correlative sciences/tumour biology committee … · correlative sciences/tumour biology committee...

Correlative Sciences/Tumour Biology Committee PI = Meyer, Ralph

NCIC CTG – CCSRI 2009 Grant Application Page 729

CORRELATIVE SCIENCES/TUMOUR BIOLOGY COMMITTEE

ABSTRACT Background: In 1997, the NCIC CTG established a Correlative Sciences/Tumour Biology Committee (CSTB) to provide scientific leadership and logistical support for the evolving translational biology program within our trials. Over time, the mandate of the CSTB Committee evolved to not only provide oversight for maintaining the biorepository, but to also coordinate and advise on appropriate correlative studies involving biomarkers in specific cancers and agents being tested across the spectrum of trials from phase I to III. The Tumour/Tissue/Data Repository (TTDR) of the NCIC CTG was established in the Department of Pathology and Molecular Medicine at Queen’s University and operates under the guidance of both the CSTB Committee and an internal TTDR Operational Committee of the Group. Accomplishments of the Past Six Years: The CSTB Committee and executive made up of academic pathologists, clinical and basic scientists, biobankers, statisticians, and Disease Site Committee representatives have led the scientific agenda, establishing the NCIC CTG as one of the world leaders in cancer biomarker research. The commitment of the Group to ensuring continued success is reflected in the recent appointment of a Directory of Laboratory Translational Research, and a Director of Clinical Translational Research. Infrastructure support has resulted in expanded storage and freezing facilities, basic histology resources, tissue microarray capabilities, and the acquisition of analytical equipment such as the Aperio Scanscope, Ventana immunostainer and the Ariol system. A custom Oracle‐based biospecimen tracking system has been internally developed and is harmonized with the clinical database. Statistical and bioinformatics support has been enhanced. Standard Operating Procedures for all aspects of tissue banking have been developed. There has been engagement of the scientific community in Canada and abroad which has resulted in translational biological endpoints being considered for all newly‐developed trials, and a growing number of requests to look at key correlative questions in the context of studies that have been completed. Translational research in many pivotal trials of the Group have resulted in high profile publications and impacted patient management in lung, gastrointestinal, breast and CNS malignancies. Results from integral biological questions such as the role of RAS in non‐small cell lung cancer (BR.10), a host of other potential biomarkers correlating with prognosis and outcome (BR.10, BR.21, BR.24) and a 15 gene signature prognostic for survival (BR.10); studies on Her2 and Topo II – alpha (MA.5) and their impact on responsiveness to anthracycline containing regimens; and definitive evidence that EGFR antibody therapies are only beneficial in KRAS wild type patients (CO.17) are all examples of the Group’s success. Education and mentoring of young clinical investigators, pathologists, and the basic science community has been a focus for the CSTB Committee with successful workshops in proteomics, antiangiogenesis agents, and circulating tumour cells and involvement in national training programs in translational research. Plans and Priorities for the Next Five Years: There are significant challenges facing the biobanking community but tremendous opportunities with the number of new therapeutic agents, potentially important tumour targets, new biomarkers, and evolving technologies to interrogate tissues. The CSTB Committee plans to expand and upgrade our resources and technologies for the next generation of clinical trials, continue biomarker validation studies and the development of hypothesis driven correlative biology questions, continue to collaborate at the national and international level, contribute to methodological advances, and contribute to the education and training of new investigators.



Table 1: Committee Executive Name Province Representation Committee

Membership Start Date

Tsao, Ming‐Sound Ontario Chair, Pathologist 23‐Aug‐06 Banerjee, Diponkar British Columbia Pathologist Bramwell, Vivien Alberta Clinical Scientist 16‐Jan‐03 Chapman, Judy‐Anne Ontario Biostatistician 10‐Mar‐05 Dancey, Janet Ontario Central Office Member 17‐Feb‐09 Matte, Corrine Ontario Lay Representative 22‐Dec‐04 O’Malley, Frances P. Ontario Pathologist Parissenti, Amadeo Ontario Clinical Scientist Pritchard, Kathleen I. Ontario Clinical Scientist Shepherd, Lois Ontario Physician Coordinator Squire, Jeremy Ontario Central Office Member 18‐Jun‐08 Virk, Shakeel Ontario Pathology Coordinator 10‐Sep‐04 Watson, Peter H. British Columbia Pathologist 30‐Oct‐06 Zeltser, Fred Ontario Central Office Tumour Bank Coordinator 10‐Mar‐09 Table 2: Publications and Abstracts, NCIC CTG Tumour/Tissue/Data Repository, by Year 2009 O'Malley FP, Chia S, Tu D, Shepherd LE, Levine MN, Bramwell VH, Andrulis IL, Pritchard KI. Topoisomerase II alpha and responsiveness of breast cancer to adjuvant chemotherapy. J Natl Cancer Inst 101: 644‐50, 2009. Dowsett M, Procter M, McCaskill‐Stevens W, de Azambuja E, Dafni U, Rueschoff J, Jordan B, Dolci S, Abramovitz M, Stoss O, Viale G, Gelber RD, Piccart‐Gebhart M, Leyland‐Jones B. Disease‐free survival according to degree of HER2 amplification for patients treated with adjuvant chemotherapy with or without 1 year of trastuzumab: The HERA Trial. J Clin Oncol 27: 2962‐9, 2009. Au H‐J, Karapetis CS, O'Callaghan CJ, Tu D, Moore MJ, Zalcberg JR, Kennecke H, Shapiro JD, Koski S, Pavlakis N, Charpentier D, Wyld D, Jefford M, Knight GJ, Magoski NM, Brundage MD, Jonker DJ. Health‐related quality of life in patients with advanced colorectal cancer treated with cetuximab: Overall and KRAS‐specific results of the NCIC CTG and AGITG CO.17 trial. J Clin Oncol 27: 1822‐8, 2009. Thiessen B, Stewart C, Tsao M, Kamel‐Reid S, Schaiquevich P, Mason W, Easaw J, Belanger K, Forsyth P, McIntosh L, Eisenhauer E. A phase I/II trial of GW572016 (lapatinib) in recurrent glioblastoma multiforme: clinical outcomes, pharmacokinetics and molecular correlation (ONLINE). Cancer Chemother Pharmacol 2009. Kathy S. Albain, William E. Barlow, Steven Shak, Gabriel N. Hortobagyi, Robert B. Livingston, I‐Tien Yeh, Peter Ravdin, Roberto Bugarini, Frederick L. Baehner, Nancy E. Davidson, George W. Sledge, Eric P. Winer, Clifford Hudis1, James N. Ingle,Edith A. Perez, Kathleen I. Pritchard, Lois Shepherd, Julie R. Gralow, Carl Yoshizawa, D. Craig Allred, C. Kent Osborne, and Daniel F. Hayes for The Breast Cancer Intergroup of North America.



Prognostic and Predictive Value of the 21‐Gene Recurrence Score Assay in Postmenopausal, Node‐Positive, Estrogen Receptor‐Positive Breast Cancer. Lancet Oncology. Accepted. 2009. Parissenti, Amadeo, Chapman, Judy‐Anne, Kahn, Harriette, Guo, Baoqing, Han, Lei, O'Brien, Patti, Clemons, Mark, Jong, Roberta, Dent, Rebecca, Fitzgerald, Barbara, Pritchard, Kathleen, Shepherd,Lois, Trudeau, Maureen. Association of Low Tumour RNA Integrity with Response toChemotherapy in Breast Cancer Patients. Breast Cancer Treatment and Research. Accepted. 2009 2008 French AJ, Sargent DJ, Burgart LJ, Foster NR, Kabat BF, Goldberg R, Shepherd L, Windschitl HE, Thibodeau SN. Prognostic significance of defective mismatch repair and BRAF V600E in patients with colon cancer. Clin Cancer Res 14: 3408‐15, 2008. Karapetis CS, Khambata‐Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au H‐J, Langer C, Moore MJ, Zalcberg JR. K‐ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359: 1757‐65, 2008. Zhu C‐Q, da Cunha Santos G, Ding K, Sakurada A, Cutz J, Liu N, Zhang T, Marrano P, Whitehead M, Squire JA, Kamel‐Reid S, Seymour L, Shepherd FA, Tsao MS. Role of KRAS and EGFR as biomarkers of response to erlotinib in NCIC Clinical Trials Group study BR.21. J Clin Oncol 26: 4268‐75, 2008. Director’s Challenge Consortium for the Molecular Classification of Lung Adenocarcinoma. Gene expression‐based survival prediction in lung adenocarcinoma: A multi‐site, blinded validation study. Nat Med 2008 2008;14(8):822‐7. Laurie SA, Gauthier I, Arnold A, Shepherd FA, Ellis PM, Chen E, Goss G, Powers J, Walsh W, Tu D, Robertson J, Puchalski TA, Seymour L. Phase I and pharmacokinetic study of daily oral AZD2171, an inhibitor of vascular endothelial growth factor tyrosine kinases, in combination with carboplatin and paclitaxel in patients with advanced non‐small cell lung cancer: The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 26: 1871‐8, 2008. 2007 Sève P, Lai R, Ding K, Winton T, Butts C, Mackey J, Dumontet C, Dabbagh L, Aviel‐Ronen S, Seymour L, Whitehead M, Tsao MS, Shepherd F, Reiman T. Class III ß‐tubulin expression and benefit from adjuvant cisplatin/vinorelbine chemotherapy in operable non‐small cell lung cancer: analysis of NCIC JBR.10. Clin Cancer Res 13: 994‐9, 2007. Tsao M‐S, Aviel‐Ronen S, Ding K, Lau D, Liu N, Sakurada A, Whitehead M, Zhu C‐Q, Livingston R, Johnson DH, Rigas J, Seymour L, Winton T, Shepherd FA. Prognostic and predictive importance of p53 and RAS for adjuvant chemotherapy in non‐small‐cell lung cancer. J Clin Oncol 25: 5240‐7, 2007.



2006 Clark GM, Zborowski D, Culbertson JL, Whitehead M, Savoie M, Seymour L, Shepherd FA. Clinical utility of epidermal growth factor receptor expression for selecting patients with advanced non‐small cell lung cancer for treatment with erlotinib. J Thoracic Oncol 1: 837‐46, 2006. Pritchard KI, Shepherd LE, O'Malley FP, Andrulis I, Andrulis IL, Tu D, Bramwell VH, Levine MN. HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med 354: 2103‐11, 2006. Perez EA, Josse RG, Pritchard KI, Ingle JN, Martino S, Findlay BP, Shenkier TN, Tozer RG, Palmer MJ, Shepherd LE, Liu S, Tu D, Goss PE. Effect of letrozole versus placebo on bone mineral density in women with primary breast cancer completing 5 or more years of adjuvant tamoxifen: a companion study to NCIC CTG MA.17. J Clin Oncol 24: 3629‐35, 2006. 2005 Hegi ME, Diserens A‐C, Gorlia T, Hamou M‐F, de Tribolet N, Weller M, Kros JM, Hainfeller JA, Mason W, Mariani L, Bromberg JEC, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R. MGMT gene silencing and benefit form temozolomide in gliobalstoma. N Engl J Med 352: 997‐1003, 2005. Klotz L, Correia A, Zhang W. The relationship between the androgen receptor CAG repeat polymorphism length and the response to intermittent androgen suppression therapy for advanced prostate cancer. Prostate Cancer Prostatic Diseases 8: 179‐83, 2005. Tsao MN, Sakurada A, Cutz J‐C, Zhu C‐Q, Kamel‐Reid S, Squire J, Lorimer I, Zhang T, Liu N, Daneshmand M, Marrano P, da Cunha Santos G, Lagarde A, Richardson F, Seymour L, Whitehead M, Ding K, Pater J, Shepherd FA. Erlotinib in Lung Cancer ‐ Molecular and clinical predictors of outcome. N Engl J Med 353(2): 133‐44, 2005. Wasan KM, Goss PE, Pritchard PH, Shepherd L, Palmer MJ, Liu S, Tu D, Ingle JN, Heath M, DeAngelis D, Perez EA. The influence of letrozole on serum lipid concentrations in postmenopausal women with primary breast cancer who have completed 5 years of adjuvant tamoxifen (NCIC CTG MA.17L). Ann Oncol 16: 707‐15, 2005. Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, Cormier Y, Goss G, Inculet R, Vallieres E, Fry W, Bethume D, Ayoub J, Ding K, Seymour L, Graham B, Tsao M‐S, Gandara D, Kesler K, Demmy T, Shepherd F. Vinorelbine plus cisplatin vs. observation in resected non‐small‐cell lung cancer. N Engl J Med 352: 2589‐97, 2005. 2004 Ma BBY, Oza A, Eisenhauer E, Stanimir G, Carey M, Chapman W, Latta E, Sidhu K, Powers J, Walsh W, Fyles A. The activity of letrozole in patients with advanced or recurrent endometrial cancer and correlation with biological markers ‐ a study of the National Cancer Institute of Canada Clinical Trials Group. Int J Gynecol Cancer 14: 650‐8, 2004.



2003 Bonnefoi H, Diebold‐Berger S, Therasse P, Hamilton A, van de Vijver M, MacGrogan G, Shepherd L, Amaral N, Duval D, Drijkoningen D, Larsimont D, Piccart M. Locally advanced/inflammatory breast cancers treated with intensive epirubicin‐based neoadjuvant chemotherapy: are there molecular markers in the primary tumour that predict for 5‐year clinical outcome? Ann Oncol 14(3): 406‐13, 2003. Ribic C, Sargent DJ, Moore M, Thibodeau SN, French AJ, Goldberg RM, Hamilton SR, Laurent‐Puig P, Gryfe R, Shepherd L, Tu D, Redston M, Gallinger S. Tumour microsatellite‐instability status as a predictor of benefit from fluorouracil‐based adjuvant chemotherapy for colon cancer. N Engl J Med 349(3): 247‐57, 2003. Abstracts 2009 Ali SM, Chapman JA, Lipton A, Leitzel K, Pritchard KI, Pu X, Wilson C, Carney WP, Shepherd L, Pollak M. Examination of TIMP –I Levels and Relapse Free Survival For Patients in NCIC CTG MA.14 Who received Adjuvant Tamoxifen +/‐ Octreotide LAR. SABCS 2009. Ingle J, A genome‐wide association study in patients experiencing musculoskeletal adverse events on aromatase inhibitors as adjuvant therapy in early breast cancer entered on NCIC CTG Trial MA.27. A Pharmacogenetics Research Network‐RIKEN Collaboration. Accepted San Antonio Breast Cancer conference. 2009. Ali SM, Chapman JW, Demers L, Shepherd L, Han L, Wilson C, Pritchard K, Leitzel K, Pollak M, Lipton A. Effect of adjuvant chemotherapy on bone resorption marker beta C‐telopeptide in post‐menopausal women. J Clin Oncol 27[15s], 2009. Bradbury PA, Addison CL, Goss G et al. Baseline TGF‐ and amphiregulin levels in non small cell lung cancer patients treated with erlotinib or placebo in the NCIC Clinical Trials Group BR.21 clinical trial. World Conference on Lung Cancer, 2009. Cheang M, Chia SK, Tu D, Jiang S, Shepherd LE, Pritchard KI, Nielsen TO. Anthracyclines in basal breast cancer: The NCIC‐CTG trial MA5 comparing adjuvant CMF to CEF. J Clin Oncol 27[15s], 2009. Craddock KJ, Buys TPH, Zhu CQ, Strumpf D, Pintillie M, Ding K, Seymour L, Jurisica I, Shepherd FA, Lam WL, Tsao M‐S. High resolution genomic analysis of NSCLC reveals regions of DNA copy number gain that may be predictive of benefit from adjuvant chemotherapy. World Conference on Lung Cancer, 2009. da Cunha Santos G, Ding K, Cutz J‐C, Le Maître A, Squire JA, Shepherd FA, Tsao MS, Seymour L. A novel algorithm for the EGFR fluorescence in situ hybridization (FISH) assay in non‐small cell lung cancer: an analysis of the NCIC Clinical Trials Group Study BR.21. World Conference on Lung Cancer, 2009. Dancey JE. Testing for biomarker driven therapy (ERCC1 and EGFR). World Conference on Lung Cancer, 2009.



Ding K, Shepherd FA, Tsao MS, Le Maître A, Seymour L. P53 IHC protein expression and tumour size predict survival benefit from adjuvant chemotherapy in stage IB non small cell lung cancer patients. BIT's 2nd Annual World Cancer Congress, 2009. Ding K, Nourijelyani K, Twumasi‐Ankrah P. Prognostic and predictive biomarker model building for time to event outcomes. Statistical Society of Canada, 2009. Goss GD, Addison C, Shepherd F, Seymour L, Le Maître A, Ding K. TGF‐alpha and amphiregulin levels in non‐small cell lung cancer patients treated with erlotinib/placebo in the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) BR.21. J Clin Oncol 27[15s], 2009. Jonker DJ, Karapetis C, Harbison C, O'Callaghan CJ, Tu D, Simes RJ, Xu L, Moore MJ, Zalcberg JR, Khambata‐Ford S. High epiregulin gene expression plus K‐ras wild‐type status as predictors of cetuximab benefit in the treatment of advanced colorectal cancer: Results from NCIC CTG CO.17 ‐ A phase III trial of cetuximab versus best supportive care. J Clin Oncol 27[15s], 2009. Lipton A, Chapman JW, Demers L, Shepherd L, Han L, Wilson CF, Pritchard KI, Leitzel K, Ali SM, Pollak M. Elevated bone resorption predicts shorter recurrence‐free survival for bone metastasis in breast cance. The Breast 18[Suppl 1]: S35, 2009. Mackay H, Gallinger S, Tsao M, McLachlin CM, Kieser K, Eisenhauer E, Tu D, Oza A. Microsatellite instability and loss of PTEN expression in early versus late‐stage endometrial cancer: Results from studies of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 27[15s], 2009. Piura E, Chapman JW, Lipton A, Zhu L, Leitzel K, Wilson CF, Pritchard KI, Shepherd L, Pollak MN. Serum 1‐OH vitamin D and prognosis of postmenopausal breast cancer patients: NCIC CTG MA14 trial. J Clin Oncol 27[15s], 2009. Reiman T, Seve P, Veillard A‐S, Soria J‐C, Rosell R, Taron M, Graziano S, Kratzke R, Seymour L, Shepherd F, Pignon J‐P, Lai R. Validation of the prognostic and predictive value of class III beta tubulin for adjuvant chemotherapy in completely resected non‐small cell lung cancer: results from four randomized trials. World Conference on Lung Cancer, 2009. Richardson F, Correlation of E‐cadherin and Vimentin IHC status with clinical Outcomes to Erlotinib in the Non Small Cell Lung Cancer (NSCLC) Clinical trial NCIC CTG BR.21. World Conference on Lung Cancer, 2009. Stadler WM, Lerner SP, Groshen S, Stein JP, Skinner DG, Raghavan D, Steinberg GD, Wood D, Klotz LH, Hall C, Cote R. Randomized trial of p53 targeted adjuvant therapy for patients with organ‐confined node‐negative urothelial bladder cancer. J Clin Oncol 27[15s], 2009. Strevel EL, Ding K, Seymour L, Tsao MS, Le Maître A, Shepherd FA, Burkes RL. Pathologic determinants of survival for adjuvant treatment of stage IB non‐small cell lung cancer: An analysis of the National Cancer Institute of Canada and Intergroup Study JBR.10. World Conference on Lung Cancer, 2009.


NCIC CTG – CCSRI 2009 Grant Application 35

Tsao M‐S, Sakurada A, Aviel‐Ronen S, Ding K, Liu N, Gandara DR, Johnson DH, Rigas JR, Seymour L, Shepherd FA. Impact of EGFR tyrosine kinase domain mutations on adjuvant chemotherapy in early stage non‐small cell lung cancer. World Conference on Lung Cancer, 2009. Graziano for the LACE‐Bio group: Cross Validation analysis of the prognostic significance of mucin expression in patients with resected non‐small cell lung cancer (NSCLC) treated with adjuvant chemotherapy: results from IALT, JBR10, and ANITA. World Conference on Lung Cancer, 2009. 2008 Bartlett JMS, Desmedt C, Munro A, O'Malley FP, Larsimont D, di Leo A, Cameron DA, Isola J, Shepherd L, Twelves CJ, Pritchard KI. Chromosome 17 polysomy: a unifying hypothesis underlying benefit from adjuvant anthracyclines? Cancer Research 69[Suppl 2], 375s, 2008. Burnell MJ, O'Connor EM, Chapman JW, Levine MN, Pritchard KI, O'Brien PS, Howarth KJ, Ding Z, Whelan TJ, Shepherd LE. Triple negative receptor status and prognosis in the NCIC CTG MA.21 adjuvant breast cancer trial. Proc.Am.Soc.Clin.Oncol. 26[15S Part I], 18s, 2008. Karapetis CS, Khambata‐Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Langer C, Moore MJ, Zalcberg JR. KRAS mutation status is a predictive biomarker for cetuximab benefit in the treatment of advanced colorectal cancer ‐ results from NCIC CTG CO.17: A phase III trial of cetuximab versus best supportive care. World Congress on Gastrointestinal Cancer, 2008. Lipton A, Chapman JW, Demers L, Shepherd L, Han L, Wilson CF, Pritchard KI, Leitzel K, Ali SM, Pollak M. Use of elevated bone turnover predicts for bone metastasis. Proc.Am.Soc.Clin.Oncol. 26[15S Part 1], 28s, 2008. Parissenti AM, Chapman J‐AW, Kahn HJ, Guo B, Han L, O'Brien P, Clemons MP, Jong R, Dent R, Fitzgerald B, Pritchard KI, Shepherd LE, Trudeau ME. Reductions in tumour RNA integrity associated with clinical response to epirubicin/docetaxel chemotherapy in breast cancer patients. Cancer Research 69[Suppl 2], 378s, 2008. Pollak MN, Chapman JW, Pritchard KI, Krook JE, Dhaliwal HS, Vandenberg TA, Norris BD, Whelan TJ, Wilson CF, Shepherd LE. NCIC CTG MA14 trial: Tamoxifen (tam) vs. tam + octreotide (oct) for adjuvant treatment of stage I or II postmenopausal breast cancer. Proc.Am.Soc.Clin.Oncol. 26[15S Part 1], 14s, 2008. Reiman T, Seve P, Vataire A, Dunant A, Rosell R, Graziano S, Seymour L, Pirker R, Lai R. Prognostic value of class III b‐tubulin in operable non‐small cell lung cancer and predictive value for adjuvant cisplatin‐based chemotherapy: A validation study on three randomized trials. Proc.Am.Soc.Clin.Oncol. 26[15S Part I], 398s, 2008. Schell AJ, Young I, Hansen C, Chi KN, Taylor S. BRAF mutation status and growth factor receptor expression do not predict baseline factors or outcome in hormone refractory prostate carcinoma. United States and Canadian Academy of Pathology, 2008.



Tsao MS, Zhu C, Ding K, Strumpf D, Pintilie M, Meyerson M, Seymour L, Jurisica I, Shepherd FA. A 15‐gene expression signature prognostic for survival and predictive for adjuvant chemotherapy benefit in JBR.10 patients. Proc.Am.Soc.Clin.Oncol. 26[15S Part I], 399s, 2008. 2007 Albain K, Barlow W, Shak S, Hortobagyi G, Livingston R, Yeh I, Ravdin P, Yoshizawa C, Baehner F, Davidson N, Sledge G, Winer E, Hudis C, Ingle J, Perez E, Pritchard K, Shepherd L, Allred C, Osborne K, Hayes D. Prognostic and predictive value of the 21‐gene recurrence score assay in postmenopausal, node‐positive, ER‐positive breast cancer (S8814,INT0100). Breast Cancer Research and Treatment 106[Suppl 1], 2007. Markovich Y, Virk S, Tsao M, Shepherd L. The NCIC CTG tumour/tissue/data repository, a Canadian resource: How have we been doing? Making Connections: A Canadian Cancer Research Conference Celebrating NCIC's 60th Anniversary, 84, 2007. Moore MJ, da Cunha Santos G, Kamel‐Reid S, Chin K, Tu D, Parulekar W, Ludkovski O, Squire J, Richardson F, Tsao M. The relationship of K‐ras mutations and EGFR gene copy number to outcome in patients treated with erlotinib on NCIC Clinical Trials Group trial study PA.3. Proc.Am.Soc.Clin.Oncol. 25[18s Part 1], 2007. Parissenti AM, Chapman JW, Kahn HJ, Guo B, O'Brien P, Han L, Clemons M, Jong R, Pritchard KI, Shepherd L, Trudeau ME. Relationship of tumour RNA integrity to clinicopathologic parameters associated with epirubicin/docetaxel chemotherapy. Making Connections: A Canadian Cancer Research Conference Celebrating NCIC's 60th Anniversary, 203‐204, 2007. Schacter B, Geary P, Ling V, Mes‐Masson A‐M, Sawyer M, Shepherd L, Watson P, Zanke B. Canadian tumour repository network facilitating translational cancer research through a national tumour bank network. Making Connections: A Canadian Cancer Research Conference Celebrating NCIC's 60th Anniversary, 79‐80, 2007. Shepherd FA, Ding K, Sakurada A, da Cunha Santos G, Zhu C, Seymour L, Whitehead M, Kamel‐Reid S, Squire J, Tsao MS. Updated molecular analyses of exons 19 and 21 of the epidermal growth factor receptor gene and codons 12 and 13 of the KRAS gene in non‐small cell lung cancer patients treated with erlotinib in NCIC Clinical Trials Group BR.21. Proc.Am.Soc.Clin.Oncol. 25[18s Part 1], 2007. Tsao M. Predictors of benefit from targeted therapy: lessons learned from the EGFR inhibitor story. Making Connections: A Canadian Cancer Research Conference Celebrating NCIC's 60th Anniversary, 17, 2007. Tsao MS, Lau S, Boutros P, Pintilie M, Zhu C‐Q, Strumpf D, Penn L, Jurisica I, Shepherd FA. Gene expression prognostic classifiers for early stage non‐small cell lung cancer. Making Connections: A Canadian Cancer Research Conference Celebrating NCIC's 60th Anniversary , 98, 2007. Tsao MS, Aviel‐Ronen S, Ding K, Lau D, Liu N, Whitehead M, Seymour L, Winton T, Shepherd FA. P53 protein over‐expression but not p53 gene mutation is a poor prognostic marker and a predictive marker for survival benefit from adjuvant chemotherapy in non‐small cell lung cancer in the JBR.10 trial. Proc.Am.Soc.Clin.Oncol. 25[18s Part 1], 2007.



2006 Dos Santos N, Chapman J, Andrews H, Meng D, Shepherd L, Pollak M, Li D, Wilson C, Dunn S. Urokinase plasminogen activator is a serum marker for breast cancer recurrence: a nested case‐control pilot study by the NCIC Clinical Trials Group. Breast Cancer Research and Treatment 100[Suppl 1], 2006. O'Malley FP, Chia S, Tu D, Shepherd LE, Levine MN, Huntsman DG, Bramwell VH, Andrulis I, Pritchard KI. Topoisomerase II alpha protein overexpression has predictive utility in a randomized trial comparing CMF to CEF in premenopausal women with node positive breast cancer (NCIC CTG MA.5). Breast Cancer Research and Treatment 100[Suppl 1],S18, 2006. O'Malley FP, Chia S, Tu D, Shepherd LE, Levine MN, Huntsman DG, Bramwell VH, Andrulis IL, Pritchard KI. Prognostic and predictive value of topoisomerase II alpha in a randomized trial comparing CMF to CEF in premenopausal women with node positive breast cancer (NCIC CTG MA.5). Proc.Am.Soc.Clin.Oncol. 24[18S Part 1], 11, 2006. Oza AM, Elit L, Biagi J, Chapman W, Tsao M, Hedley D, Hansen C, Dancey J, Eisenhauer E. Molecular correlates associated with a phase II study of temsirolimus (CCI‐779) in patients with metastatic or recurrent endometrial cancer ‐‐ NCIC IND 160. Proc.Am.Soc.Clin.Oncol. 24[18S Part 1], 121, 2006. Pollak M, Chapman JW, Shepherd L, Meng D, Richardson P, Wilson C, Orme B, Pritchard KI. Insulin resistance, estimated by serum C‐peptide level, is associated with reduced event‐free survival for post menopausal women in NCIC CTG MA.14 adjuvant breast cancer trial. Proc.Am.Soc.Clin.Oncol. 24[18S Part 1], 9, 2006. Reiman T, Lai R, Ding K, Winton T, Butts C, Mackey J, Dabbagh L, Seymour L, Tsao M, Shepherd F, Seve P. Class III beta tubulin expression and benefit from adjuvant cisplatin/vinorelbine chemotherapy in operable non‐small cell lung cancer: Analysis of the NCIC Clinical Trials Group study JBR.10. Proc.Am.Soc.Clin.Oncol. 24[18S Part 1], 376, 2006. Tsao M, Zhu C, Sakurada A, Zhang T, Whitehead M, Kamel‐Reid S, Ding K, Seymour L, Shepherd F. An analysis of the prognostic and predictive importance of K‐ras mutation status in the NCIC Clinical Trials Group BR.21 study of erlotinib versus placebo in the treatment of non‐small cell lung cancer. Proc.Am.Soc.Clin.Oncol. 24[18S Part 1], 365, 2006. 2005 Gauthier I, Seymour L. Target effect and predictors of efficacy using laboratory correlative studies in early clinical trials: The Investigational New Drug Program at the NCIC Clinical Trials Group perspective. CIHR/NCIC National Meeting for Trainees, 2005. Green JA, Duffaud F, Coens C, Laframboise S, Vergote I, Eisenhauer E, Bacon M, Chapman W, van der Burg ME, Oza A. Prognostic value of clinical and molecular markers in advanced ovarian cancer: importance of residual disease. Translational study using tumour specimens from EORTC 55931/NCIC OV10 phase III randomized clinical trial. Proc.Am.Soc.Clin.Oncol. 23[16S Part], 456s, 2005.



Kovacs M, Chapman J‐A.W, Shepherd L, Meyer R, Keeney M, MacKinnon K, Stewart K, Paul N. The NCIC CTG Investigators on MY.10. Maintenance therapy with thalidomide/prednisone post autologous stem‐cell transplant for patients with multiple myeloma elevates d‐dimer and possibly factor VIII levels. Blood 106[11(suppl 1)], 720a, 2005. Tsao MS, Sakurada A, Lorimer I, Cutz J, Kamel‐Reid S, Squire J, Ding K, Frank R, Seymour L, Shepherd F. Molecular analysis of the epidermal growth factor receptor gene and protein expression in patients treated with erlotinib in NCIC Clinical Trials Group trial BR.21. Proc.Am.Soc.Clin.Oncol. 23[16S Part 1], 622s, 2005. 2004 Hegi ME, Diserens A‐C, Hamou M‐F, Gorlia T, Weller M, Kros JM, Hainfeller J, Bogdahn U, Cairncross G, Stupp R. Temozolomide targets only glioblastoma with a silenced MGMT‐gene. Results of a translational companion study to EORTC 26981/NCIC CE.3 of Radiotherapy ± TMZ. Eur J Can Supplements 2[8], 14, 2004. Sloan JA, McLeod H, Sargent D, Zhao X, Fuchs C, Ramanathan RK, Williamson S, Findlay B, Morton R, Goldberg RM. Preliminary evidence of relationship between genetic markers and oncology patient quality of life. Proc.Am.Soc.Clin.Oncol. 23, 2, 2004. 2003 Shepherd L, Sadura A, Pritchard K, Feener T. A tumour/tissue/data bank for the Breast Disease Site Committee of the NCIC Clinical Trials Group. How have we been doing? Reasons for Hope Conference, 2003. Shepherd L, Sadura A, Feener T. Compliance with central pathology review and tumour block submission in a national cooperative clinical trials group: The NCIC CTG experience. Controlled Clin.Trials 24(3S), 230S, 2003.



1.0 Background

1.1 History, Scope and Mandate of Program The Correlative Sciences and Tumour Biology/Banking Committee (CSTB) mandate is to provide the scientific leadership and logistical support in biospecimen collection/banking for NCIC CTG translational research activities that will further our understanding of cancer biology and lead to optimal individual patient treatment. The Committee’s mandate encompasses the spectrum of NCIC CTG trials from phase I to phase III studies in the prevention, adjuvant, and advanced disease settings. The CSTB Committee was established in 1997 with members including pathology, clinical, and basic sciences experts interested in addressing correlative science/translational research questions in clinical trials. The CSTB Committee and its members have led the scientific agenda that established NCIC CTG as one of the world leaders in the area of therapeutic/predictive cancer biomarkers research. To facilitate the Committee’s mandate, the Tumour/Tissue/Data Repository (TTDR) was established in the Department of Pathology and Molecular Medicine at Queen’s University. The TTDR currently processes, stores and distributes formalin fixed paraffin embedded (FFPE) tumours, normal tissue, whole blood, plasma, serum, and urine samples that are collected from trial centres worldwide participating in NCIC CTG‐led or North American intergroup trials. More recently, with correlative sciences and biomarker research assuming increasingly greater importance in oncology clinical trials, the CSTB Committee’s strategic priorities have expanded from addressing the ongoing practical issues in sample collection and biorepositories to shaping the scientific agenda of NCIC CTG‐led trials.

1.2 Strategic Priorities of the Past Six Years The Committee’s strategic goals and activities over the last six years have focused on building intellectual, technological and resource capacity, developing and implementing “best practice” standards for biospecimen collection, storage and analysis, conducting high quality translational and correlative study research, and enhancing education and training in biomarker and clinical translational research. Priorities included: 1. The engagement of the pathology, basic and translational scientific community to enable

translational research within clinical trials; 2. The enhancement of the infrastructure and resources to support biospecimen collection and

correlative research; 3. The development of thematic approaches to translational and correlative study research initiatives

within and across Disease Site Committees; 4. The ability to respond to new technologies and contribute to methodological advances in clinical

translational research; and, 5. The provision of education, training, and mentoring.

1.3 Structure and Interactions with NCIC CTG

The CSTB Committee has the following key components: CSTB Committee Executive, CSTB Committee with its Disease Site Committee liaisons, the Central Office staff, the TTDR Operational Committee, and associated biorepository personnel.



The Committee Chair is Dr. Ming Sound Tsao, a senior scientist and surgical pathologist at the Ontario Cancer Institute/Princess Margaret Hospital, with specialized interest in lung and pancreatic pathobiology. The co‐chair is Dr. Lois Shepherd, a hematopathologist and NCIC CTG Physician Coordinator and the TTDR Director. The CSTB Executive Committee is selected from the CSTB Committee members with in‐depth expertise in the science and technologies that are used in translational and biomarker research on clinical samples and representing the diverse clinical/scientific specialties, Central Office personnel, and a lay representative. The Executive interacts with the TTDR and Translational Research Central Office staff on tumour banking and translational research prioritization and strategic directions. The Committee membership is made up of academic pathologists from across Canada with different disease site expertise, clinical and basic scientists conducting translational and biomarker research, clinical research associates who are responsible for coordinating requests for tissue at trial centres, all Disease Site Chairs or designates, Canadian Institutional biobankers, NCIC CTG Central Office biostatisticians responsible for conducting correlative data analyses, TTDR personnel and a lay representative. The CSTB Committee’s tasks include developing policies, procedures, and strategic directions for NCIC CTG correlative science/translational research projects. The committee meets twice yearly to review ongoing trials and discuss new correlative study proposals and initiatives. The policies and strategic direction that are developed by the CSTB Committee are implemented during the planning and performance of biomarker studies on NCIC CTG‐led trials by the Disease Site Correlative Science Review Subcommittees and Working Groups, which have been formed within each of the major Disease Site Committees. Membership of the Subcommittees and Working Groups is overlapping, with the Subcommittees chaired by the Central Office Physician Coordinator for the disease site and the Working Groups chaired by an external clinical scientist. Members of these Disease specific Subcommittees/Working Groups are usually also CSTB Committee members. The Working Groups advise, plan, or review the translational/correlative studies proposed for individual trials, while the Review Subcommittee review and approve external applications for correlative science projects utilizing banked trial samples. The Central Office staff include Dr. Lois Shepherd who is the TTDR Operational Director. Dr. Shepherd leads the activities directly related to the tissue repository. During the last two years, the group has recruited a Director of Laboratory Translational Research, Dr. Jeremy Squire, and a Director of Clinical Translational Research, Dr. Janet Dancey, to provide additional leadership roles in shaping the strategic direction of the CSTB Committee to achieve its mandate. Dr. Squire liaises with national translational researchers and advises, coordinates, and facilitates the development of laboratory studies and assays used on clinical trial specimens. Dr. Dancey liaises with the clinical trial translational researchers and advises, coordinates and develops research activities and proposals relevant to clinical trial interventions. Roles and responsibilities are synergistic between Dr. Shepherd who directs activities related to the optimal collection, storage and distribution of specimens, Dr. Dancey who coordinates the identification of relevant biomarkers for evaluation for a particular therapeutic, and Dr Squire who provides expertise and coordinates activities to identify expert researchers, laboratory settings and appropriateness of assays for evaluating biomarkers within and across trials and translational research proposals. An overview of the various relationships within the CSTB Committee is presented in Figure 1.



Figure 1: Relationships of the External Scientific Community and the Central Office with the Correlative Sciences/ Tumour Biology Committee

Correlative Sciences/Tumour BiologyTumour/Tissue/Data Repository

Correlative Science & Tumour Biology Committee (CSTB)

OperationalCommittee

Tumour/Tissue/Data Repository (TTDR)

Disease Site Committees

CSTB Working Group

Correlative Science Review Committees

Internal Central OfficeEthics/Regulatory

Data Management/Operational

ExternalScientific Agenda

The TTDR Operational Committee and personnel are Central Office staff that coordinate the NCIC CTG tissue banking activities. The Operational Committee is populated by the Director of the TTDR, the TTDR Pathology Coordinator, the TTDR Study Coordinator, representatives from the IND Program, the Ethics and Regulatory Office, and the Biostatistics and Programming teams. This Committee establishes and reviews policies, procedures, and templates related to the tissue banking activities, informed consent process, letters of agreement or contracts with investigators for research projects, the database linkages between TTDR and clinical data sets, and the external and internal website for correlative science and tissue banking. It also assists in the activities of the CS Disease Site Subcommittees/Working Groups and coordinates requests for access to material. Standard operating procedures for all aspects of tissue banking have been developed in compliance with current NCI Best Practices for Biospecimen Resources, the Canadian Tumour Repository Network (CTRNet), and recommendations of the International Society for Biological and Environmental Repositories (ISBER). Informed consent templates are regularly reviewed and updated to conform to national and international standards. TTDR personnel, infrastructure, processes, and communications are described in Section 4.0 of this application. . TTDR

1.4 Key Collaborations The CSTB Committee membership is structured to enable interactions between key groups within the NCIC CTG and with national and international researchers and research organizations. Representative expertise ensures coverage of the translational research spectrum from laboratory to clinic. CSTB Committee members are cross‐appointed to the Investigational New Drug, and Disease Site Committees. These cross‐appointments ensure that the CSTB Committee is aware of disease specific



research interests, enables the CSTB Committee to input and participate in individual trial proposals, and ensures that the CSTB Committee cross‐cutting research initiatives are efficiently communicated. National and international collaborations are essential for the success of trials and trial‐related correlative studies. With an expanding number of molecular targeted therapies, an increasingly sophisticated disease categorization combined with the rapidly evolving science and technology, collaborations are required for timely accrual and trial completion and for identifying and answering the best scientific questions utilizing the most current technologies. The NCIC CTG actively participates in US cooperative group clinical trials, translational research, and banking activities. We have participated in the protocol‐mandated specimen collection and translational research activities on intergroup trials in breast, lung, haematological and gastrointestinal malignancies. More recently as the coordinating group of large North American intergroup trials, we have been responsible for leading the development of the translational research studies for these protocols and for collecting and maintaining the tissue banks associated with these trials (NCIC CTG MA.17, MA.27, BR.19). The success of our collaborations with the US cooperative groups has been noteworthy. We are active in US NCI initiatives, including the recently established Disease Site Intergroup Correlative Science Committees. Dr. Dancey is a member of the CTEP Investigational Drug Steering Committee, Chair of its Biomarker Task Force and member of the Cancer Diagnosis Program for the Assessment of Clinical Cancer Tests (PACCT). Breast DSC members, Drs. K. Pritchard, J.A. Chapman and others have been active participants in the scientific review of proposals submitted to the Breast Cancer Intergroup Correlative Science Committee for samples collected on intergroup studies and played key roles in the development of international guidelines for the collection of fresh frozen tissue, FFPE, and blood in breast cancer. Drs. Ming Tsao and Frances Shepherd represent NCIC CTG on the Lung Intergroup Correlative Science Committee, which reviews correlative science projects involving biospecimens from North American intergroup trials. Selected samples from the BR.10 snap‐frozen tumour samples have also been provided to the Director’s Challenge Consortium for the Molecular Classification of Lung Adenocarcinoma. NCIC CTG (PI: Dr. Geoffrey Liu) is leading the pharmacogenomic study for the intergroup study N0723 (NCIC CTG BRC.4) “Phase III Biomarker Validation Study of Second‐Line Therapy in Patients with Advanced Non‐Small Cell Lung Cancer (NSCLC) Randomized to Pemetrexed Versus Erlotinib”. Members have participated in several US NCI State of the Science meetings including those focused on gastrointestinal, ovarian, lung and brain cancer. In spite of the unavailability of funding from the US for our intergroup banking activities, we believe it is important to maintain our involvement in the development of policies and procedures associated with the Cooperative Group Banks as we continue to participate in, and lead intergroup trials. We are one of the 10 active and voting members of the Group Banking Committee of the US NCI, are members of the Steering Committee, and have representation on four subcommittees addressing Best Practices, Ethics and Regulatory, Access and Marketing, and Informatics. There are also a number of networks and initiatives in Canada with which the CSTB Committee has developed ongoing relationships or partnerships. These have included amongst others, CTRNet funded by the Canadian Institutes of Health Research (CIHR), the Princess Margaret Hospital (PMH) Consortium for phase I/II developmental studies funded by NIH, the Advanced Molecular Profiling Laboratory (AMPL) at PMH, developmental phase I/II programs at McGill, the Genetic Pathology Evaluation Centre (GPEC) and the Centre for Translational and Applied Genetics (CTAG) laboratories at



the British Columbia Cancer Agency, the Ontario Translational Research Network (OTRN) and Ontario Biomarker Research Network (OBRN) funded by the Ontario Government. These networks provide expertise, support and research capabilities which can be used by the CSTB Committee and TTDR directly or for specific investigator‐initiated projects using material and clinical data collected on NCIC CTG studies. CTRNet has been particularly active in developing standard operating procedures for tissue banks that are being reviewed throughout the international community. Representatives of the TTDR have been instrumental in this process.

2.0 Accomplishments 2003‐2009

To date, more than 70 phase III trials and 44 IND trials have incorporated translational research questions or biospecimen collections. Protocol associated research and additional use of banked specimens has led to 21 publications and 53 abstracts/presentations with findings that have resulted in changes in clinical practice. At present the TTDR houses more than 12,500 individual patient cases with tumour blocks, 2500 cases with slides alone, and in many cases accompanying normal tissue. Frozen serum/plasma or whole blood is available from more than 10,000 cases from over 20 trials. The preparation and release of samples to the research community has increased from two‐four trials per year to the current situation where the biorespository personnel are preparing and sending out material on 10‐15 trials at any one time. This reflects a growing awareness of the resources and potential of the bank, and the number of requests for access to material. More than 20 peer review funded grants have been obtained to carry out this work. Our accomplishments based on our strategic directions have been as follows: 1. Engage the pathology, basic, translational and clinical scientific community to enable

translational research within clinical trials. Strong translational research within clinical trials requires collaboration across scientific and clinical disciplines over a period of years. Over the last six years, the CSTB Committee has expanded its membership and activities to ensure correlative studies within trials benefit from the expertise of scientists, pathologists, biostatisticians, and clinicians. This has been accomplished by forming within Disease Site Committees, Working Groups and Subcommittees. The correlative science working groups advises on the relevant biological studies for new trials being developed. It considers the state of science, technology, the specimens to be collected and the laboratory analytical and biostatistical methods of analysis. At the completion of a trial, the translational research hypothesis and proposed biomarker studies may be re‐evaluated based on the current state of science and technology, the numbers and types of specimens successfully acquired and banked. At the completion of the protocol‐specified correlative studies, results are disseminated and samples are then made available for additional or new research initiatives submitted by Group or independent investigators to the relevant Correlative Science Working Group/Subcommittees. This broad engagement of the pathology, clinical and basic science community ensures high quality translational research questions are posed within clinical trials, facilitates tissue sample acquisition, and ensures that the research potential of clinical trial associated material is realized.



2. Enhance the infrastructure and resources to support biospecimen collection and correlative research.

As interest in conducting translational research in trials has increased, issues related to specimen management, regulations, ethics, and logistics have had to be addressed (Section 4.0 of this grant application). Additional activities include the development of standardized operating procedures (SOPs), a network of correlative cancer biology expert researchers and specialized laboratories, and enhanced biostatistical and bioinformatics support. The CSTB Committee and TTDR have SOPs for the collection, preparation and storage of biological materials that are regularly reviewed to ensure compliance with national and international guidelines. SOPs have also been developed for the access and release of trial materials, ensuring that contractual, regulatory and ethical standards are being met. The multidisciplinary membership of the CSTB Committee has led to a network of laboratories with specialized technologies across the country and an inventory of leaders in cancer research with unique expertise to conduct biomarker research. Enhancement of the NCIC CTG biostatistical and bioinformatics support needed for the design, execution, and analysis of correlative research questions has been accomplished through the recent hire of a fourth group biostatistician (Dr. B.Chen) and an expert in bioinformatics (Dr. Paulo Nuin). Infrastructure support has included increased storage and freezer facilities, upgrading of tissue microarray (TMA) capabilities, creation of digital images of bank specimens for external review of pathology, expansion of functionality and capabilities of the database, and acquisition of analytic equipment such as Aperio Scanscope, laser capture microscopy, Ventana Immunostainer and the Ariol System (Dr. Squire’s laboratory). An ongoing relationship with the Queen’s Laboratory for Molecular Pathology is important for the sharing of both expertise and equipment. 3. Develop and execute biospecimen‐based correlative studies within clinical trials and develop

thematic approaches to research initiatives within and across Disease Site Committees. Most phase III and IND trials undertaken or planned since the last review have incorporated translational/biomarker research questions. In addition, the group has developed translational research initiatives that allowed the evaluation of specific markers across trials within and between disease settings. Examples of thematic research initiatives include the assessment of HER2 and topoisomerase expression in breast cancer studies, evaluation of intrinsic biologic subtypes across breast cancer trials, EGFR pathway markers in EGFR inhibitors trials in lung, pancreatic and gastrointestinal malignancies, pharmacogenetics to assess host factors related to response, adverse events, quality of life, and the insulin growth factor pathway in breast and prostate. NCIC CTG specimen collections and translational research in several of its pivotal trials have led to a number of high profile publications on prognostic and predictive biomarkers for targeted therapies in breast, lung, gastrointestinal, and CNS cancers. These hypothesis‐driven correlative studies exemplify effective application of biomarker research by CSTB Committee members, as well as the close interdisciplinary collaboration involved in these important studies. The results of several such representative studies involving samples collected from phase III trials led by the NCIC CTG, trials to which NCIC CTG provided significant contributions and early clinical trials conducted by the IND Programs are described below. Other successful studies are described in the Disease Site Committee



and IND sections of this application. Table 3 provides an overall summary of this work for the Phase III Program.

Table 3: Overview of Correlative Science Initiatives on Phase III Group Trials: 2003‐2009

LUNG

Proposal Tumour Type

Laboratory Studies

Tissue Status Publication/Abstracts

A PHASE III PROSPECTIVE RANDOMIZED STUDY OF ADJUVANT CHEMOTHERAPY WITH VINORELBINE AND CISPLATIN IN COMPLETELY RESECTED NON‐SMALL CELL LUNG CANCER WITH COMPANION TUMOUR MARKER EVALUATION (BR.10)

Evaluation of prognostic and predictive tumour markers in the BR.10 trial

NSCLC Integral: RAS Integrated: p53, EGRF, p27,Kip1, BCL2

Fresh Frozen Paraffin Embedded TMA

C Director’s Challenge Consortium, Nat Med 2008 Winton, NEJM 2005 Tsao, JCO 2007 Butts, JCO 2009 Tsao, 2007 (Abs)

To determine a gene signature prognostic for survival and predictive for adjuvant chemotherapy benefit

NSCLC Gene expression profiling

Fresh Frozen Paraffin Embedded

C Tsao, ASCO 2008 (Abs)

Beta Tubulin III immunohistochemistry as a predictor of benefit from adjuvant vinorelbine and cisplatin chemotherapy in early stage non‐small cell lung cancer (NSCLC) in the NCIC CTG BR.10 clinical trial

NSCLC Beta tubulin III Paraffin Embedded TMA

C Seve, Clin Cancer Res 2007 Reiman, ASCO 2006 (Abs) Reiman, ASCO 2008 (Abs) Reiman, World Conference on Lung Cancer 2009 (Abs)

ERCC1 and expression and benefit of cisplatin‐based adjuvant chemotherapy in resected NSCLC

NSCLC ERCC1 Paraffin Embedded TMA

C PA

A PHASE II/III DOUBLE BLIND RANDOMIZED TRIAL OF BMS‐275291 VERSUS PLACEBO IN PATIENTS RECEIVING PACLITAXEL/CARBOPLATIN CHEMOTHERAPY FOR THE TREATMENT OF ADVANCED OR METASTATIC NON‐SMALL CELL LUNG CANCER. (BR.18)

Investigation of estrogen receptor and epidermal growth factor pathways and possible cross‐talk in human lung cancer

NSCLC ER, EGFR & pathways

Paraffin Embedded TMA

C PA

A PHASE III PROSPECTIVE RANDOMIZED, DOUBLE‐BLIND,PLACEBO‐CONTROLLED TRIAL OF THE EPIDERMAL GROWTH FACTOR RECEPTOR ANTAGONIST, ZD1839 (IRESSA) IN COMPLETELY RESECTED PRIMARY STAGE IB, II AND IIIA NON‐SMALL CELL LUNG CANCER (BR.19)

Molecular predictors of outcome in BR.19, a phase III trial of adjuvant gefitinib in post‐resection, early stage non‐small cell lung cancer

NSCLC Integrated: EGFR protein expression Gene copy number EGFR, ras mutation pAKT, amphiregulin, TGF‐alpha


O



Proposal

Tumour Type

Laboratory Studies Tissue Status Publication/Abstracts

A RANDOMIZED PLACEBO CONTROLLED STUDY OF OSI‐774 (TARCEVATM) IN PATIENTS WITH INCURABLE STAGE IIIB/IV NON‐SMALL CELL LUNG CANCER WHO HAVE FAILED STANDARD THERAPY FOR ADVANCED OR METASTATIC DISEASE (BR.21)

EGFR mutations as a marker of response to EGFR inhibitor treatment in lung cancer

NSCLC Integrated: EGFR expression EGFR gene copy number EGFR mutations

Paraffin Embedded

C Tsao, NEJM 2005 Tsao, ASCO 2006 (Abs) Shepherd, ASCO 2007 (Abs) Tsao, World Conference on Lung Cancer 2009 (Abs)

Prognostic and Predictive Importance of K‐RAS mutation status in BR.21

NSCLC K‐RAS Paraffin Embedded

C Tsao, ASCO 2006 (Abs)

Correlation of E‐cadherin and Vimentin using IHC with clinical outcomes in BR.21

NSCLC E‐cadherin Vimentin

Paraffin Embedded

C Richardson F, World Conference on Lung Cancer 2009 (Abs)

To develop an algorithm for the EGFR fluorescence in situ hybridization (FISH) assay using BR.21 results

NSCLC EGFR gene copy number

Paraffin Embedded

C Da Cunha Santos, World Conference on Lung Cancer 2009 (Abs)

Plasma Proteomic predictors of response to Erlotinib

NSCLC Proteomic signature Plasma O

A PHASE II/III DOUBLE BLIND RANDOMIZED TRIAL OF AZD2171 VERSUS PLACEBO IN PATIENTS RECEIVING PACLITAXEL/CARBOPLATIN CHEMOTHERAPY FOR THE TREATMENT OF ADVANCED OR METASTATIC NON‐SMALL CELL LUNG CANCER (BR.21/BR.24)

Evaluation of levels of EGFR group 1 ligands and their correlation with response to OSI‐774 (Tarceva) in patients with Non‐small cell lung cancer

NSCLC EGFR Group 1 Ligands: TGF‐alpha amphiregulin

Serum BR.21 C BR.24 O

Goss, ASCO 2009 (Abs)

BREAST

COOPERATIVE CLINICAL TRIAL OF INTENSIVE CEF VERSUS STANDARD CMF AS ADJUVANT THERAPY FOR BREAST CARCINOMA IN PREMENOPAUSAL PATIENTS WITH HISTOLOGICALLY INVOLVED AXILLARY NODES (MA.5)

To look at Her 2/neu and Topo II‐alpha as markers of prognosis in breast cancer and as predictors of sensitivity to anthracycline containing chemotherapy

Invasive Breast Cancer Stage II/III

Her 2/neu and Topo II‐alpha gene and protein expression

Paraffin Embedded DNA TMA

C Pritchard, NEJM 2006 O’Malley, JNCI 2009 O’Malley, ASCO 2006 (Abs)

Basal‐like breast cancer defined by a 5 marker panel predicts poor response to anthracycline‐based chemotherapy


ER, PgR, Her2, CK 5/6, EGFR Immunohistochemistry


C Cheang, ASCO 2009 (Abs)

To look at the predictive value of breast cancer intrinsic biological classification in MA.5 by quantitative RT‐PCR (PAM50)


50 gene expression profile

Paraffin Embedded

C PA



Proposal Tumour Type Laboratory Studies Tissue Status Publication/Abstracts

Predictive and prognostic value of TIMP‐1 expression in tumours from patients in MA.5


TIMP‐1 and Topo ll alpha protein expression


C PA

A pooled analysis to look at chromosome 17 polysomy and the benefit with anthracycline containing chemotherapy regimens


Chromosome 17 polysomy using FISH


C

Bartlett, SABCS 2008 (Abs)

PHASE III COMPARISON OF ADJUVANT CHEMOENDOCRINE THERAPY WITH CAF AND CONCURRENT OR DELAYED TAMOXIFEN TO TAMOXIFEN ALONE IN POSTMENOPAUSAL PATIENTS WITH INVOLVED AXILLARY LYMPH NODES AND POSITIVE RECEPTORS (MA.9)

21 gene oncotype in node positive disease

Post‐Menopausal Invasive Breast Cancer Stage II/III

Oncotype Dx – 21 gene assay

Paraffin Embedded

C

Albain, Lancet Oncology 2009

DOUBLE‐BLIND RANDOMIZED TRIAL OF TAMOXIFEN VS PLACEBO IN PATIENTS WITH NODE POSITIVE OR. HIGH RISK NODE NEGATIVE BREAST CANCER WHO HAVE COMPLETED CMF, CEF, OR AC ADJUVANT CHEMOTHERAPY (MA.12)

Estrogen receptor profiling of human breast cancer towards a better prediction of endocrine therapy response

Invasive Breast Cancer Stage I‐III

P‐ER alpha, ERB1 ER/B2/cx PgR


O

Predictive value of osteopontin in tumour samples to evaluate bone metastasis


Osteopontin TMA PA

Evaluation of baseline FSH, LH, estradiol post chemotherapy and pre tamoxifen to evaluate reproductive axis


Integrated: FSH, LH, Estradiol

Serum O

A RANDOMIZED TRIAL OF ANTIESTROGEN THERAPY VERSUS COMBINED ANTIESTROGEN AND OCTREOTIDE THERAPY IN THE ADJUVANT TREATMENT OF BREAST CANCER IN POST‐MENOPAUSAL WOMEN (MA.14)

Companion study to MA.14 to evaluate Insulin‐like growth factor physiology and correlation with outcomes

Post Menopausal Invasive Breast Cancer Stage I‐III

Integrated: IGF1‐R, INSR


O

IGF‐1 C‐peptide IGF‐BP3 25 OH Vit D

Serum C Pollak, ASCO 2006 (Abs) Pollak, ASCO 2008 (Abs) Piura, ASCO 2009 (Abs)

uPA as a marker of recurrence in a case controlled study


uPA Serum C Dos Santos, SABCS 2006 (Abs)




Determination of pretreatment serum C‐telopeptide and ability to predict development of bone metastasis in adjuvant breast cancer patients enrolled in MA.14

Post‐MenopausalInvasive Breast Cancer Stage II/III

Serum C‐telopeptide (Pretreatment)

Serum C Lipton, ASCO 2008 (Abs) Ali, ASCO 2009 (Abs) Lipton, St. Gallen 2009 (Abs)

Predictive value of osteopontin in tumour samples Predictive value of osteopontin in plasma samples collected from a cohort of patients on MA.14


Osteopontin in tumour and plasma pre‐treatment

Paraffin Embedded Plasma

PA O

TIMP‐1 in serum as a predictive marker for relapse free survival


TIMP‐1 Serum C Ali, SABC 2009 (Abs)

Serum Stromal cell‐derived factor (SDF)‐1: Predictive marker for distant metastasis in breast cancer


Stromal cell derived factor

Serum PA

Translational studies to identify predictors of outcome in estrogen receptor positive women treated with tamoxifen in the MA.14 trial


2 gene signature for tamoxifen sensitivity ER, PgR, EGF, EGFR, Her 2 (AQUA, IHC)


O

A PHASE III RANDOMIZED DOUBLE BLIND STUDY OF LETROZOLE VERSUS PLACEBO IN WOMEN WITH PRIMARY BREAST CANCER COMPLETING FIVE OR MORE YEARS OF ADJUVANT TAMOXIFEN (MA.17)

Quantitative protein and gene expression biomarkers of tamoxifen and letrozole recurrence in the MA17 cohort

Post‐ Menopausal Invasive Breast Cancer Stage II/III

MGH 2 gene signature GHI 21 gene signature ER, PgR, Her 2, tumour aromatase COX‐2, GATA3, Nat1


O

A PHASE III ADJUVANT TRIAL OF SEQUENCED EC + FILGRASTIM + EPOETIN ALFA FOLLOWED BYPACLITAXEL VERSUS SEQUENCED AC FOLLOWED BY PACLITAXEL VERSUS CEF AS THERAPY FOR PREMENOPAUSAL WOMEN AND EARLY POSTMENOPAUSAL WOMEN WHO HAVE HAD POTENTIALLY CURATIVE SURGERY FOR NODE POSITIVE OR HIGH RISK NODE NEGATIVE BREAST CANCER (MA.21)

Prognostic effect of fasting insulin and related factors in high risk breast cancer: a companion study


Integrated: Insulin, IGF1, Sex binding hormone, Leptin, glucose, Estradiol, 25 OH Vit D

Serum PA




PHASE I / II STUDY OF INCREASING DOSES OF EPIRUBICIN AND DOCETAXEL PLUS PEGFILGRASTIM FOR LOCALLY ADVANCED OR INFLAMMATORY BREAST CANCER (MA.22)

Prediction of chemoresistance in patients with inflammatory breast cancer

Locally advanced or inflammatory breast cancer

Gene expression profiling (baseline, mid, post chemo) ER, PgR, Her 2

Fresh Frozen Paraffin Embedded

O O

Parissenti, BCTR 2009 Parissenti, SABCS 2008 (Abs) Parissenti, ASCO 2007 (Abs)

Proteomic and genomic analysis to correlate therapeutic response and side‐effects of a combination of epirubicin and docetaxel in order to determine prognostic and predictive markers of outcome: MA.22 substudy

Locally Advanced or Inflammatory Breast Cancer

DASL platform molecular profiling (exploratory)

Paraffin Embedded

C

A RANDOMIZED PHASE III TRIAL OF EXEMESTANE VERSUS ANASTROZOLE IN POSTMENOPAUSAL WOMEN WITH RECEPTOR POSITIVE PRIMARY BREAST CANCER (MA.27)

To conduct a GWAS study in patients experiencing MSK adverse events on Aromatase Inhibitors on the MA.27 trial. A PGRN‐RIKEN collaboration

Post‐Menopausal Invasive Breast Cancer Stage I‐III

SNP analysis‐genome wide

Whole Blood DNA

C Ingle, SABCS 2009 (Abs)

GASTROINTESTINAL & PANCREAS

A RANDOMIZED PLACEBO CONTROLLED STUDY OF OSI‐774 PLUS GEMCITABINE IN PATIENTS WITH LOCALLY ADVANCED, UNRESECTABLE OR METASTATIC PANCREATIC CANCER ( PA.3)

K‐ras mutation and EGFR gene copy as predictive marker for survival benefit in pancreatic cancer patients treated by erlotinib

Advanced Pancreatic Cancer

Integrated: EGFR EGFR gene copy number K‐RAS

Paraffin Embedded

C Moore, ASCO 2007 (Abs)

E‐cadherin and vimentin: predicive role of markers in response to erlotinib

Advanced Pancreatic Cancer

E‐cadherin, vimentin Paraffin Embedded

O

CLINICAL TRIAL OF ADJUVANT THERAPY WITH 5‐FLUOROURACIL AND FOLINIC ACID IN PATIENTS WITH RESECTABLE ADENOCARCINOMA OF THE COLON (CO.3)

Tumour Microsatellite‐Instability status as a predictor of benefit from fluorouracil‐based adjuvant chemotherapy for colon cancer

Adeno‐carcinoma Stage I‐III

Microsatellite stability assays

Paraffin Embedded

C Ribic, NEJM 2003




A PHASE III EVALUATION OF HIGH‐DOSE LEVAMISOLE PLUS 5FU AND LEUCOVORIN AS SURGICAL ADJUVANT THERAPY FOR HIGH RISK COLON CANCER (CO.9)

To evaluate mismatch repair mechanisms and BRAF V600E in patients with colon cancer

Adeno‐carcinoma Stage II/III

BRAF V600E Paraffin Embedded

C French, Clin Cancer Res 2008

GENITOURINARY

A PHASE III RANDOMIZED TRIAL COMPARING INTERMITTENT VERSUS CONTINUOUS ANDROGEN SUPPRESSION FOR PATIENTS WITH PROSTATE‐SPECIFIC‐ANTIGEN PROGRESSION IN THE CLINICAL ABSENCE OF DISTANT METASTASES FOLLOWING RADIOTHERAPY FOR PROSTATE CANCER (PR.7) The relationship between the androgen receptor CAG repeat polymorphism length and the response to intermittent androgen suppression therapy for advanced prostate cancer

Adeno‐ carcinoma Prostate cancer

CAG repeat polymorphism IGF, markers of oxidative stress

Serum C Klotz, Prostate Cancer Prostatic Disease, 2005

A PHASE III INTERGROUP TRIAL OF IRINOTECAN (CPT‐11) (NSC #616348) PLUS FLUOROURACIL/LEUCOVORIN (5‐FU/LV) VERSUS FLUOROURACIL / LEUCOVORIN ALONE AFTER CURATIVE RESECTION FOR PATIENTS WITH STAGE III COLON CANCER (CO.15)

To evaluate microsatellite instability and the correlation with response to adjuvant chemotherapy

Adeno‐ carcinoma Stage II/III

MSI evaluated by mono and di‐nucleotide markers

Paraffin Embedded DNA

C Bertagnolli, ASCO 2006 (Abs)

A PHASE III RANDOMIZED STUDY OF CETUXIMAB (ERBITUX TM, C225) AND BEST SUPPORTIVE CARE VERSUS BEST SUPPORTIVE CARE IN PATIENTS WITH PRETREATED METASTATIC EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) ‐ POSITIVE COLORECTAL CARCINOMA (CO.17)

To evaluate K‐ras mutations and the benefit from cetuximab in advanced colorectal cancer

Adeno‐ carcinoma Advanced Stage IV

K‐ras mutations Paraffin Embedded DNA

C

Karapetis, NEJM 2008 Au, JCO 2009

PTEN and P13KCA status and correlation with outcome in CO.17


PTEN, PIK3CA, BRAF, IGFRI, FCRII/II

Paraffin Embedded

O

To evaluate epiregulin gene expression plus wild type k‐ras as a predictor of cetuximab benefit


Epiregulin gene expression K‐RAS mutations

Paraffin Embedded RNA

C Jonker, ASCO 2009 (Abs)




HEMATOLOGY

A PHASE II STUDY OF ORAL FLUDARABINE PHOSPHATE IN PATIENTS WITH PREVIOUSLY UNTREATED B‐CELL CHRONIC LYMPHOCYTIC LEUKEMIA (CL.2)

To evaluate the immunophenotype, chromosomal abnormalities, IgVH mutations, ZAP‐70 status and the correlation with outcomes in symptomatic B‐CLL

B‐CLL Integrated: Immunophenotyping Interphase genetics (FISH) IgVH mutational analysis ZAP‐70 status

Peripheral lymphocytes Serum

C Shustik, Leukemia & Lymphoma 2009

To evaluate serum free light chains and correlation with outcomes

B‐CLL Serum free light chains Serum C Shustik, ASH 2009 (Abs)

A RANDOMIZED PHASE III STUDY OF THALIDOMIDE AND PREDNISONE AS MAINTENANCE THERAPY FOLLOWING AUTOLOGOUS STEM CELL TRANSPLANT IN PATIENTS WITH MULTIPLE MYELOMA (MY.10)

Identification of novel prognostic markers and molecular targets in myeloma

Multiple Myeloma

Integrated: Interphase genetics (FISH and PCR) wnt signalling

Bone marrow O

To evaluate markers of thrombogeneticity and correlative with thromboembolic events

Multiple Myeloma

Integrated: D‐dimer Factor VIII

Plasma O Kovacs, ASH 2005 (Abs)

BRAIN

A RANDOMIZED PHASE III STUDY OF CONCOMITANT AND ADJUVANT TEMOZOLOMIDE AND RADIOTHERAPY FOR NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME (CE.3)

Molecular analysis of tumour tissue obtained at reoperation of patients treated in the EORTC trial 26981/22981 for newly diagnosed GBM

Glioblastoma Multiforme

MGMT‐DNA Repair Protein

Paraffin embedded DNA

C Hegi, NEJM 2005

GYNECOLOGY

INTERGROUP PHASE III COMPARISON OF A COMBINATION OF TAXOL‐PLATINUM AND A COMBINATION OF CYCLOPHOSPHAMIDE‐PLATINUM CHEMOTHERAPY IN THE TREATMENT OF ADVANCED EPITHELIAL OVARIAN CANCER. NCIC CTG OV.10/EORTC 55931/BMS CA139‐209 ( OV.10)

Prognostic value of clinical and molecular markers in advanced ovarian cancer

Ovarian Cancer Stage III/IV

P53, Bel 2, p21, Mib‐1, c‐Erb‐B2 DNA ploidy

Paraffin Embedded

C Green, ASCO 2005 (Abs)




A PHASE III STUDY OF CISPLATIN PLUS TOPOTECAN FOLLOWED BY PACLITAXEL PLUS CARBOPLATIN VERSUS PACLITAXEL PLUS CARBOPLATIN AS FIRST LINE CHEMOTHERAPY IN WOMEN WITH NEWLY DIAGNOSED ADVANCED EPITHELIAL OVARIAN CANCER (OV.16)

What is the outcome of a prospective cohort study examining the correlation between tumour expression of BRCA1 with progression‐free survival in sub‐optimally resected patients with stage II‐IV ovarian cancer receiving adjuvant intravenous platinum and paclitaxel

Ovarian Cancer Stage II‐IV

BRCA1 Paraffin Embedded TMA

O

A PHASE III RANDOMIZED TRIAL COMPARING TAH BSO VERSUS TAH BSO PLUS ADJUVANT PELVIC IRRADIATION IN INTERMEDIATE RISK, STAGE I CARCINOMA OF THE ENDOMETRIUM (EN.5)

To compare the prognostic value of MSI and PTEN in early stage versus advanced/recurrent endometrial cancer

Endometrial Adeno‐ carcinoma Stage I‐IV

MSI PTEN

Paraffin Embedded

C Mackay, ASCO 2005 (Abs)

LEGEND: Status Column : C = Completed, PA= Pending analysis, O= Ongoing Tumour Type: NSCLC= Non Small Cell Lung Cancer B‐CLL= B Cell Chronic lymphocytic leukemia

NCIC CTG‐Led Studies: MA.5: Phase III trial of intensive CEF versus standard CMF as adjuvant chemotherapy in premenopausal women with breast cancer with positive axillary nodes. This trial demonstrated the superiority of adjuvant CEF versus CMF in improving overall survival of patients with lymph node positive breast carcinoma. Correlative biology results increased significantly our understanding of the prognostic and predictive value of HER2 and topoisomerase 2 in the setting of anthracycline chemotherapy (Pritchard, NEJM 2006; O’Malley, JNCI 2009). We obtained 639 FFPE specimens from 710 study patients. HER2 amplification or overexpression was evaluated with the use of fluorescence in situ hybridization (FISH), immunohistochemical analysis (IHC), and polymerase‐chain‐reaction (PCR) analysis. Amplification of HER2 was associated with a poor prognosis regardless of the type of treatment. In patients whose tumours showed amplification of HER2, CEF was superior to CMF when assessed on the basis of relapse‐free survival (RFS) (hazard ratio (HR), 0.52; (95% CI), 0.34 to 0.80; p=0.003) and overall survival (OS) (HR, 0.65; 95% CI, 0.42 to 1.02; p=0.06). For women whose tumours lacked amplification of HER2, CEF did not improve RFS. The adjusted hazard ratio for the interaction between treatment and HER2 amplification was significant for both RFS and OS. These results indicate that amplification of HER2 in breast‐cancer cells is associated with clinical



responsiveness to anthracycline‐containing chemotherapy. The resources developed for the HER2 work in MA.5 have led to other translational research, examples of which are outlined below: • Evaluation of 438 tumours from the MA.5 patient population for TOP2A alterations

(amplifications or deletions), demonstrated that treatment with CEF in the cohort with altered TOP2A had a statistically significant superior outcome with CEF for RFS (adjusted HR, 0.35, 95% CI = 0.17‐0.73, p=0.005) and OS (adjusted HR, 0.33, 95% CI = 0.15‐0.75, p=0.008). Conclusions from this work suggest that TOP2A gene alterations are associated with an increase in responsiveness to anthracycline‐containing chemotherapy, similar to that seen in patients with HER2 amplification. In partnership with British and Danish colleagues, work is ongoing to look at whether polysomy 17, or the combination of TIMP‐1 and Topo II, are more sensitive predictors of anthracycline response than Topo II alone.

• Population‐based data has suggested that patients with a core basal phenotype have a worse

survival on anthracycline containing chemotherapy regimens. Using TMAs prepared form MA.5, a six marker IHC profile was used to define intrinsic biological subtypes. In the CEF arm, patients with core basal tumours had a HR, 1.8, p=0.02 for OS relative to other subtypes. In the CMF arm there was no significant difference. This work is being explored further with the use of the PAM 50, a 50 gene panel that uses FFPE tissue and quantitative real time PCR to define the intrinsic subtypes.

JBR.10: A prospective randomized trial of adjuvant chemotherapy with vinorelbine and cisplatin compared to observation alone in completely resected NSCLC. Initiated in 1994, this phase III trial was among the first to include putative molecular prognostic marker, RAS mutation, as a stratification factor and prospective snap‐frozen and FFPE tumour banking. Of the 482 randomized patients, tumour samples were collected from 451 patients; 445 patients also provided consent to conduct future biomarker studies on their samples. Snap‐frozen tumour (and corresponding ”normal” lung) tissue was collected from 171 consenting patients, paraffin blocks from 331 patients, and 10‐20 unstained sections from 159 patients. TMA was constructed from the available FFPE blocks. Molecular analyses on 450 patient samples (93% of trial patients) showed that RAS mutation was not a weak and statistically not significant poor prognostic factor (HR 1.23, 95% CI 0.76‐1.97, p=0.40). Adjuvant chemotherapy improved overall survival in whole study population (hazard ratio for death, 0.69; p=0.04), and in the RAS wild type patients (HR 0.69, 95% CI 0.49‐0.97; p=0.03), but not in patients with RAS mutation (HR 0.95, 95% CI 0.53‐1.71; p=0.87) (Winton, NEJM 2007, Tsao, JCO 2007). Although in the Cox model, significant interaction between chemotherapy and RAS mutation was not detected (p=0.29), partly limited by sample size, the results persisted in a recent re‐analysis using long term follow‐up (mean 9.3 years) data (Butts, JCO in press). The tissue resources, including genomic DNA and TMA slides, from this trial have led to several additional translational research projects. These include the following: • Evaluation of the prognostic and predictive value of p53 mutations on exon 5‐9 and p53 and

tubulin (TUB) protein expression by immunohistochemistry (IHC). These results revealed that high protein levels of TUB class 3 and p53 but not p53 mutation status correlated with poor prognosis (Seve, Clin Can Res 2007; Tsao, JCO 2007).



Selected Results from Retrospective Analyses JBR.10 Specimens

Marker HR for Death

95% CI P value

TUB IHC 1.72 1.02‐2.88 0.04 P53 IHC 1.89 1.07‐3.34 0.03 P53 Mutation 1.15 0.75‐1.77 NS

The overall survival benefit of adjuvant chemotherapy was significant in p53 IHC+ (HR 0.54, 95% CI 0.32‐0.92, p=0.02) but not in p53 IHC‐ patients (HR 1.4, 95% CI 0.78‐2.52, p=0.26), with a significant interaction p‐value of 0.02.

• Gene expression‐based survival prediction in lung adenocarcinoma: a multi‐site, blinded validation

study (Shedden K, Nat Med 2008). RNA from 39 snap‐frozen adenocarcinoma samples was contributed to this high priority NCI initiative. This large, training‐testing, multi‐site, blinded validation study examined whether gene expression profiling either alone or combined with basic clinical covariates (stage, age, sex) could be used to predict overall survival in lung cancer subjects. Several models examined produced risk scores that substantially correlated with actual subject outcome. This study also provides the largest available set of microarray data with extensive pathological and clinical annotation for lung adenocarcinomas.

• Microarray (Affymetrix U133A) analyses of RNA from 133 NSCLC (62 observation, 71 adjuvant

chemotherapy) patients resulted in the identification of a 15‐gene signature that is prognostic for survival (multivariate adjusted HR 18.00, 95% CI 5.78‐56.05, p<0.0001). The significance of this prognostic signature is validated in four large publicly available microarray datasets, and more importantly, is predictive of benefit from adjuvant chemotherapy (HR 0.33 vs 3.67, interaction p=0.001) (Tsao, ASCO 2008; Zhu, submitted).

BR.21: A randomized placebo controlled study of erlotinib (Tarceva, OSI‐774) in patients with stage IIIB/IV NSCLC who have failed standard chemotherapy. This international trial involving 731 patients from centres in Canada, Europe, South America and Asia showed that erlotinib improved overall survival of patients with previously treated advanced lung carcinoma and led to the approval of erlotinib in this indication (Shepherd NEJM, 2005). Correlative studies on this paradigm‐shifting trial provided significant insight into the roles of EGFR tyrosine kinase domain mutations, EGFR gene copy number changes and KRAS mutation as predictive biomarkers for EGFR TKI therapy. The BR.21 tumour bank samples were collected prospectively from 328 consenting patients. Translational research studies showed that higher response rates and overall survival were associated with EGFR protein expression, high gene copy number deletion 19 and exon 21 point mutation L858R and absence of KRAS mutations (Tsao, NEJM 2005; Zhu et al, JCO 2008). Study results also showed that EGFR mutations were associated with improved prognosis and demonstrated the value of randomized controlled trials to determine the prognostic versus predictive value of biomarkers (Shepherd and Tsao, JCO 2007).



Selected Results from Analyses of NCIC CTG Trial BR.21 Samples

ORR % p‐value OS HR 95% CI p‐value EGFR IHC Positive (+) Negative (‐)

11 4

P = 0.1

0.68

0.49‐0.95

0.02

Gene Copy No.

Increased Normal

21 5

P = 0.02

0.43

0.23‐0.78

0.004

EGFR Genotype Mutation Wild type

27 7

P = 0.035

0.55

0.25‐1.19

0.12

KRAS Genotype Mutation Wild type

10 5

P = 0.69

1.67 0.69

0.62‐4.50 0.49‐0.97

0.31 0.03

CO.17: A phase III randomized study of cetuximab (Erbitux, C225) and best supportive care versus best supportive care in patients with pretreated metastatic epidermal growth factor receptor (EGFR)‐positive colorectal carcinoma. In this trial of 572 patients, cetuximab was found to improve overall survival (OS; HR 0.77; 95% CI 0.64‐0.92; p=0.005) (Jonker, NEJM 2007). Tumour samples collected from 394 of 572 patients (68.9%) were analyzed for KRAS mutation, and 42.3% were positive for exon‐2 mutations. Cetuximab improved OS and PFS of patients with wild‐type KRAS tumours, (OS HR 0.55, 95% CI 0.41‐0.74, p<0.001; PFS HR 0.40, 95% CI 0.30‐0.54, p<0.001). Cetuximab did not improve PFS or OS among patients with mutated KRAS tumours (OS HR 0.98, p = 0.89; PFS HR 0.99, p= 0.96). In patients receiving BSC alone, KRAS mutation was not a prognostic factor (HR 1.01, p=0.97). The results of CO.17 provided the definitive evidence that EGFR antibody therapies are beneficial only in KRAS wild type patients. Importantly, the CO.17 results contributed to the revision of the approval of cetuximab and to the timely revision of the CO.20 protocol “A phase III randomized study of brivanib alaninate (BMS‐582664) in combination with cetuximab versus placebo in combination with cetuximab in patients previously treated with combination chemotherapy for metastatic colorectal carcinoma”, restricting accrual to patients only with KRAS wild type tumours. NCIC CTG Contributions to Other Trials and Studies: CO.3: A phase III trial of adjuvant therapy with 5‐fluorouracil and folinic acid (5FU/FA) in patients with resectable adenocarcinoma of the colon.



This trial accrued 370 patients and contributed to a meta‐analysis which demonstrated the superiority of 5FU/FA adjuvant treatment (IMPACT Investigators Lancet 1995). Tumour blocks from 292 patients (79%) were retrospectively collected, combined with samples from four other 5FU adjuvant trials and analyzed for microsatellite instability. Results from 570 patient samples showed that adjuvant chemotherapy improved overall survival among patients with microsatellite‐stable tumours or tumours exhibiting low‐frequency microsatellite instability, according to a multivariate analysis adjusted for stage and grade (HR 0.72, 95% CI 0.53 to 0.99, p=0.04). By contrast, there was no benefit of adjuvant chemotherapy in the group with high‐frequency microsatellite instability (Ribic, NEJM 2003). This was the first report that suggests that mismatch repair gene status may be prognostic and predictive of benefit from adjuvant chemotherapy in colorectal cancer patients and was led by investigators from our group. CE.3 (EORTC 26981/22981): A randomized comparison of temozolomide chemotherapy concurrent with and following radiotherapy vs radiotherapy alone in patients with newly diagnosed glioblastoma multiforme. This phase III trial showed that the addition of temozolomide to radiotherapy improved overall survival of patients with glioblastoma multiforme. Tissue sections and tumour blocks were collected from 307/573 patients (53.6%), of which approximately 25% came from NCIC CTG MGMT (O6‐methylguanine–DNA methyltransferase) methylation status was determined 206 of the 307 tumours (67.1% or 36.0 % of the tumours from the overall study population (Hegi, NEJM 2005)). The MGMT promoter was methylated in 45% of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (HR 0.45, 95% CI 0.32‐0.61, p<0.001). Among patients with tumour with methylated MGMT, temozolomide and radiotherapy conferred significant benefit (median survival 21.7 months, 95% CI 17.4‐30.4) as compared with patients assigned to only radiotherapy (median survival 15.3 months, 95% CI 13.0‐20.9, p=0.007). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups. The results provide strong rationale for assaying for methylated MGMT promoter in glioblastoma patients who are considered for treatment with radiotherapy and temozolomide. Translational Research in Early Clinical Trials: Many studies of pharmacodynamic changes in target or pathway in phase I trials and assessment of molecular markers to explore relationships with response (or non‐progression) in phase II trials have been conducted. Serial biopsies have been successfully performed in phase I studies to measure target/pathway modulation. Archival tissue submission is mandatory for those phase II protocols where correlative research is a secondary endpoint and compliance with its collection has been excellent: generally in excess of 90% of cases have tumour submitted. Correlative studies are summarized in Table 5 of the IND Program (see Section 6 of this grant application). Translational research highlights from these trials are the observation of dose‐related target (clusterin) inhibition by OGX‐011 in prostate tumour (IND.153), evidence of dose‐related increase in histone H3 acetylation in PBMCs by SB939 (HDAC inhibitor) (IND.188), and observation of preliminary relationship of flt‐3 mutation and anti‐leukemic effect in phase I trial of sorafenib (IND.141). Some important negative findings include the lack of relationship of PTEN loss with mTOR inhibitor effect in the endometrial studies (IND.160A, 160B) and the non‐confirmation of the previously reported association of PTEN



normal/EGFRvIII and response to EGFR inhibitors. Our results are similar to other groups so it is unlikely these markers define a “responsive” subgroup. IND.165: A randomized phase II study of OGX‐011 in combination with docetaxel and prednisone or docetaxel and prednisone alone in patients with metastatic hormone refractory prostate cancer. This randomized trial of doxetaxel with/without the anti‐sense oligonucleotide clusterin did not show a difference in PFS (the study primary endpoint) but did show an improvement in overall survival. Having previously demonstrated a dose related fall in tumour clusterin mRNA and protein in the phase I trial, the phase II trial tested whether serum clusterin changed as a result of treatment. By the end of cycle 1, there was a significant fall in serum clusterin in OGX‐011 treated patients versus those in control group, thus biological effect of treatment on target seen. Modelling undertaken to explore relationship between degree of fall in clusterin and survival was undertaken but no correlation was found. 4. Respond to new technologies and contribute to methodological advances in clinical translational

research. As technologies advance, the CSTB Committee has positioned itself to explore these new approaches through collaborative research initiatives using NCIC CTG clinical trials material. Examples have included quantitative immunohistochemistry using the AQUA system in breast cancer trials (MA.12, MA.14, MA.17); the definition of intrinsic biological subtypes in breast cancer using immunohistochemical panels, the PAM 50 assay and future plans to compare results with nanostring technology (MA.5, MA.12, MA.21); the serendipitous finding of the potential of RNA integrity as a biomarker to predict response to treatment observed in MA.22 and now being validated using samples collected in the I‐SPY consortium; and the potential of the 15 gene expression profile described above in JBR.10. The successful collection of serial samples in neoadjuvant trials such as MA.22, the incorporation of imaging as a biomarker in MA.29, a metastatic substudy in MA.31 where serial samples will be obtained at diagnosis and at the time of progression and the collection of CTCs in a new IND study in prostate (IND.195) all illustrate the commitment of the group to capitalize on the changing environment in translational research. Pharmacogenomics looking at the host response to disease and therapies have recently been intergrated into many new trials. Examples have included musculoskeletal symptoms associated with aromatase inhibitors and the identification of SNPs that correlate with these symptoms, and proposed future work with efficacy outcomes and quality of life (MA.27), and the C‐PATH initiative described above in the BRC.4 lung study. 5. Provide education, training and mentoring in oncology translational research The NCIC CTG and CSTB Committee members have identified and organized transdisciplinary meetings and workshops to address the state of science and technology in emerging areas of translational research. Over the last granting period, three workshops focusing on Proteomics, Circulating Tumour Cells and Biomarkers for Angiogenesis Inhibitors have been held. In February 2005, the first of our workshops was held, bringing together those with an interest or expertise in the area of proteomics from across Canada to review the current state of knowledge in this area and to explore the potential of using plasma/serum samples collected on lung and breast cancer trials. Although the conclusions at the time was that the science in the setting of clinical trials was immature, the need for protocol



mandated, carefully collected samples was recognized and a precedent set for ongoing workshops and educational initiatives in emerging and new technologies/targeted agents. In February 2008, a workshop was held to examine the state of the science for angiogenesis inhibitory (AI) agents. The output of this workshop was to bring some focus to the assays recommended for our AI trials. It was concluded that a number of assays were relevant to consider including germline DNA and SNPs, CAF, VEGF, and s‐VEGFR. These recommendations have been built into newer trials (e.g. BR.29). In March 2009, NCIC CTG and the Ontario Institute of Cancer Research (OICR) co‐hosted a national Circulating Tumour Cell workshop. The workshop goals were to share current knowledge on the methods for detection and analysis of CTCs, review their utility in addressing cancer treatment related hypotheses in clinical trials and to determine areas of future research and potential collaboration. Research recommendations from the workshop were to develop research studies and trials that would result in the molecular characterization CTCs, develop standardized protocols for collection and biobanking to allow future detailed analyses of CTC and develop a technology evaluation group that would keep abreast of developments in this rapidly evolving area. Subsequently, proceedings of the workshop were submitted for publication, and OICR has issued an RFA for CTCs in clinical trials based on the workshop recommendations. The IND Program has also designed its first study to incorporate CTC measures of target as well as enumeration in a prostate study (IND.195). A fourth workshop has been proposed focusing on the potential role of primary human xenografts in drug and biomarker development. A catalogue of primary xenograft laboratories in Canada has been created and a workshop will be organized in 2010 on the potential collaboration of these laboratories in the prospective evaluation of new agent activity/biomarker elucidation and the role this could play in drug development within the CTG. Members of the CSTB Committee have participated in the development of a national New Investigators Clinical Trials Course that NCIC CTG conducted in 2007 and 2009. Drs. Shepherd, Dancey, Squire and Tsao were faculty in the course(s). Many members of the CSTB Committee are leading faculties of two national training programs in translational research funded by the Canadian Institutes of Health Research (CIHR) and Terry Fox Foundation (TTF): The TTF Training Program in Molecular Pathology for Cancer (www.molecularpathology.ca) involving the Princess Margaret Hospital, British Columbia Cancer Agency, Queen’s University and Alberta Cancer Agency) and the TTF Training Program in Transdisciplinary Cancer Research (http://qcri.queensu.ca/CIHR_Training_Program.html) based at Queen’s University. Both programs were funded initially in 2002 and were recently renewed in 2009. Several trainees from these Programs were involved in the NCIC CTG correlative studies, including pivotal biomarker studies of the BR.10 and BR.21 trials.

3.0 Most Significant Accomplishments

• Established a highly efficient biospecimen collection system for acquiring tissue and blood samples from national and international centres that participate in NCIC CTG‐led cooperative

http://www.molecularpathology.ca/

http://qcri.queensu.ca/CIHR_Training_Program.html



trials and establishing an equitable process for access and release of tissue for investigative projects.

• Established a collaborative network of translational research clinical/basic scientists in Canada to conduct leading edge biomarker studies in the context of the cancer biology associated with each clinical trial undertaken, the highlights of which are summarized in Section 2.0.

• Established disease specific correlative science working groups and a mechanism to enable individual Disease Site Committees to develop, conduct and explore collaborative opportunities in disease/drug specific biomarker research.

• Integrated new technologies and methodologies into CSTB Committee activities including TTDR and translational research projects.

• Participated in international and intergroup biomarker and/or correlative science projects.

4.0 Challenges and Opportunities The next five years present tremendous opportunities but also challenges for the CSTB Committee. Never before has there been such a wealth of new agents affecting a wide array of potentially important tumour targets entering the clinic, new biomarkers proposed to correlate with clinical outcomes, and new technologies to interrogate tissues. Although clearly exciting, this provides challenges in selecting the most promising agents/biomarkers and assays for study. By enhancing leadership in translational research at NCIC CTG, and by networking with national experts, opportunities for the development of trials that prospectively test different biomarkers, assays and treatment is enhanced. • Amongst the challenges, the CSTB Committee faces is the need to balance increasing interest and

excitement around novel biomarkers in patient specimens by academic investigators, by industry, and the need to undertake such collections and analyses in NCIC CTG sponsored trials. The “competition” for a scant resource – the patient’s tumour sample – is a significant challenge for continuing high quality translational research through the NCIC CTG. Enhanced dialogue and recognition of the vital role of pathologists are key. The CSTB Committee will create a culture where engagement of translational researchers within member institutions and the training of the new generation of molecular pathologists/clinician scientists will help to ensure our ability to acquire tissue specimens. There is as well a pressing need to evaluate biomarkers in more readily accessible samples such as blood, and to utilize new technologies that permit global amplification of nucleic acids so that accurate evaluation of multiple biomarkers will be possible in small tissue samples.

• The regulatory requirements for investigational drug and diagnostics, the contract negotiations

with the pharmaceutical industry, diagnostic companies, and commercial laboratories, the negotiations with the contracts departments at collaborating institutions over intellectual property and data rights that may arise from multicentre biomarker research projects linked to a trial present additional challenges.

• The enhanced complexity of trials is a challenge to the successful execution of correlative studies.

Sample collections for these endpoints and other secondary outcomes such as quality of life and



economic evaluations within phase III trials are significant additional burdens in terms of cost and time.

• Increasingly, pathology and interventional radiology departments are requesting greater

reimbursement for specimen acquisition, processing and shipping. Increased funding for these activities and support for the central biobank will be required. Alternative sources of funding from industry, through grant agencies and philanthropy, may be needed to maintain research activities.

• Although the retrospective analysis of specimens for validation of biomarkers will continue to be

important, trials are likely to move to the prospective/real‐time analysis of tissue to determine patient eligibility or stratification. The infrastructure and other resources required for such biomarker assays will need to be identified. Collaborations with individuals and laboratories that are moving toward Good Clinical Laboratory Practice Standards and CLIA certification are already forged, such that this challenge can be met through the CSTB Committee.

• The rapid evolution of scientific knowledge and technology is likely to render protocol prescribed

translational research obsolete by the time a trial is completed. Ensuring the best scientific knowledge and most robust assays are used requires ongoing processes to review and modify translational research projects as needed to reflect the current state of science. Input from the CSTB Committee will ensure access to the most robust assays and appropriately trained staff.

5.0 Priorities and Initiatives for the Next Five Years

In the preceding six years, our evaluation of markers has not only contributed to the fundamental understanding of the biology of cancer, but has led to the identification of markers (e.g. KRAS and EGFR mutations) that predict for drug benefit. As we learned more about the conduct of these studies, we have been cognizant that biomarkers correlative science questions prioritized at the start of a trial may change during the course of the study. As such, we have adapted protocol and informed consent language that covers future unplanned studies that is compliant with national research ethics standards. However, it has also become apparent that the selection of biomarkers for evaluation within and across trials requires greater consideration on the strength of scientific association between the molecular targets of therapeutic intervention and the marker, the frequency of expression of the marker(s) of interest in the study population, the type and quantity of tissue that can be collected from patients, and the robustness of the assays. As our understanding of cancer genetics and biology is advancing at a very brisk pace, CSTB Committee activities will need to more closely engage the scientific community that is leading these knowledge discoveries. In addition, the CSTB Committee will also need to be aware of rapidly changing development in nano‐scale molecular assays, and develop a system to rapidly implement these new advances into CTG correlative science/biomarker studies. Our priorities for the next five years will be: 1. To expand and upgrade resources and technologies to conduct the next generation of clinical

trials. The CSTB Committee and TTDR will actively seek to expand the repertoire of biospecimens collected in clinical trials. Types of biospecimens will include fine needle aspiration (FNA) tumour samples,



circulating tumour cells (CTC), snap‐frozen tumour specimens, live tumour cell banking and primary human xenograft models. The ongoing research and development work being performed at several NCIC CTG affiliated centres in Canada is enhancing correlative biology in these areas:

Sample Collection ‐ FNA samples: While FNA is the most common diagnostic procedure used to make a rapid diagnosis of malignancy, especially in advanced stage disease, the material remaining is often not sufficient for doing molecular analyses that are now common in most clinical trials, such as mutation or gene copy number determination. Although some centres have moved towards doing core rather than FNA biopsy to obtain more tumour tissue for doing these additional assays, core biopsy may be associated with lower diagnostic yield than FNA, thus precipitating the need for repeat biopsies. CSTB Committee members will explore the ability to use FNA samples for molecular assays described above, ways to increase the amount of materials that FNA procedures can provide and novel assays that may give the highest yield using this material. ‐ CTC collection: There is ample evidence that numbers of detected CTC may have prognostic and predictive value. With rapid advances occurring in the development of nanotechnologies that allow improved cell isolation, identification and genetic characterization of low number of cells, it is possible that in the near‐intermediate future, CTCs may be used as “realtime biopsies” to monitor drug activities, response and disease progression. The CSTB Committee will continue to monitor and explore the development in CTC technologies and their implementation in NCIC CTG clinical trials. ‐ Snap‐frozen tumour sample collection: During the last five years, we have witnessed the “coming of age” for prognostic gene expression signature in several cancer types. Gene‐signature assays are largely still conducted on snap‐frozen tumour samples, as RNA in FFPE tissue is highly degraded. Building on the 15‐gene prognostic and predictive expression signature identified in the JBR.10 study, the Lung Disease Site Committee is contemplating a future adjuvant trial that include stratification/selection of patients with the 15‐gene signature. To this end, a Canadian biotech company, Med BioGene (Vancouver, BC), is developing a LungExpress DxTM Gene Expression Test for the 15‐gene signature assay in CLIA/clinical diagnostic laboratories adapted for FFPE samples. The alternative tissue preservation method using RNARetain™ (Asuragen, Austin, TX) or RNAlaterTM (Qiagen, Mississauga, ON) is also being explored. ‐ Live tumour cell banking and primary xenograft models: The lack of predictive power may reflect the inability of existing models to capture the diversity of genomic change in different cancers (given the relatively small number of available cell lines and their incomplete genetic characterization) and additional heterogeneity imposed by features of the tumour microenvironment (e.g. hypoxia and tumour stroma). Human tumour xenografts established directly from patient samples (primary xenografts) may better reflect the properties of bona fide human malignancies. Live tumour cells and primary tumour xenograft models allow functional assays to be carried out. In the case of hematopoietic malignancies, especially leukemia, live cell banking is common; however, for solid tumours, the value of live cell banking in the form primary tumour xenografts is just beginning to be explored. At some NCIC CTG affiliated centres such as PMH and BCCA, primary tumour xenograft establishment from resected cancer tissue is in place,



with high success rates (e.g. >90% for pancreas, ovary, colon and >60% for resected NSCLC). In future IND trials, such xenograft models allow parallel ex‐patient studies to be carried out on drugs being studied. As the xenograft tumours can be characterized more deeply for their molecular abnormalities, ex‐patient studies may allow parallel biomarker discovery studies conducted in parallel to in patient studies, thus providing greater chance of identification of predictive markers that may be tested in subsequent trials. Assay Technologies ‐ High throughput multiplex assays: Multiplex assays can greatly increase the throughput of biomarker studies. In the context of genetic and microenvironmental heterogeneity of cancers, it is most likely that patient selection for optimal therapy requires multiple markers. In collaboration with genome and/or proteome centres across the county, we shall be following closely the development of these techniques, including next generation parallel sequencing, mass spectrometry and bead technologies, and facilitate their early implementation for analysis of clinical trial samples. ‐ Expression profiling on FFPE samples: Technological advancement has permitted assays of mRNA transcript and DNA copy number variations using FFPE samples. Examples include the Illumina DASL® gene expression array (San Diego, CA), the British Columbia Cancer Agency’s SMRT array for array‐CGH studies of gene copy number variations, the qNPA™ quantitative RNase protection assay of High Throughput Genomics (Tucson, AZ), and the nCounter Analysis System by NanoString (Seattle, WA) for digital assay of hundreds of genes/transcripts. In specific instances, these technologies shall facilitate our ability to conduct novel biomarker discovery research using very small amount of materials.

2. To continue biomarker validation studies and development of hypothesis driven translational or

correlative biology studies within and across NCIC CTG trials. The goal of achieving personalized medicine in cancer care will, in many situations, drive the development and implementation of clinical trials in the next five years. Although retrospective analyses on diagnostic and archived FFPE samples will remain of value, new trials will increasingly consider alternative specimens, assays and trial designs. The CSTB Committee will continue to initiate and conduct translational and correlative study research on ongoing and completed clinical studies. Companion biomarker and correlative science studies will continue to be a priority in all clinical trials, and most trials will continue to collect specimens for biomarker and future translational research studies. The CSTB Committee has developed criteria for the prioritization of biomarkers to be considered, based on the strength of the science, robustness of assay methodologies, the trial design, feasibility, and likelihood of the impact of the results (Table 4).



Table 4: Proposed Prioritization Criteria of Translational Research Studies

Trials Scientific Aspects

Operational Aspects

Phase III Trials Prospective Marker Validation Adjuvant Trials, Metastatic trials testing novel agents, Early Phase Trials Phase II Randomized Trials, Non‐randomized trials with agent of known activity, Phase I Trials Demonstrating POM*, Phase II Screening Trials where Activity is uncertain. Phase I/II combination trials where the effect of new agent is not a isolated

Strength of science supporting relationship between biomarker, intervention and outcome, Assay technology, analytical validation and “fitness‐for‐purpose Expertise Trial design to answer biomarker question

Specimen management

Banking

Analysis

Funding

*Proof of Mechanism Biomarker profiles and outcomes, sample sizes Assay evaluations: which assays, effects on failure, false positives/negatives on outcomes Adaptive designs – selections of treatments and assays Economic Evaluations – model treatment benefit, assay sensitivity, and treatment/assays costs

While existing protocols prioritizes the use of trial samples, especially from positive trials for validation/confirmatory biomarker studies, the CSTB Committee will entertain or explore scientific questions that would justify the use of samples for exploratory and discovery studies. In addition, the CSTB Committee will also work closely with Disease Site Committees to support the conduct of novel trials that focus on biomarker validation or use of biomarkers to stratify or select patients for treatment. Two examples of such studies are illustrated. The first trial is the BRC.4 (NCCTG N0723) Phase III Biomarker Validation Study of Second‐Line Therapy in Patients with Advanced Non‐Small Cell Lung Cancer (NSCLC) Randomized to Pemetrexed Versus Erlotinib. This trial is designed to prospectively validate EGFR copy number measured by FISH as a predictive marker for benefit from erlotinib. Dr. Geoffrey Liu from our group is leading the pharmacogenomic study for this trial, which will evaluate known and novel single nucleotide polymorphisms (SNPs) of the EGFR gene promoter sequences as potential predictive markers for erlotinib benefit. The second trial is currently under development. NCIC CTG will lead international phase III trial evaluating the role of the mTOR inhibitor deforolimus as second‐line treatment in patients with recurrent/metastatic endometrial carcinoma that will be



conducted through the International Gyne‐Oncology Intergroup. However, NCIC CTG has already received a commitment for collaboration from the Ontario Institute for Cancer Research (OICR). The OICR is the Secretariat and Data Warehouse for the International Cancer Genome Consortium. The OICR genomics group will identify mutations, copy number variation and deletions from 100 frozen samples of endometrial carcinoma specimens from the Ontario Tumour Bank. The identified genetic abnormalities will then be sought in the banked specimens from patients enrolled on NCIC CTG‐sponsored phase II studies of mTOR inhibitors in endometrial carcinoma (70 samples) and correlated with clinical outcomes. Genetic abnormalities that correlate with patient outcomes will then be tested on samples obtained from the phase III trial. This trial will move forward based on final results from a company‐sponsored randomized phase II trial that is currently accruing patients. The model of parallel laboratory translation research projects conducted concurrently and that will lead to results that can inform biomarker analyses at the completion of a phase III trial can be explored in other settings. 3. To continue to engage key collaborators at the national and international level. The CSTB Committee will continue to forge collaborations with the high quality molecular pathology laboratories across Canada described in 1.4 as well as independent academic researchers with questions that can only be answered in the context of clinical trials. We will also seek new collaborations with translational research groups developing imaging for biospecimen biomarkers. The collaboration on the proposed phase III endometrial trials with OICR and the Ontario Tumour Bank is one example. Recently, the Terry Fox Research Institute has funded a group with a mandate to identify biomarkers for cancer detection, prognosis and treatment. In addition, a group of researchers interested in molecular imaging has been created in Canada. As these activities evolve, the CSTB Committee plans to develop a joint workshop to explore where and how best to collaborate in the context of cancer trials. 4. To contribute to methodological advances in biomarker assay and clinical application. The development and validation of new assays, clinical trial design and analysis methods are needed to efficiently determine whether a biomarker may be a useful clinical test. One of the most concerning issues involves the assay methodology and reproducibility, within/between laboratories. The robustness of biomarker assays assumes paramount importance as they are considered for potential commercialization. With this in mind, the CSTB Committee will conduct future correlative studies with investigators and laboratories that demonstrate rigorously validated reagents and standardized assays. Alternative statistical approaches to evaluating correlations between biomarker profiles and outcomes, sample sizes calculations, the effects of assay failure, false positives/negatives on outcomes can be developed within the CSTB. In addition, the exploration of adaptive designs – selections of treatments and assays and the incorporation of economic evaluations to model treatment benefit, assay sensitivity, and treatment/assays costs will all be considered for future research. An approach to biomarker development is outlined in Figure 2.



Figure 2: Proposed Biomarker Pipeline and Stages of Evaluation

Biomarker Development & Application

Group 4 - Exploratory MarkersPre-clinical evidence is promising. More direct interrogation of pathways/biology at

mechanistic level in mouse model and other pre-clinical modelsNeed organized effort to chose potential “winners’ that should be selected to move into

humans

Group 3 markers – Clinical Proof of ConceptProof of concept in humans but requires specialized centres due to specimen, assay,

technology requirements2a: evaluate potential to move to group 1

2b: likely will stay specialized due to specific requirementsDetermine if sufficient clinical evidence to justify moving to group 1

Group 2 biomarker pipeline: safety, early clinical data, preclinical rationale, assay standardization, feasibility.

Group 2 markers – Clinical ValidationTest in an established or defined clinical setting, drug, therapy; Multiple sites with ability to accrue a large number of patients.

Choose biomarker/assay that can be used across sitesChoose a drug/clinical setting with clear cut evidence of efficacy so can understand

clinical correlations with biomarker; Outcomes serve as a baseline for evaluating new assays, therapies, interventions or

new biomarkers after evaluating the biomarker with established agentsCollect data for cost effectiveness as well as clinical outcomes

Group 1 markers – Clinical Application –Determine economics, laboratory proficiency for broad clinical application Knowledge

Translations

Late Clinical Evaluation

Early Clinical Evaluation

Laboratory Translational Research

Pre

clin

ical

To

Clin

ical

Tra

nsla

tion

and

App

licat

ion

Com

mer

cial

izat

ion

5. To contribute to the education and training of new investigators. The CSTB Committee will continue to assess emerging research areas through workshops exploring

the previously described primary human xenografts in drug and biomarker development, and imaging with opportunities for young investigators to attend. Training the new generation of molecular pathologists/clinician scientists is critically important to the rapid development and implementation of personalized medicine. CSTB Committee members who are faculty in CIHR and TTF training programs in translational research will mentor individual trainees from these programs, seek to engage them in NCIC CTG correlative studies, and develop curricula that will address laboratory, translational, biospecimen banking and clinical trial methodologies for correlative science. To underscore the role of the CSTB Committee in this regard, Dr. Squire will be liaising with the Chair and committee to organize a new “correlative biology and translational research in clinical trials course” aimed at encouraging new investigators and interested experienced researchers to become engaged in novel biomarker‐driven NCIC CTG trials.

correlative sciences/tumour biology committee … · correlative sciences/tumour biology committee...

Documents