FeatureCommunity Report Genomic oncology: moving beyond the tip of the iceberg Jane de Lartigue, PhD istorically, cancer has been diagnosed and in patients with lung cancer, even the most efec- treated on the basis of the tissue of ori- tive targeted therapies can fail if used in the wrong Hgin. Te promise of personalized therapy, patient population.5,6 matched more precisely to an individual’s tumor, In recognition of this issue, the oncology feld has was ushered in with the development of molecularly developed molecular biomarkers that can predict targeted therapies, based on a greater understanding response, or lack thereof, to targeted therapy. Drugs of cancer as a genomic-driven disease. Here, we dis- are now commonly being evaluated in trials that cuss some of the evolution of genomic oncology, the select eligible patients on the basis of biomarker pos- inherent complexities and challenges, and how novel itivity, and a number of companion diagnostics have clinical trial designs are among the strategies being been codeveloped to assist in these eforts (Table 1). developed to address them and shape the future of Notable successes include the development of the personalized medicine in cancer. monoclonal antibody trastuzumab for patients with breast cancers that have human epidermal growth The evolution of genomic oncology factor receptor 2 (HER2) gene amplifcation or In the 15 years since the frst map of the human HER2 protein overexpression,7 and the small mol- genome emerged, genetics has become an inte- ecule BRAF kinase inhibitor vemurafenib in mela- gral part of medical practice worldwide.1 Oncology noma patients with mutations in the BRAF gene.8 is no exception; the genetic origins of cancer were Te rapid clinical development of anaplastic lym- suspected more than a century ago and it is now phoma kinase (ALK) inhibitors like crizotinib for well understood that most cancers are driven by the treatment of ALK-driven non-small-cell lung genetic alterations that disrupt key cellular pathways cancer (NSCLC), demonstrates the potential for involved in tumor survival and progression.2 more streamlined development of drugs when tar- Drugs targeting these alterations have been geted patient populations are evaluated from an ear- developed, giving rise to a novel treatment para- lier stage.9 digm. Genomic oncology uses the genetic aberra- Te identifcation of molecular drivers in various tions within a tumor to direct “personalized” cancer cancer types and the development of biomarker- care with targeted therapies that include biologics, based diagnostics, to identify patients with these small molecules, and immunotherapies.3 Te small specifc alterations, have helped to select patients molecule tyrosine kinase inhibitor imatinib was the most likely to beneft from targeted therapies, prototypical targeted cancer drug and demonstrated resulting in the approval of more than 30 targeted signifcant success in patients with chronic myeloid therapies for oncologic indications.4 However, in leukemia (CML) whose disease is driven by a chro- the decades following the development of ima- mosomal aberration that results in a fusion between tinib, researchers have come to realize that it is an the breakpoint cluster region (BCR) and Abelson exception rather than the rule. CML is driven pre- murine leukemia viral oncogene homolog 1 (ABL) dominantly by a single genetic driver – BCR-ABL genes.4 – identifed in more than 90% of patients, but in Targeted therapies such as imatinib can be safer the majority of cancer types, there may be multiple and more efective than broad-acting, indiscrimi- drivers in play, which are all causally implicated in nate cytotoxic therapies like chemotherapy, but it the development and progression of a given tumor. has become increasingly clear that greater efect In addition to these drivers, studies have unveiled a is derived from these drugs when they are used host of molecular alterations that occur as a result of in molecularly-selected patient sub-populations. the genetic disarray of cancer and don’t necessarily Indeed, as exemplifed by the use of epidermal confer a selective advantage to the tumor, so-called growth factor receptor (EGFR)-targeted therapy passenger mutations. Distinguishing between the JCSO 2015;13:300-306. ©2015 Frontline Medical Communications. DOI 10.12788/jcso.0157. 300 THE JOURNAL OF COMMUNITY AND SUPPORTIVE ONCOLOGY g August 2015 www.jcso-online.com New Therapies TABLE 1 Oncology drugs FDA-approved in molecularly-defned patient populations Molecular alteration Cancer Type Approved drugs Approved companion diagnostics ALK gene rearrangements NSCLC Crizotinib (Xalkori; Pfzer) VYSIS ALK Break Apart FISH Probe Kit Ceritinib (Zykadia; Novartis) (Abbott Molecular) BCR-ABL translocation CML and AML Imatinib (Gleevec; Novartis) To date there are no FDA-approved tests Dasatinib (Spycel; Bristol-Myers for BCR-ABL, tests are available only as Squibb) laboratory developed tests regulated Nilotinib (Tasigna; Novartis) under CLIA. Bosutinib (Bosulif; Pfzer) Ponatinib (Iclusig; Ariad Pharmaceuticals) BRAF V600E/K mutation Melanoma Vemurafenib (Zelboraf; Genentech/ THxID BRAF Kit (bioMerieux) Daiichi Sankyo) Cobas 4800 BRAF V600 Mutation Test Dabrafenib (Tafnlar; GlaxoSmithKline) (Roche Molecular Systems) Trametinib (Mekinist; GlaxoSmithKline) BRCA1/2 mutation Ovarian cancer Olaparib (Lynparza; AstraZeneca) BRACAnalysis CDx (germline) c-KIT mutation GIST Imatinib DAKO c-KIT PharmDx Kit (Dako) Sunitinib (Sutent: Pfzer) EGFR mutations NSCLC Afatinib (Gilotrif; Boehringer Ingelheim) Therascreen EGFR RGQ PCR Kit (Qiagen) Erlotinib (Tarceva; Genentech) Cobas EGFR Mutation Kit (Roche Molecular Systems) EGFR protein Colorectal cancer Cetuximab (Erbitux; Bristol-Myers DAKO EGFR PharmDx Kit overexpression Squibb/Eli Lilly) Panitumumab (Vectibix; Amgen) HER2 protein Breast cancer Trastuzumab (Herceptin; Genentech) PATHWAY ANTI-HER2 (4B5) Rabbit overexpression Pertuzumab (Perjeta; Roche) Monoclonal Antibody Lapatinib (Tykerb; GlaxoSmithKline) HERCEPTEST T-DM1 (Kadcyla; Genentech) HER2 amplifcation Breast cancer Trastuzumab INFORM HER2/NEU (Ventana Medical Gastric cancer Lapatinib Systems) Pertuzumab PATHYVISION HER2 DNA Probe Kit T-DM1 (Abbott Molecular) SPOT-LIGHT HER2 CISH Kit (Life Technologies) HER2 CISH PharmDx Kit (Dako) INFORM HER2 DUAL ISH DNA Probe Cocktail (Ventana Medical Systems) HER2 FISH PharmDx Kit (Dako) KRAS mutation-negative Colorectal cancer Cetuximab (Erbitux; Bristol-Myers Therascreen KRAS RCQ PCR Kit (Qiagen) Squibb/Eli Lilly) Panitumumab (Vectibix; Amgen) ALK, anaplastic lymphoma kinase; NSCLC, non-small cell lung cancer; FISH, fuorescent in situ hybridization; CML, chronic myeloid leukemia; AML, acute myeloid leu- kemia; FDA, US food and drug administration; CLIA, clinical laboratory improvement amendments; BRCA, breast cancer susceptibility gene; GIST, gastrointestinal stro- mal tumors; EGFR, epidermal growth factor receptor; PCR, polymerase chain reaction; HER2, human epidermal growth factor receptor 2; DNA, deoxyribose nucleic acid; CISH, chromogenic in situ hybridization; ISH, in situ hybridization two can be a daunting task10 and, adding to the challenge, recurrence all but inevitable. Many lessons have been learnt researchers have recently identifed another type of altera- from these failures and limitations and it is becoming tion – latent drivers, which are mutations that behave like increasingly clear that we have merely touched the tip of passengers but, coupled with other mutations, can drive the iceberg in genomic oncology. cancer development and drug resistance.11 In spite of many laudable successes, there have been a Cataloguing cancer genes greater number of failures in the development of targeted Since the early days of the Human Genome Project, the therapies. Furthermore, they have not proven to be the cure development of next-generation sequencing (NGS) tech- many hoped for; responses are often short-lived and tumor nologies have made it substantially cheaper and faster to Volume 13/Number 8 August 2015 J THE JOURNAL OF COMMUNITY AND SUPPORTIVE ONCOLOGY 301 Feature sequence an entire genome. We have entered the much- mal tissue pairs in 21 tumor types. Using a technique called anticipated era of the “$1,000 genome” from a cost of several down-sampling, the researchers examined how the number hundred million dollars just a decade ago.12 Oncologists of cancer genes identifed changes with sample size. Tey are taking advantage of the ready availability of this tech- found that there is still an upward trend in the cancer gene nology to sequence tumor genomes using biopsied samples discovery curve, which suggests that many novel genes are in an efort to unravel the molecular underpinnings of dif- yet to be discovered; indeed, this study itself identifed 33 ferent cancers and facilitate broader, more efective imple- new cancer genes.18 mentation of personalized cancer therapy. Te National Cancer Institute (NCI) and National Challenges and complexity Human Genome Research Initiative (NHGRI) funded Te identifcation of novel cancer genes and the wide- Te Cancer Genome Atlas (TCGA) in 2006 in a compre- spread clinical application of this vast array of genomic data hensive and coordinated efort to catalog all cancer genes, to guide personalized medicine is not without challenges. starting with ovarian cancer and glioblastoma multiforme Pan-cancer analyses, such as the Lawrence et al study, have and expanding to include samples from 11,000 patients highlighted one of the most