NCCN Working Group Report: Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies

Defining treatment-susceptible or -resistant populations of patients with cancer through the use of genetically defined biomarkers has revolutionized cancer care in recent years for some disease/patient groups. Research continues to show that histologically defined diseases are diverse in their expression of unique mutations or other genetic alterations, however, which presents opportunities for the development of personalized cancer treatments, but increased difficulty in testing these therapies, because potential patient populations are divided into ever smaller numbers. To address some of the growing challenges in biomarker development and clinical trial design, NCCN assembled a group of experts across specialties and solid tumor disease types to begin to define the problems and to consider alternate ways of designing clinical trials in the era of multiple biomarkers and targeted therapies. Results from that discussion are presented, focusing on issues of clinical trial design from the perspective of statisticians, clinical researchers, regulators, pathologists, and information developers.

  • 1.

    Arrowsmith J, Miller P. Trial watch: phase II and phase III attrition rates 2011-2012. Nat Rev Drug Discov 2013;12:569.

  • 2.

    Amiri-Kordestani L, Fojo T. Why do phase III clinical trials in oncology fail so often? J Natl Cancer Inst 2012;104:568569.

  • 3.

    Gan HK, You B, Pond GR, Chen EX. Assumptions of expected benefits in randomized phase III trials evaluating systemic treatments for cancer. J Natl Cancer Inst 2012;104:590598.

    • Search Google Scholar
    • Export Citation
  • 4.

    Munoz J, Swanton C, Kurzrock R. Molecular profiling and the reclassification of cancer: divide and conquer. Am Soc Clin Oncol Educ Book 2013;2013:127134.

    • Search Google Scholar
    • Export Citation
  • 5.

    Gerlinger M, Rowan AJ, Horswell S et al.. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012;366:883892.

    • Search Google Scholar
    • Export Citation
  • 6.

    Sequist LV, Waltman BA, Dias-Santagata D et al.. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011;3:75ra26.

    • Search Google Scholar
    • Export Citation
  • 7.

    Gridelli C, Rossi A. EURTAC first-line phase III randomized study in advanced non-small cell lung cancer: erlotinib works also in European population. J Thorac Dis 2012;4:219220.

    • Search Google Scholar
    • Export Citation
  • 8.

    Sequist LV, Yang JC, Yamamoto N et al.. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013;31:33273334.

    • Search Google Scholar
    • Export Citation
  • 9.

    Romond EH, Perez EA, Bryant J et al.. Trastuzumab plus adjuvant chemotherapy for operable HER2+ breast cancer. N Engl J Med 2005;353:16731684.

  • 10.

    Slamon D. Herceptin: increasing survival in metastatic breast cancer. Eur J Oncol Nurs 2000;4:2429.

  • 11.

    Slamon D, Eiermann W, Robert N et al.. Adjuvant trastuzumab in HER2+ breast cancer. N Engl J Med 2011;365:12731283.

  • 12.

    Slamon DJ, Leyland-Jones B, Shak S et al.. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783792.

    • Search Google Scholar
    • Export Citation
  • 13.

    Gradishar WJ, Anderson BO, Blair SL et al.. NCCN Guidelines: Breast Cancer. Version 3, 2014. Available at: NCCN.org. Accessed July 16, 2014. To view the most recent and complete version of the NCCN Guidelines, visit NCCN.org.

    • Search Google Scholar
    • Export Citation
  • 14.

    Barker AD, Sigman CC, Kelloff GJ et al.. I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Clin Pharmacol Ther 2009;86:97100.

    • Search Google Scholar
    • Export Citation
  • 15.

    Albain KS, Barlow WE, Ravdin PM et al.. Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial. Lancet 2009;374:20552063.

    • Search Google Scholar
    • Export Citation
  • 16.

    Guidance for industry: pathologic complete response in neoadjuvant treatment of high-risk early-stage breast cancer: use as an endpoint to support accelerated approval. Draft guidance. 2012. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM305501.pdf. Accessed August 8, 2014.

    • Search Google Scholar
    • Export Citation
  • 17.

    Antolin AA, Mestres J. Linking off-target kinase pharmacology to the differential cellular effects observed among PARP inhibitors. Oncotarget 2014;5:30233028.

    • Search Google Scholar
    • Export Citation
  • 18.

    San Antonio Breast Cancer Symposium Newsletter. I-SPY 2: novel study design. Available at: http://www.sabcs.org/UserPortal/Documents/SABCS_2013_Issue4.pdf. Accessed August 8, 2014.

    • Search Google Scholar
    • Export Citation
  • 19.

    New presurgery combination therapy for triple-negative breast cancer. CenterWatch News Online Web site. Available at: http://www.centerwatch.com/news-online/article/5737/new-presurgery-combination-therapy-for-triple-negative-breast-cancer#sthash.lxxDiwJK.1WpOa3bu.dpbs. Accessed August 8, 2014.

    • Search Google Scholar
    • Export Citation
  • 20.

    Printz C. I-SPY2 trial yields first results on combination therapy for triple-negative breast cancer. Cancer 2014;120:773.

  • 21.

    Bose P, Ozer H. Neratinib: an oral, irreversible dual EGFR/HER2 inhibitor for breast and non-small cell lung cancer. Expert Opin Investig Drugs 2009;18:17351751.

    • Search Google Scholar
    • Export Citation
  • 22.

    Neratinib graduates to I-SPY 3. Cancer Discov 2014;4:624.

  • 23.

    Puma Biotechnology Announces Positive Top Line Results from Phase III PB272 Trial in Adjuvant Breast Cancer (ExteNET Trial). Available at: http://www.businesswire.com/news/home/20140722005059/en/Puma-Biotechnology-Announces-Positive-Top-Line-Results#.VA3vma90zkh. Accessed September 8, 2014.

    • Search Google Scholar
    • Export Citation
  • 24.

    Jones D. Adaptive trials receive boost. Nat Rev Drug Discov 2010;9:345348.

  • 25.

    Berry DA. Bayesian clinical trials. Nat Rev Drug Discov 2006;5:2736.

  • 26.

    Berry DA. Next generation clinical trials. Clin Adv Hematol Oncol 2011;9:601603.

  • 27.

    Berry DA. Adaptive clinical trials: the promise and the caution. J Clin Oncol 2011;29:606609.

  • 28.

    Berry DA. Adaptive clinical trials in oncology. Nat Rev Clin Oncol 2012;9:199207.

  • 29.

    Lung Cancer Master Protocol Activation Announcement. 2013. Available at: http://www.focr.org/events/2013-friends-brookings-conference-clinical-cancer-research. Accessed August 8, 2014.

    • Search Google Scholar
    • Export Citation
  • 30.

    Trial offers new model for drug development. Cancer Discov 2014;4:266267.

  • 31.

    Fox JL. Master Protocol for squamous cell lung cancer readies for launch. Nat Biotechnol 2014;32:116118.

  • 32.

    Abrams J, Conley B, Mooney M et al.. National Cancer Institute’s Precision Medicine Initiatives for the new National Clinical Trials Network. Am Soc Clin Oncol Educ Book 2014;34:7176.

    • Search Google Scholar
    • Export Citation
  • 33.

    Tsimberidou AM, Iskander NG, Hong DS et al.. Personalized medicine in a phase I clinical trials program: the MD Anderson Cancer Center initiative. Clin Cancer Res 2012;18:63736383.

    • Search Google Scholar
    • Export Citation
  • 34.

    Arcila M, Lau C, Nafa K, Ladanyi M. Detection of KRAS and BRAF mutations in colorectal carcinoma roles for high-sensitivity locked nucleic acid-PCR sequencing and broad-spectrum mass spectrometry genotyping. J Mol Diagn 2011;13:6473.

    • Search Google Scholar
    • Export Citation
  • 35.

    Kabiawu Ajise OE, Feldstein JT, Soslow R et al.. Assessment of BRAF V600E mutation status by immunohistochemistry in lung and ovarian carcinomas [abstract]. Mod Pathol 2013;26(Suppl 2):Abstract 2060.

    • Search Google Scholar
    • Export Citation
  • 36.

    Liu Y, Casanova J, Nafa K et al.. Detection of BRAF V600E mutation in hairy cell leukemia: comparison of high-sensitivity locked nucleic acid-PCR sequencing and IHC with the VE1 mutation-specific antibody. J Mol Diagn 2013;15:871872.

    • Search Google Scholar
    • Export Citation
  • 37.

    Levy MA, Lovly CM, Horn L et al.. My Cancer Genome: Web-based clinical decision support for genome-directed lung cancer treatment [abstract]. J Clin Oncol 2011;29(Suppl):Abstract 7576.

    • Search Google Scholar
    • Export Citation
  • 38.

    Van Allen EM, Wagle N, Levy MA. Clinical analysis and interpretation of cancer genome data. J Clin Oncol 2013;31:18251833.

  • 39.

    Carney PH. Information technology and precision medicine. Semin Oncol Nurs 2014;30:124129.

  • 40.

    Levy MA, Lovly CM, Pao W. Translating genomic information into clinical medicine: lung cancer as a paradigm. Genome Res 2012;22:21012108.

  • 41.

    SEER Stat Fact Sheets: melanoma of the skin. SEER Web site. Available at: http://seer.cancer.gov/statfacts/html/melan.html. Accessed August 8, 2014.

    • Search Google Scholar
    • Export Citation
  • 42.

    Davies H, Bignell GR, Cox C et al.. Mutations of the BRAF gene in human cancer. Nature 2002;417:949954.

  • 43.

    Hall RD, Kudchadkar RR. BRAF mutations: signaling, epidemiology, and clinical experience in multiple malignancies. Cancer Control 2014;21:221230.

    • Search Google Scholar
    • Export Citation
  • 44.

    Chapman PB, Hauschild A, Robert C et al.. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:25072516.

  • 45.

    Flaherty KT, Infante JR, Daud A et al.. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012;367:16941703.

  • 46.

    Turajlic S, Furney SJ, Stamp G et al.. Whole-genome sequencing reveals complex mechanisms of intrinsic resistance to BRAF inhibition. Ann Oncol 2014;25:959967.

    • Search Google Scholar
    • Export Citation
  • 47.

    Falchook GS, Lewis KD, Infante JR et al.. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol 2012;13:782789.

    • Search Google Scholar
    • Export Citation
  • 48.

    Falchook GS, Long GV, Kurzrock R et al.. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet 2012;379:18931901.

    • Search Google Scholar
    • Export Citation
  • 49.

    Sosman JA, Daud A, Weber JS et al.. BRAF inhibitor (BRAFi) dabrafenib in combination with the MEK1/2 inhibitor (MEKi) trametinib in BRAFi-naive and BRAFi-resistant patients (pts) with BRAF mutation-positive metastatic melanoma (MM) [abstract]. J Clin Oncol 2013;31(Suppl):Abstract 9005.

    • Search Google Scholar
    • Export Citation
  • 50.

    Haarberg HE, Smalley KS. Resistance to Raf inhibition in cancer. Drug Discov Today Technol 2014;11:2732.

  • 51.

    Huang V, Hepper D, Anadkat M, Cornelius L. Cutaneous toxic effects associated with vemurafenib and inhibition of the BRAF pathway. Arch Dermatol 2012;148:628633.

    • Search Google Scholar
    • Export Citation
  • 52.

    Sloot S, Fedorenko IV, Smalley KS, Gibney GT. Long-term effects of BRAF inhibitors in melanoma treatment: friend or foe? Expert Opin Pharmacother 2014;15:589592.

    • Search Google Scholar
    • Export Citation
  • 53.

    Perez-Lorenzo R, Zheng B. Targeted inhibition of BRAF kinase: opportunities and challenges for therapeutics in melanoma. Biosci Rep 2012;32:2533.

    • Search Google Scholar
    • Export Citation
  • 54.

    Holderfield M, Deuker MM, McCormick F, McMahon M. Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond. Nat Rev Cancer 2014;14:455467.

    • Search Google Scholar
    • Export Citation
  • 55.

    Planchard D, Mazieres J, Riely GJ et al.. Interim results of phase II study BRF113928 of dabrafenib in BRAF V600E mutation-positive non-small cell lung cancer (NSCLC) patients [abstract]. J Clin Oncol 2013;31(Suppl):Abstract 8009.

    • Search Google Scholar
    • Export Citation
  • 56.

    Kopetz S, Desai J, Chan E et al.. PLX4032 in metastatic colorectal cancer patients with mutant BRAF tumors [abstract]. J Clin Oncol 2010;28(Suppl):Abstract 3534.

    • Search Google Scholar
    • Export Citation
  • 57.

    Prahallad A, Sun C, Huang S et al.. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 2012;483:100103.

    • Search Google Scholar
    • Export Citation
  • 58.

    Kris MG, Johnson BE, Berry LD et al.. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 2014;311:19982006.

    • Search Google Scholar
    • Export Citation
  • 59.

    Mok TS, Wu YL, Thongprasert S et al.. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947957.

  • 60.

    Rosell R, Moran T, Queralt C et al.. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009;361:958967.

  • 61.

    Yang JC, Shih JY, Su WC et al.. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncol 2012;13:539548.

    • Search Google Scholar
    • Export Citation
  • 62.

    Shaw AT, Engelman JA. ALK in lung cancer: past, present, and future. J Clin Oncol 2013;31:11051111.

  • 63.

    Camidge DR, Pao W, Sequist LV. Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol 2014;11:473481.

  • 64.

    Kwak EL, Bang YJ, Camidge DR et al.. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010;363:16931703.

  • 65.

    Camidge DR, Bang YJ, Kwak EL et al.. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol 2012;13:10111019.

    • Search Google Scholar
    • Export Citation
  • 66.

    Kwak EL, Camidge DR, Clark J et al.. Clinical activity observed in a phase I dose escalation trial of an oral c-met and ALK inhibitor, PF-02341066 [abstract]. J Clin Oncol 2009;27(Suppl):Abstract 3509.

    • Search Google Scholar
    • Export Citation
  • 67.

    Hanna N, Shepherd FA, Fossella FV et al.. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004;22:15891597.

    • Search Google Scholar
    • Export Citation
  • 68.

    Shaw AT, Kim DW, Nakagawa K et al.. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013;368:23852394.

  • 69.

    Weickhardt AJ, Scheier B, Burke JM et al.. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. J Thorac Oncol 2012;7:18071814.

    • Search Google Scholar
    • Export Citation
  • 70.

    Costa DB, Kobayashi S, Pandya SS et al.. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol 2011;29:e443445.

  • 71.

    Lin NU, Lee EQ, Aoyama H et al.. Challenges relating to solid tumour brain metastases in clinical trials, part 1: patient population, response, and progression. A report from the RANO group. Lancet Oncol 2013;14:e396406.

    • Search Google Scholar
    • Export Citation
  • 72.

    Riely GJ, Kris MG, Zhao B et al.. Prospective assessment of discontinuation and reinitiation of erlotinib or gefitinib in patients with acquired resistance to erlotinib or gefitinib followed by the addition of everolimus. Clin Cancer Res 2007;13:51505155.

    • Search Google Scholar
    • Export Citation
  • 73.

    Weickhardt A, Doebele R, Oton A et al.. A phase I/II study of erlotinib in combination with the anti-insulin-like growth factor-1 receptor monoclonal antibody IMC-A12 (cixutumumab) in patients with advanced non-small cell lung cancer. J Thorac Oncol 2012;7:419426.

    • Search Google Scholar
    • Export Citation
  • 74.

    Hutchins G, Southward K, Handley K et al.. Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. J Clin Oncol 2011;29:12611270.

    • Search Google Scholar
    • Export Citation
  • 75.

    Marshall JL. Risk assessment in Stage II colorectal cancer. Oncology (Williston Park) 2010;24:913.

  • 76.

    Sanz-Pamplona R, Berenguer A, Cordero D et al.. Clinical value of prognosis gene expression signatures in colorectal cancer: a systematic review. PLoS One 2012;7:e48877.

    • Search Google Scholar
    • Export Citation
  • 77.

    Gavin PG, Colangelo LH, Fumagalli D et al.. Mutation profiling and microsatellite instability in stage II and III colon cancer: an assessment of their prognostic and oxaliplatin predictive value. Clin Cancer Res 2012;18:65316541.

    • Search Google Scholar
    • Export Citation
  • 78.

    Douillard JY, Rong A, Sidhu R. RAS mutations in colorectal cancer. N Engl J Med 2013;369:21592160.

  • 79.

    Douillard JY, Oliner KS, Siena S et al.. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 2013;369:10231034.

  • 80.

    COSMIC: Catalogue of Somatic Mutations in Cancer. Available at: http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/. Accessed August 8, 2014.

    • Search Google Scholar
    • Export Citation
  • 81.

    Lochhead P, Kuchiba A, Imamura Y et al.. Microsatellite instability and BRAF mutation testing in colorectal cancer prognostication. J Natl Cancer Inst 2013;105:11511156.

    • Search Google Scholar
    • Export Citation
  • 82.

    Hann CL, Rudin CM. Fast, hungry and unstable: finding the Achilles’ heel of small-cell lung cancer. Trends Mol Med 2007;13:150157.

  • 83.

    Kalemkerian GP, Jiroutek M, Ettinger DS et al.. A phase II study of all-trans-retinoic acid plus cisplatin and etoposide in patients with extensive stage small cell lung carcinoma: an Eastern Cooperative Oncology Group Study. Cancer 1998;83:11021108.

    • Search Google Scholar
    • Export Citation
  • 84.

    Peifer M, Fernandez-Cuesta L, Sos ML et al.. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet 2012;44:11041110.

    • Search Google Scholar
    • Export Citation
  • 85.

    Rudin CM, Durinck S, Stawiski EW et al.. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet 2012;44:11111116.

    • Search Google Scholar
    • Export Citation
  • 86.

    Sos ML, Dietlein F, Peifer M et al.. A framework for identification of actionable cancer genome dependencies in small cell lung cancer. Proc Natl Acad Sci U S A 2012;109:1703417039.

    • Search Google Scholar
    • Export Citation
  • 87.

    Boldrini L, Ursino S, Gisfredi S et al.. Expression and mutational status of c-kit in small-cell lung cancer: prognostic relevance. Clin Cancer Res 2004;10:41014108.

    • Search Google Scholar
    • Export Citation
  • 88.

    LaPoint RJ, Bourne PA, Wang HL, Xu H. Coexpression of c-kit and bcl-2 in small cell carcinoma and large cell neuroendocrine carcinoma of the lung. Appl Immunohistochem Mol Morphol 2007;15:401406.

    • Search Google Scholar
    • Export Citation
  • 89.

    Lopez-Martin A, Ballestin C, Garcia-Carbonero R et al.. Prognostic value of KIT expression in small cell lung cancer. Lung Cancer 2007;56:405413.

  • 90.

    Naeem M, Dahiya M, Clark JI et al.. Analysis of c-kit protein expression in small-cell lung carcinoma and its implication for prognosis. Hum Pathol 2002;33:11821187.

    • Search Google Scholar
    • Export Citation
  • 91.

    Rossi G, Cavazza A, Marchioni A et al.. Kit expression in small cell carcinomas of the lung: effects of chemotherapy. Mod Pathol 2003;16:10411047.

  • 92.

    Sihto H, Sarlomo-Rikala M, Tynninen O et al.. KIT and platelet-derived growth factor receptor alpha tyrosine kinase gene mutations and KIT amplifications in human solid tumors. J Clin Oncol 2005;23:4957.

    • Search Google Scholar
    • Export Citation
  • 93.

    Dy GK, Miller AA, Mandrekar SJ et al.. A phase II trial of imatinib (ST1571) in patients with c-kit expressing relapsed small-cell lung cancer: a CALGB and NCCTG study. Ann Oncol 2005;16:18111816.

    • Search Google Scholar
    • Export Citation
  • 94.

    Krug LM, Crapanzano JP, Azzoli CG et al.. Imatinib mesylate lacks activity in small cell lung carcinoma expressing c-kit protein: a phase II clinical trial. Cancer 2005;103:21282131.

    • Search Google Scholar
    • Export Citation
  • 95.

    Schneider BJ, Kalemkerian GP, Ramnath N et al.. Phase II trial of imatinib maintenance therapy after irinotecan and cisplatin in patients with c-Kit-positive, extensive-stage small-cell lung cancer. Clin Lung Cancer 2010;11:223227.

    • Search Google Scholar
    • Export Citation
  • 96.

    SEER Stat Fact Sheets: kidney and renal pelvis cancer. SEER Web site. Available at: http://seer.cancer.gov/statfacts/html/kidrp.html. Accessed August 8, 2014.

    • Search Google Scholar
    • Export Citation
  • 97.

    Di Napoli A, Signoretti S. Tissue biomarkers in renal cell carcinoma: issues and solutions. Cancer 2009;115:22902297.

  • 98.

    Choueiri TK. Clinical treatment decisions for advanced renal cell cancer. J Natl Compr Canc Netw 2013;11:694697.

  • 99.

    Hudes GR, Carducci MA, Choueiri TK et al.. NCCN Task Force report: optimizing treatment of advanced renal cell carcinoma with molecular targeted therapy. J Natl Compr Canc Netw 2011;9(Suppl 1):S129.

    • Search Google Scholar
    • Export Citation
  • 100.

    Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol 2012;24:207212.

    • Search Google Scholar
    • Export Citation
  • 101.

    Thompson RH, Dong H, Kwon ED. Implications of B7-H1 expression in clear cell carcinoma of the kidney for prognostication and therapy. Clin Cancer Res 2007;13:709s715s.

    • Search Google Scholar
    • Export Citation
  • 102.

    Topalian SL, Hodi FS, Brahmer JR et al.. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:24432454.

  • 103.

    Cho DC, Sosman JA, Sznol M et al.. Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with metastatic renal cell carcinoma (mRCC) [abstract]. J Clin Oncol 2013;31(Suppl):Abstract 4505.

    • Search Google Scholar
    • Export Citation
  • 104.

    Choueiri TK, Fishman MN, Escudier BJ et al.. Immunomodulatory activity of nivolumab in previously treated and untreated metastatic renal cell carcinoma (mRCC): Biomarker-based results from a randomized clinical trial [abstract]. J Clin Oncol 2014;32(Suppl):Abstract 5012.

    • Search Google Scholar
    • Export Citation
  • 105.

    Armstrong DK, Bundy B, Wenzel L et al.. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006;354:3443.

  • 106.

    McCluggage WG. Morphological subtypes of ovarian carcinoma: a review with emphasis on new developments and pathogenesis. Pathology 2011;43:420432.

    • Search Google Scholar
    • Export Citation
  • 107.

    Bookman MA. Molecular wanderings through the DNA damage response and risk for ovarian cancer. J Natl Cancer Inst 2014;106:djt350.

  • 108.

    Bast RC Jr, Hennessy B, Mills GB. The biology of ovarian cancer: new opportunities for translation. Nat Rev Cancer 2009;9:415428.

  • 109.

    Bast RC Jr. CA 125 and the detection of recurrent ovarian cancer: a reasonably accurate biomarker for a difficult disease. Cancer 2010;116:28502853.

    • Search Google Scholar
    • Export Citation
  • 110.

    Bast RC Jr, Feeney M, Lazarus H et al.. Reactivity of a monoclonal antibody with human ovarian carcinoma. J Clin Invest 1981;68:13311337.

  • 111.

    Kaneko O, Gong L, Zhang J et al.. A binding domain on mesothelin for CA125/MUC16. J Biol Chem 2009;284:37393749.

  • 112.

    Rustin GJ, van der Burg ME, Griffin CL et al.. Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial. Lancet 2010;376:11551163.

    • Search Google Scholar
    • Export Citation
  • 113.

    Paik S, Shak S, Tang G et al.. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 2004;351:28172826.

    • Search Google Scholar
    • Export Citation
  • 114.

    Sorlie T, Perou CM, Tibshirani R et al.. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 2001;98:1086910874.

    • Search Google Scholar
    • Export Citation
  • 115.

    Goldhirsch A, Winer EP, Coates AS et al.. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol 2013;24:22062223.

    • Search Google Scholar
    • Export Citation
  • 116.

    Nielsen T, Wallden B, Schaper C et al.. Analytical validation of the PAM50-based Prosigna Breast Cancer Prognostic Gene Signature Assay and nCounter Analysis System using formalin-fixed paraffin-embedded breast tumor specimens. BMC Cancer 2014;14:177.

    • Search Google Scholar
    • Export Citation
  • 117.

    Martin M, Brase JC, Calvo L et al.. Clinical validation of the EndoPredict test in node-positive, chemotherapy-treated ER+/HER2-breast cancer patients: results from the GEICAM 9906 trial. Breast Cancer Res 2014;16:R38.

    • Search Google Scholar
    • Export Citation
  • 118.

    Connolly RM, Stearns V. Current approaches for neoadjuvant chemotherapy in breast cancer. Eur J Pharmacol 2013;717:5866.

  • 119.

    Cortazar P, Zhang L, Untch M et al.. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014;384:164172.

    • Search Google Scholar
    • Export Citation
  • 120.

    Goncalves R, Ma C, Luo J et al.. Use of neoadjuvant data to design adjuvant endocrine therapy trials for breast cancer. Nat Rev Clin Oncol 2012;9:223229.

    • Search Google Scholar
    • Export Citation
  • 121.

    Paik S, Kim C, Wolmark N. HER2 status and benefit from adjuvant trastuzumab in breast cancer. N Engl J Med 2008;358:14091411.

  • 122.

    Carey LA, Dees EC, Sawyer L et al.. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 2007;13:23292334.

    • Search Google Scholar
    • Export Citation
  • 123.

    Lehmann BD, Bauer JA, Chen X et al.. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 2011;121:27502767.

    • Search Google Scholar
    • Export Citation
  • 124.

    Department of Health and Human Services. Limited competition: biospecimen banks to support NCI-Clinical Trials Network (NCTN) (U24). Available at: http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-14-501.html#_Part_2._Full. Accessed August 8, 2014.

    • Search Google Scholar
    • Export Citation
  • 125.

    Department of Health and Human Services. NCI to provide $12M for biobanks to support Clinical Trials Network. Available at: http://www.genomeweb.com/nci-provide-12m-biobanks-support-clinical-trials-network. Accessed August 6, 2014.

    • Search Google Scholar
    • Export Citation
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 575 325 95
PDF Downloads 80 51 4
EPUB Downloads 0 0 0