10.1200/JCO.2005.02.6187.
• Background Bear HD, Anderson S, Brown A, Smith R, Mamounas EP, Fisher B, Margolese R, Theoret H, Soran A, Wickerham DL, Wolmark N; National Surgical Adjuvant Breast and Bowel Project Protocol B-27. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2003 Nov 15;21(22):4165-74. doi: 10.1200/JCO.2003.12.005. Epub 2003 Oct 14.
• Background Gradishar WJ, Wedam SB, Jahanzeb M, Erban J, Limentani SA, Tsai KT, Olsen SR, Swain SM. Neoadjuvant docetaxel followed by adjuvant doxorubicin and cyclophosphamide in patients with stage III breast cancer. Ann Oncol. 2005 Aug;16(8):1297-304. doi: 10.1093/annonc/mdi254. Epub 2005 May 19.
• Background Foote M. Using nanotechnology to improve the characteristics of antineoplastic drugs: improved characteristics of nab-paclitaxel compared with solvent-based paclitaxel. Biotechnol Annu Rev. 2007;13:345-57. doi: 10.1016/S1387-2656(07)13012-X.
• Background Gradishar WJ, Krasnojon D, Cheporov S, Makhson AN, Manikhas GM, Clawson A, Bhar P. Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol. 2009 Aug 1;27(22):3611-9. doi: 10.1200/JCO.2008.18.5397. Epub 2009 May 26.
• Background Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O'Shaughnessy J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005 Nov 1;23(31):7794-803. doi: 10.1200/JCO.2005.04.937. Epub 2005 Sep 19.
• Background Yardley D, Burris H 3rd, Peacock N, Raefsky E, Melnik M, Inhorn R, Shipley D, Hainsworth J. A pilot study of adjuvant nanoparticle albumin-bound (nab) paclitaxel and cyclophosphamide, with trastuzumab in HER2-positive patients, in the treatment of early-stage breast cancer. Breast Cancer Res Treat. 2010 Sep;123(2):471-5. doi: 10.1007/s10549-010-1047-0. Epub 2010 Jul 24.
• Background Dang C, Fornier M, Sugarman S, Troso-Sandoval T, Lake D, D'Andrea G, Seidman A, Sklarin N, Dickler M, Currie V, Gilewski T, Moynahan ME, Drullinsky P, Robson M, Wasserheit-Leiblich C, Mills N, Steingart R, Panageas K, Norton L, Hudis C. The safety of dose-dense doxorubicin and cyclophosphamide followed by paclitaxel with trastuzumab in HER-2/neu overexpressed/amplified breast cancer. J Clin Oncol. 2008 Mar 10;26(8):1216-22. doi: 10.1200/JCO.2007.12.0733.
• Background Kaklamani VG, Siziopikou K, Scholtens D, Lacouture M, Gordon J, Uthe R, Meservey C, Hansen N, Khan SA, Jeruss JS, Bethke K, Cianfrocca M, Rosen S, Von Roenn J, Wayne J, Parimi V, Jovanovic B, Gradishar W. Pilot neoadjuvant trial in HER2 positive breast cancer with combination of nab-paclitaxel and lapatinib. Breast Cancer Res Treat. 2012 Apr;132(3):833-42. doi: 10.1007/s10549-011-1411-8. Epub 2011 Feb 27.
• Background Khasraw M, Brogi E, Seidman AD. The need to examine metastatic tissue at the time of progression of breast cancer: is re-biopsy a necessity or a luxury? Curr Oncol Rep. 2011 Feb;13(1):17-25. doi: 10.1007/s11912-010-0137-9.
• Background Kumaki N, Umemura S, Tang X, Saito Y, Suzuki Y, Tokuda Y. Alteration of immunohistochemical biomarkers between pre- and post-chemotherapy: hormone receptors, HER2 and Ki-67. Breast Cancer. 2011 Apr;18(2):98-102. doi: 10.1007/s12282-010-0238-1. Epub 2011 Feb 3.
• Background Iwamoto T, Bianchini G, Booser D, Qi Y, Coutant C, Shiang CY, Santarpia L, Matsuoka J, Hortobagyi GN, Symmans WF, Holmes FA, O'Shaughnessy J, Hellerstedt B, Pippen J, Andre F, Simon R, Pusztai L. Gene pathways associated with prognosis and chemotherapy sensitivity in molecular subtypes of breast cancer. J Natl Cancer Inst. 2011 Feb 2;103(3):264-72. doi: 10.1093/jnci/djq524. Epub 2010 Dec 29.
• Background Partridge SC, Gibbs JE, Lu Y, Esserman LJ, Tripathy D, Wolverton DS, Rugo HS, Hwang ES, Ewing CA, Hylton NM. MRI measurements of breast tumor volume predict response to neoadjuvant chemotherapy and recurrence-free survival. AJR Am J Roentgenol. 2005 Jun;184(6):1774-81. doi: 10.2214/ajr.184.6.01841774.
• Background O'Flynn EA, DeSouza NM. Functional magnetic resonance: biomarkers of response in breast cancer. Breast Cancer Res. 2011 Feb 23;13(1):204. doi: 10.1186/bcr2815.
• Background Robidoux A, Buzdar AU, Quinaux E, Jacobs S, Rastogi P, Fourchotte V, Younan RJ, Pajon ER, Shalaby IA, Desai AM, Fehrenbacher L, Geyer CE Jr, Mamounas EP, Wolmark N. A phase II neoadjuvant trial of sequential nanoparticle albumin-bound paclitaxel followed by 5-fluorouracil/epirubicin/cyclophosphamide in locally advanced breast cancer. Clin Breast Cancer. 2010 Feb;10(1):81-6. doi: 10.3816/CBC.2010.n.011.
• Background Findlay B, Tonkin K, Crump M, Norris B, Trudeau M, Blackstein M, Burnell M, Skillings J, Bowman D, Walde D, Levine M, Pritchard KI, Palmer MJ, Tu D, Shepherd L. A dose escalation trial of adjuvant cyclophosphamide and epirubicin in combination with 5-fluorouracil using G-CSF support for premenopausal women with breast cancer involving four or more positive nodes. Ann Oncol. 2007 Oct;18(10):1646-51. doi: 10.1093/annonc/mdm277. Epub 2007 Aug 22.
• Background Khasraw M, Bell R, Dang C. Epirubicin: is it like doxorubicin in breast cancer? A clinical review. Breast. 2012 Apr;21(2):142-9. doi: 10.1016/j.breast.2011.12.012. Epub 2012 Jan 17.
• Background Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thurlimann B, Senn HJ; Panel members. Strategies for subtypes--dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol. 2011 Aug;22(8):1736-47. doi: 10.1093/annonc/mdr304. Epub 2011 Jun 27.
• Background Dowsett M, Nielsen TO, A'Hern R, Bartlett J, Coombes RC, Cuzick J, Ellis M, Henry NL, Hugh JC, Lively T, McShane L, Paik S, Penault-Llorca F, Prudkin L, Regan M, Salter J, Sotiriou C, Smith IE, Viale G, Zujewski JA, Hayes DF; International Ki-67 in Breast Cancer Working Group. Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. J Natl Cancer Inst. 2011 Nov 16;103(22):1656-64. doi: 10.1093/jnci/djr393. Epub 2011 Sep 29.
• Background Untch M, Loibl S, Konecny GE, von Minckwitz G. Neoadjuvant clinical trials for the treatment of primary breast cancer: the experience of the German study groups. Curr Oncol Rep. 2012 Feb;14(1):27-34. doi: 10.1007/s11912-011-0212-x.
• Background Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D. Molecular portraits of human breast tumours. Nature. 2000 Aug 17;406(6797):747-52. doi: 10.1038/35021093.
• Background Cheang MC, Chia SK, Voduc D, Gao D, Leung S, Snider J, Watson M, Davies S, Bernard PS, Parker JS, Perou CM, Ellis MJ, Nielsen TO. Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst. 2009 May 20;101(10):736-50. doi: 10.1093/jnci/djp082. Epub 2009 May 12.
• Background Visvader JE. Cells of origin in cancer. Nature. 2011 Jan 20;469(7330):314-22. doi: 10.1038/nature09781.
• Background Zoller M. CD44: can a cancer-initiating cell profit from an abundantly expressed molecule? Nat Rev Cancer. 2011 Apr;11(4):254-67. doi: 10.1038/nrc3023. Epub 2011 Mar 10.
• Background Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-8. doi: 10.1073/pnas.0530291100. Epub 2003 Mar 10.
• Background Stratford AL, Reipas K, Maxwell C, Dunn SE. Targeting tumour-initiating cells to improve the cure rates for triple-negative breast cancer. Expert Rev Mol Med. 2010 Jul 26;12:e22. doi: 10.1017/S1462399410001535.
• Background Hebbard L, Steffen A, Zawadzki V, Fieber C, Howells N, Moll J, Ponta H, Hofmann M, Sleeman J. CD44 expression and regulation during mammary gland development and function. J Cell Sci. 2000 Jul;113 ( Pt 14):2619-30. doi: 10.1242/jcs.113.14.2619.
• Background Munz M, Baeuerle PA, Gires O. The emerging role of EpCAM in cancer and stem cell signaling. Cancer Res. 2009 Jul 15;69(14):5627-9. doi: 10.1158/0008-5472.CAN-09-0654. Epub 2009 Jul 7.
• Background Shigdar S, Ward AC, De A, Yang CJ, Wei M, Duan W. Clinical applications of aptamers and nucleic acid therapeutics in haematological malignancies. Br J Haematol. 2011 Oct;155(1):3-13. doi: 10.1111/j.1365-2141.2011.08807.x. Epub 2011 Aug 2.
• Background Yu C, Hu Y, Duan J, Yuan W, Wang C, Xu H, Yang XD. Novel aptamer-nanoparticle bioconjugates enhances delivery of anticancer drug to MUC1-positive cancer cells in vitro. PLoS One. 2011;6(9):e24077. doi: 10.1371/journal.pone.0024077. Epub 2011 Sep 1.
• Background Wu S, Duan N, Wang Z, Wang H. Aptamer-functionalized magnetic nanoparticle-based bioassay for the detection of ochratoxin A using upconversion nanoparticles as labels. Analyst. 2011 Jun 7;136(11):2306-14. doi: 10.1039/c0an00735h. Epub 2011 Apr 8.
• Background Buchwald M, Kramer OH, Heinzel T. HDACi--targets beyond chromatin. Cancer Lett. 2009 Aug 8;280(2):160-7. doi: 10.1016/j.canlet.2009.02.028. Epub 2009 Apr 1.
• Background Li L, Bhatia R. Stem cell quiescence. Clin Cancer Res. 2011 Aug 1;17(15):4936-41. doi: 10.1158/1078-0432.CCR-10-1499. Epub 2011 May 18.
• Background Tan J, Cang S, Ma Y, Petrillo RL, Liu D. Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents. J Hematol Oncol. 2010 Feb 4;3:5. doi: 10.1186/1756-8722-3-5.
• Background Lemoine M, Younes A. Histone deacetylase inhibitors in the treatment of lymphoma. Discov Med. 2010 Nov;10(54):462-70.
• Background Yu KD, Huang AJ, Fan L, Li WF, Shao ZM. Genetic variants in oxidative stress-related genes predict chemoresistance in primary breast cancer: a prospective observational study and validation. Cancer Res. 2012 Jan 15;72(2):408-19. doi: 10.1158/0008-5472.CAN-11-2998. Epub 2011 Dec 6.
• Background Hubackova M, Vaclavikova R, Ehrlichova M, Mrhalova M, Kodet R, Kubackova K, Vrana D, Gut I, Soucek P. Association of superoxide dismutases and NAD(P)H quinone oxidoreductases with prognosis of patients with breast carcinomas. Int J Cancer. 2012 Jan 15;130(2):338-48. doi: 10.1002/ijc.26006. Epub 2011 Apr 20.
• Background Anwar A, Dehn D, Siegel D, Kepa JK, Tang LJ, Pietenpol JA, Ross D. Interaction of human NAD(P)H:quinone oxidoreductase 1 (NQO1) with the tumor suppressor protein p53 in cells and cell-free systems. J Biol Chem. 2003 Mar 21;278(12):10368-73. doi: 10.1074/jbc.M211981200. Epub 2003 Jan 14.
• Background Tsvetkov P, Reuven N, Shaul Y. Ubiquitin-independent p53 proteasomal degradation. Cell Death Differ. 2010 Jan;17(1):103-8. doi: 10.1038/cdd.2009.67.
• Background Nioi P, Hayes JD. Contribution of NAD(P)H:quinone oxidoreductase 1 to protection against carcinogenesis, and regulation of its gene by the Nrf2 basic-region leucine zipper and the arylhydrocarbon receptor basic helix-loop-helix transcription factors. Mutat Res. 2004 Nov 2;555(1-2):149-71. doi: 10.1016/j.mrfmmm.2004.05.023.
• Background Siegel D, Anwar A, Winski SL, Kepa JK, Zolman KL, Ross D. Rapid polyubiquitination and proteasomal degradation of a mutant form of NAD(P)H:quinone oxidoreductase 1. Mol Pharmacol. 2001 Feb;59(2):263-8. doi: 10.1124/mol.59.2.263.
• Background Fagerholm R, Hofstetter B, Tommiska J, Aaltonen K, Vrtel R, Syrjakoski K, Kallioniemi A, Kilpivaara O, Mannermaa A, Kosma VM, Uusitupa M, Eskelinen M, Kataja V, Aittomaki K, von Smitten K, Heikkila P, Lukas J, Holli K, Bartkova J, Blomqvist C, Bartek J, Nevanlinna H. NAD(P)H:quinone oxidoreductase 1 NQO1*2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer. Nat Genet. 2008 Jul;40(7):844-53. doi: 10.1038/ng.155. Epub 2008 May 30.
• Murphy C, Muscat A, Ashley D, Mukaro V, West L, Liao Y, Chisanga D, Shi W, Collins I, Baron-Hay S, Patil S, Lindeman G, Khasraw M. Tailored NEOadjuvant epirubicin, cyclophosphamide and Nanoparticle Albumin-Bound paclitaxel for breast cancer: The phase II NEONAB trial-Clinical outcomes and molecular determinants of response. PLoS One. 2019 Feb 14;14(2):e0210891. doi: 10.1371/journal.pone.0210891. eCollection 2019.
• Murphy C, Mukaro V, Tobler R, Asher R, Gibbs E, West L, Giuffre B, Baron-Hay S, Khasraw M. Evaluating the role of magnetic resonance imaging post-neoadjuvant therapy for breast cancer in the NEONAB trial. Intern Med J. 2018 Jun;48(6):699-705. doi: 10.1111/imj.13617.

Drugs

Indications