A Phase I Pharmacologic Study of Necitumumab (IMC-11F8), a Fully Human IgG1 Monoclonal Antibody

The Mammary Prevention 3 (MAP.3) placebo-controlled randomized trial in 4,560 high-risk postmenopausal women showed a 65% reduction in invasive breast cancer with the use of exemestane at 35 months of median follow-up. Few differences in adverse events were observed between the arms, suggesting a promising risk:benefi t balance with exemestane for use in chemoprevention. Yet, the MAP.3 design and implementation raise concerns about limited data maturity and not prospectively including key bone-related and other toxicities as study endpoints. Exemestane for prevention is juxtaposed against selective estrogen receptor modulators and the other aromatase inhibitors. Additional issues for prevention, including the infl uence of obesity, alternative dosing, and biomarker use in phase III trials, are addressed. SIGNIFICANCE: The recently completed MAP.3 trial of exemestane for breast cancer prevention offers a potential new standard for pharmaceutical risk reduction in high-risk postmenopausal women. In addition to describing key fi ndings from the publication of MAP.3 and related trials, our review undertakes a detailed analysis of the strengths and weaknesses of MAP.3 as well as the implications for future prevention research. Cancer Discov; 2(X); XXX–XXX. ©2012 AACR. ABSTRACT Cisplatin-based chemotherapy is the standard of care for patients with muscle-invasive urothelial carcinoma. Pathologic downstaging to pT0/pTis after neoadjuvant cisplatin-based chemotherapy is associated with improved survival, although molecular determinants of cisplatin response are incompletely understood. We performed whole-exome sequencing on pretreatment tumor and germline DNA from 50 patients with muscle-invasive urothelial carcinoma who received neoadjuvant cisplatin-based chemotherapy followed by cystectomy (25 pT0/pTis “responders,” 25 pT2+ “nonresponders”) to identify somatic mutations that occurred preferentially in responders. ERCC2 , a nucleotide excision repair gene, was the only signifi cantly mutated gene enriched in the cisplatin responders compared with nonresponders ( q < 0.01). Expression of representative ERCC2 mutants in an ERCC2 -defi cient cell line failed to rescue cisplatin and UV sensitivity compared with wild-type ERCC2. The lack of normal ERCC2 function may contribute to cisplatin sensitivity in urothelial cancer, and somatic ERCC2 mutation status may inform cisplatin-containing regimen usage in muscle-invasive urothelial carcinoma. SIGNIFICANCE: Somatic ERCC2 mutations correlate with complete response to cisplatin-based chemosensitivity in muscle-invasive urothelial carcinoma, and clinically identifi ed mutations lead to cisplatin sensitivity in vitro . Nucleotide excision repair pathway defects may drive exceptional response to conventional chemotherapy. Cancer Discov; 4(10); 1140–53. ©2014 AACR. See related commentary by Turchi et al., p. 1118. Som tic ERCC2 Mutations Correlate with Cisplatin Sensitivity in Muscle-Invasive Urothelial Carcinoma Eliez r M. Van Allen 1,2 , Kent W. Mouw 3,4 , Philip Kim 5 , Gopa Iyer 6,7 , Nikhil Wagle 1,2 , Hikmat Al-Ahmadie 6,8 , Cong Zhu 2 , Irina Ostrovnaya 9 , Gregory V. Kryukov 2 , Kevin W. O’Connor 3 , John Sfakianos 5 , Ilana Garcia-Grossman 7 , Jaegil Kim 2 , Elizabeth A. Guancial 10 , Richard Bambury 7 , Samira Bahl 2 , Namrata Gupta 2 , Deborah Farlow 2 , Angela Qu 1 , Sabina Signoretti 11 , Justine A. Barletta 11 , Victor Reuter 6,8 , Jesse Boehm 2 , Michael Lawrence 2 , Gad Getz 2,12 , Philip Kantoff 1 , Bernard H. Bochner 5,6 , Toni K. Choueiri 1 , Dean F. Bajorin 6,7 , David B. Solit 6,7,13 , Stacey Gabriel 1 , Alan D’Andrea 3,4 , Levi A. Garraway 1,2 , and Jonathan E. Rosenberg 6,7 1 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. 2 Broad Institute of MIT and Harvard, Cambridge, Massachusetts. 3 Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. 4 Harvard Radiation Oncology Program, Boston, Massachusetts. 5 Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. 6 Weill Cornell Medical College, Cornell University, New York, New York. 7 Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. 8 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. 9 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York. 10 Division of Hematology/Oncology, Department of Medicine, University of Rochester Medical Center School of Medicine and Dentistry, Rochester, New York. 11 Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. 12 Massachusetts General Hospital Cancer Center and Department of Pathology, Boston, Massachusetts. 13 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/). E.M. Van Allen and K.W. Mouw contributed equally to this article. L.A. Garraway and J.E. Rosenberg contributed equally to this article. Corresponding Authors: Jonathan E. Rosenberg, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065. Phone: 646-422-4461; Fax: 646-227-2417; E-mail: [email protected] ; and Levi A. Garraway, Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, D1542, Boston, MA 02115. Phone: 617-632-6689; Fax: 617-582-7880; E-mail: [email protected] doi: 10.1158/2159-8290.CD-14-0623 ©2014 American Association for Cancer Research. on June 19, 2017. © 2014 American Association for Cancer Research. cancerdiscovery.aacrjournals.org Downloaded from Published OnlineFirst August 5, 2014; DOI: 10.1158/2159-8290.CD-14-0623