Cancer is a disease of genomic alterations and, based on the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines), the use of therapeutic agents that target specific genomic alterations is standard of care for several tumor types, including lung and breast carcinomas.1,2 First-line treatment of lung adenocarcinomas that have a sensitizing EGFR mutation or ALK rearrangement includes the use of a tyrosine kinase inhibitor, such as erlotinib or crizotinib, whereas ceritinib is currently approved for ALK-positive patients in the second-line setting.2 Similarly, first-line treatment of breast carcinomas with amplification of ERBB2 (HER2) includes trastuzumab and pertuzumab, whereas in the second-line setting, ado-trastuzumab emtansine and lapatinib have been approved (NCCN Guidelines for Breast Cancer).1 Given the central role of targeted agents in the management of patients with tumors harboring these types of changes, testing for genomic alterations is recommended as part of the workup in the NCCN Guidelines for several tumor types. Importantly, as the number of clinically relevant genes and targeted therapies for different tumor types expand, testing using a multiplex, high-throughput next-generation sequencing (NGS) platform offers a method for analyzing the mutation status of multiple cancer-related genes, thus providing a genetic mutational profile of the tumor. This article describes a case in which the unique cancer signature (genetic mutational profile) of a tumor not only established the correct diagnosis, but also dramatically changed the course of treatment.
Dr. Boumber has disclosed that he receives research support from Synta Pharmaceuticals Corp for product development; is on the advisory board for Bristol-Myers Squibb Company and Clovis Oncology; and is on the speakers' bureau for Synta Pharmaceuticals Corp. The remaining authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.
Wolff AC, Hammond ME, Schwartz JN. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 2007;25:118–145.
Wolff AC, Hammond ME, Hicks DG. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 2013;31:3997–4013.
Dent R, Hanna WM, Trudeau M. Pattern of metastatic spread in triple-negative breast cancer. Breast Cancer Res Treat 2009;115:423–428.
Dent R, Trudeau M, Pritchard KI. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 2007;13(15 Pt 1):4429–4434.
Lin NU, Claus E, Sohl J. Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases. Cancer 2008;113:2638–2645.
Mazieres J, Peters S, Lepage B. Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives. J Clin Oncol 2013;31:1997–2003.
Bose R, Kavuri SM, Searleman AC. Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov 2013;3:224–237.
Anders CK, Carey LA. Biology, metastatic patterns, and treatment of patients with triple-negative breast cancer. Clin Breast Cancer 2009;9(Suppl 2):S73–81.
Su YC, Hsu YC, Chai CY. Role of TTF-1, CK20, and CK7 immunohistochemistry for diagnosis of primary and secondary lung adenocarcinoma. Kaohsiung J Med Sci 2006;22:14–19.
Dennis JL, Hvidsten TR, Wit EC. Markers of adenocarcinoma characteristic of the site of origin: development of a diagnostic algorithm. Clin Cancer Res 2005;11:3766–3772.
Robens J, Goldstein L, Gown AM, Schnitt SJ. Thyroid transcription factor-1 expression in breast carcinomas. Am J Surg Pathol 2010;34:1881–1885.
Erlander MG, Ma XJ, Kesty NC. Performance and clinical evaluation of the 92-gene real-time PCR assay for tumor classification. J Mol Diagn 2011;13:493–503.
Varadhachary G. New strategies for carcinoma of unknown primary: the role of tissue-of-origin molecular profiling. Clin Cancer Res 2013;19:4027–4033.
Ettinger DS, Handorf CR, Agulnik M. Occult primary, version 3.2014. J Natl Compr Canc Netw 2014;12:969–974. To view the most recent version of these guidelines, visit NCCN.org.
Ganesan P, Moulder S, Lee JJ. Triple-negative breast cancer patients treated at MD Anderson Cancer Center in phase I trials: improved outcomes with combination chemotherapy and targeted agents. Mol Cancer Ther 2014;13:3175–3184.
Tsimberidou AM, Iskander NG, Hong DS. Personalized medicine in a phase I clinical trials program: the MD Anderson Cancer Center initiative. Clin Cancer Res 2012;18:6373–6383.
Weber JS, Levit LA, Adamson PC. American Society of Clinical Oncology policy statement update: the critical role of phase I trials in cancer research and treatment. J Clin Oncol 2015;33:278–284.
Abrams J, Conley B, Mooney M. National Cancer Institute's precision medicine initiatives for the new national clinical trials network. Am Soc Clin Oncol Educ Book 2014:71–76.
Fabi A, Di Benedetto A, Metro G. HER2 protein and gene variation between primary and metastatic breast cancer: significance and impact on patient care. Clin Cancer Res 2011;17:2055–2064.
Curtit E, Nerich V, Mansi L. Discordances in estrogen receptor status, progesterone receptor status, and HER2 status between primary breast cancer and metastasis. Oncologist 2013;18:667–674.
Liedtke C, Broglio K, Moulder S. Prognostic impact of discordance between triple-receptor measurements in primary and recurrent breast cancer. Ann Oncol 2009;20:1953–1958.
Phillips KA, Pletcher MJ, Ladabaum U. Is the “$1000 Genome” really $1000? Understanding the full benefits and costs of genomic sequencing [published online ahead of print February 6, 2015]. Technol Health Care, in press.
Aertgeerts K, Skene R, Yano J. Structural analysis of the mechanism of inhibition and allosteric activation of the kinase domain of HER2 protein. J Biol Chem 2011;286:18756–18765.
Stamos J, Sliwkowski MX, Eigenbrot C. Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J Biol Chem 2002;277:46265–46272.
Baselga J, Cortes J, Kim SB. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012;366:109–119.
Pettersen EF, Goddard TD, Huang CC. UCSF Chimera—a visualization system for exploratory research and analysis. J Comput Chem 2004;25:1605–1612.
Hall TA. BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucleic Acids Symp Ser 1999;41:95–98.