The delineation of signaling pathways to understand tumor biology combined with the rapid development of technologies that allow broad molecular profiling and data analysis has led to a new era of personalized medicine in oncology. Many academic institutions now routinely profile patients and discuss their cases in meetings of personalized medicine tumor boards before making treatment recommendations. Clinical trials initiated by pharmaceutical companies often require specific markers for enrollment or at least explore multiple options for future markers. In addition to the still small number of targeted agents that are approved for the therapy of patients with histological and molecularly defined tumors, a broad range of novel targeted agents in development are undergoing clinical studies with companion profiling to determine the best-responding patient population. Although the present focus of profiling lies in genetic analyses, additional tests of RNA, protein, and immune parameters are being developed and incorporated in clinical research, and these methods are likely to contribute significantly to future patient selection and treatment approaches. As the advances in tumor biology and human genetics have identified promising tumor targets, the ongoing clinical evaluation of novel agents will now need to show if the promise can be translated into benefit for patients. Clin Cancer Res; 20(17); 4425–35. ©2014 AACR.
Disclosure of Potential Conflicts of Interest
J.M. Jürgensmeier was an employee of and reports receiving a commercial research grant from AstraZeneca. R.S. Herbst reports receiving a commercial research grant from Genentech and is a consultant/advisory board member for Biothera, Diatech, Kolltan, and N-of-One. No potential conflicts of interest were disclosed by the other author.
CME Staff Planners' Disclosures
The members of the planning committee have no real or apparent conflict of interest to disclose.
Upon completion of this activity, the participant should have a better understanding of the new era of personalized medicine in oncology, particularly the advancement of signaling pathways in tumor biology, the identification of promising tumor targets through rapid developments in molecular profiling and data analysis, and the ongoing clinical evaluation of novel agents.
Acknowledgment of Financial or Other Support
This activity does not receive commercial support.
Over the past decade, the delineation of signaling pathways to understand tumor biology has laid the foundation for the discovery of novel targets and development of multiple therapies for cancer. The identification of driver mutations and critical pathway dependencies, as well as genomic sequencing and other large-scale “-omics” approaches, have facilitated the discovery and development of novel targeted anticancer therapeutics, or at least provided the scientific rationale for their development. This increased molecular understanding of tumors has led to a new era of personalized medicine that has begun to influence common practice for oncologists beyond academic institutions.
The National Cancer Institute (NCI) defines “personalized medicine,” often also called “precision medicine,” as “a form of medicine that uses information about a person's genes, proteins, and environment to prevent, diagnose, and treat disease.” Personalized medicine uses specific markers in patients' tumors to diagnose particular cancers or make treatment decisions. A specific marker may have prognostic significance for biologic behavior or predict therapeutic outcome with a particular anticancer agent. This review focuses on predictive markers associated with tumors but does not discuss host genetic factors that also can determine treatment and prognosis.
Traditionally, the site of tumor origin, together with histology, was used to make treatment decisions. This approach has been changed to include molecular tumor parameters. Markers presently used to guide decisions for personalized medicine treatment with targeted agents are either protein based [immunohistochemistry (IHC)] or based on detection of genetic aberrations and are summarized in Table 1. For genetic aberrations, a range of methods, including fluorescence in situ hybridization (FISH) tests, polymerase chain reaction (PCR), sequencing—nowadays often next-generation sequencing (NGS) of either multiple selected genes in parallel or whole exome sequencing—are used, in particular in early clinical trials or for exploratory purposes. These large panels of genes offer the opportunity not only to detect aberrations for which treatment options already exist but also to generate data on additional driver mutations or resistance pathways (1, 2). Treatment decisions may be based on the data when tests have been performed in Clinical Laboratory Improvement Amendment (CLIA)–certified laboratories.
Antihormonal agents such as tamoxifen have been used for decades, initially without molecular profiling. Studies later correlated outcome with the expression of estrogen receptor (ER), progesterone receptor (PR), and androgen receptor (AR). The presence of ER, PR, and AR not only categorizes breast and prostate cancers into different prognostic groups, but also determines treatment. Trastuzumab, a monoclonal antibody targeting human epithelial growth factor receptor-2 (HER-2), was approved for patient populations with a specific molecular profile: HER-2–overexpressing breast and gastric cancer (3–5). The first agent targeting a chromosomal translocation, imatinib, was originally approved for the treatment of Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia, based on inhibiting the Bcr–Abl tyrosine kinase (6). In 2008, based on the additional activity of imatinib to inhibit c-Kit, approval by the FDA for the treatment of adult patients with c-Kit (CD117)–positive unresectable and/or metastatic gastrointestinal stromal tumors (GIST) followed (7, 8). Other recent successes in targeting molecularly defined tumor subtypes include the development of vemurafenib for advanced BRAFV600-mutated melanoma (9), and of crizotinib for patients with non–small cell lung cancer (NSCLC) with ALK translocations (10). Molecular profiling can also lead to a negative selection, as the retrospective studies showing consistent lack of benefit from the anti-EGFR antibodies cetuximab or panitumumab in patients with colorectal cancer with KRAS codon 12/13 mutations led to the recommendation to restrict the use of these antibodies to patients with wild-type KRAS tumors (11–14).
Lung cancer has become the prototype for genetically tailored cancer therapy. The remarkable advances in understanding molecular drivers in NSCLC, together with the development of targeted agents, allow classification of NSCLC on a molecular basis, and molecular profiling has become routine practice in thoracic oncology. EGFR mutations were discovered in 2004 in parallel to the development of gefitinib, an EGFR tyrosine kinase inhibitor (TKI), when retrospective studies revealed that patients with responses harbor exon 19 deletions or exon 21 point mutations (15, 16). These findings led to the use of the EGFR TKIs gefitinib and erlotinib as initial treatment for patients with these mutations. The discovery of EGFR mutations and the large benefit of targeted treatment have boosted profiling and the search for novel targets. The development of crizotinib to treat patients with ALK fusions, detected by a FISH assay, highlights one of the outstanding successes in lung cancer with rapid development of a treatment (17). More recently, the additional activity of crizotinib in patients with ROS fusions (18, 19) was discovered, and patients with RET fusions are beginning to be treated with the RET inhibitors vandetanib and carbozantinib (20–24).
Although these targeted therapies have brought significant improvements, all patients eventually develop therapeutic resistance. Multiple resistance mechanisms have been characterized, such as secondary mutations preventing inhibitor binding, EGFR or HER2 gene amplifications, HGF/Met pathway activations as well as PI3K and BRAF mutations (25, 26). Multiple resistance mechanisms have also been identified in patients with ALK fusions who progress on crizotinib. These include ALK mutations, copy gain number, and mutations in alternative pathways, including EGFR mutations. Second- and third-generation inhibitors of EGFR and ALK, such as AZD9291 with activity against EGFRT790M and alectinib or ceritinib, especially active against the L11986M ALK mutation that confers resistance to crizotinib, are now in development with initial promising data (17, 27–32).
Multiple deregulated pathways have been identified across a range of tumor types, which could potentially be targeted by novel agents (summarized in Table 2). However, often several genetic aberrations are found in the same tumor and it is not always clear which are driver mutations, which are secondary changes, and which are the determinants of inherent or acquired resistance. Moreover, mutations that clearly act as driver mutations in one tumor type may not be of similar relevance in another tumor. For example, patients with malignant melanoma with BRAF V600E mutations respond to treatment with vemurafenib, (33), whereas patients with colorectal cancer that harbor the same mutation seem to derive little benefit from BRAF inhibitors because of complex mechanisms that include a feedback loop that increases EGFR expression (34). Multiple ongoing studies are testing these hypotheses. Encouraging preliminary results have come from studies of PI3K/AKT/mTOR inhibitors in PIK3CAmt-deficient or PTEN-deficient cancers (35).
On the Horizon
Many cancer centers now profile patients by genetic testing, RNA expression profiling, or protein analyses and use the obtained data to direct patients to clinical trials at their centers or elsewhere (36, 37). Genetic profiling is booming, and molecular profiling is discussed in multidisciplinary tumor boards and contributes to treatment recommendations. Some academic cancer centers now hold a weekly precision tumor board meeting in which oncologists together with radiologists and molecular pathologists present cases. The multidisciplinary team, which also includes basic and translational scientists, surgeons, and nurses, discusses the cases and potential treatment options. Presently, molecular profiling is mostly limited to genetic aberrations [mutations, translocations, fusions, copy number variation (CNV)], but it is planned to extend the profiling to include RNA and immune profiling (Fig. 1). Although currently genetic profiling is only performed for patients for whom additional data are critical to guide treatment, it is envisioned that in the near future all patients treated at academic cancer centers will have a diagnostic tumor sample analyzed for genetic aberrations, and with repeat-biopsy programs in place, ideally also at progression. The ultimate goal of the profiling is to find the best available treatment for the patient, mostly by enrollment in a clinical trial, if such a trial exists. There is an urgent need for more studies with molecularly targeted agents that are open for patients across tumor types to investigate if these treatments can benefit other patient populations.
Several institutions and companies have launched trials that assign patients based on molecular profiling of tumors in specific cancer types (BATTLE I and II; ref. 38), but also independent of cancer type. These investigations include observational studies as well as nonrandomized and randomized studies (2, 39–41). Nonrandomized studies building on the ability of academic cancer centers to perform molecular profiling in CLIA-certified laboratories have been initiated in 2013 by pharmaceutical companies making a number of agents available for use in molecularly defined patient populations. These include agents for which safety data already exist and a phase II dose is defined, and exclude patient populations for which the drugs are either already registered or for which dedicated randomized studies exist or populations for which a lack of benefit for the agent was already observed. For example, the Novartis SIGNATURE studies offer independent trials with investigational agents from a pharmaceutical company for patients with a specific molecular profile (42). These agents would otherwise not be available for patients with many tumor types, as specific studies in all tumor types do not exist. The NCI plans to open a similar study in 2014, NCI-MATCH, which is expected to include agents from multiple companies (43). For the NCI-MATCH studies, genomic profiling will be performed by a consortium of NCI-selected CLIA-certified laboratories using NGS of a defined number of genes as the basis for enrollment. The arms of the NCI-MATCH study are still under discussion. It is expected to include agents from multiple companies under NCI sponsorship and will validate the proposed broad sequencing platform. The SHIVA study randomizes patients with a particular molecular abnormality with any type of cancer between the matched agent and conventional cytotoxic therapy, with crossover on progression (39). The SHIVA study is different from the other two studies mentioned here in that it has system-on-Chip (SoC) comparator arms for each newly tested agent and will therefore collect data on the outcome of SoC therapies in molecular segments. More studies of this type with agents in development would be of high interest, but such studies are difficult to initiate and coordinate if they involve multiple companies. The results of these ongoing studies are likely to identify additional patient populations for targeted therapy and hopefully will aid registration for additional indications. Data collection is critical for the future direction of personalized medicine and may trigger additional basic research to fully understand the contributions of newly discovered mutations to tumor development and progression.
Is testing for certain mutations sufficient or should broad testing be applied to all samples? Single mutation or small panel testing has the clear advantage of requiring smaller amounts of tissue, is less costly, and makes interpretation of data simpler and hence often quicker. Although there are only a few tests that clearly direct patient treatment at this time (see Table 1), broader testing will facilitate better understanding of tumor drivers and mechanisms of resistance critical for future direction. Multiplexing also requires less tissue than multiple single tests. The latter is becoming an increasing problem for phase I trials, for which companies require large amounts of tissue for testing to evaluate eligibility that exhausts archival diagnostic tissue, resulting in patients requiring new biopsies or even depriving them of enrollment if a new sample cannot be obtained.
Advanced technology has revealed intratumor and intertumor heterogeneity at the protein, genetic, and epigenetic level (44, 45). Genetic analyses, RNA and protein profiling of primary carcinomas, and metastases from the same patients with renal carcinomas showed a large degree of heterogeneity with most detected genetic aberrations not consistent between lesions and tumor regions that confirm that multiple clonal subpopulations exist within a single lesion (46, 47). In contrast, genetic analyses of colorectal and lung cancer lesions showed more concordant data for a limited gene set (48, 49). Indeed, the effectiveness of available targeted treatments for patients with advanced cancer such as gefitinib in EGFRmt lung cancer and cetuximab or panitumumab in KRASwt colorectal cancer has largely been demonstrated in clinical trials that identified the mutations from archival diagnostic biopsies. In light of the heterogeneity, it is questionable, if a single archival biopsy taken for diagnostic purposes in early stages of the disease is sufficient as a sample for molecular profiling to guide treatment. Even if a new biopsy is available for analysis, is one sample sufficient, if multiple lesions may have a very different molecular profile? How many areas of a single tumor need to be biopsied to obtain comprehensive information of the drivers of the tumor in a patient? Answers to these questions are urgently needed.
Given the emergence of resistance as described above, it is expected that future patients' tumors will need to be profiled at several times during treatment in order to determine the best treatment options. Indeed, some academic cancer centers have repeat-biopsy programs in place, allowing them to pursue new biopsies when patients progress on targeted treatment, in particular with EGFR or ALK inhibitors. How realistic are multiple longitudinal biopsies for a majority of patients with cancer across tumor types, and do we urgently need to increase our efforts to further explore other technologies that may be able to assess tumor mutations without multiple longitudinal biopsies or parallel biopsies of different lesions?
To minimize invasive procedures, the analysis of cfDNA or circulating tumor cells should be explored further to evaluate if these technologies can replace multiple biopsies for molecular analysis, especially as patients move through successive lines of treatment. Initial results are promising (50–52). Is genetic profiling really enough? How do we approach the many targets for which treatment options do not yet exist, including the ones that are presently considered undruggable, like TP53 and KRAS (53–56)? Do we need broader molecular profiling that includes other endpoints to strengthen scientific understanding and other selection methods, especially if they can be applied to samples other than tumor biopsies?
Serum proteins have been established as general prognostic factors, for example PSA levels in patients with prostate cancer. Carcinoembryonic antigen (CEA) is measured as a tumor marker across multiple tumor types, and high levels have been shown to correlate with poor prognosis (57–59). Attempts to identify serum proteins as predictors for response to targeted agents so far have had limited success (60, 61), but this has not been assessed broadly. Furthermore, serum marker studies in clinical trials should be encouraged, especially if tumor samples are available at the baseline of these trials and could be compared with serum assays.
Other areas presently being explored are RNA profiling (mRNA and miRNA), epigenetic profiling, and immune profiling (62–64). RNA analyses will strengthen the understanding of deregulated signaling pathways in cancer that genetic profiling alone may not reveal and may lead to novel hypotheses for targets. Immune profiling will become important as new therapies, especially immune checkpoint therapies, demonstrate striking activity in several cancer types.
Although great progress has been made toward molecular profiling for personalized cancer therapy, it is expected that with rapidly developing technology, molecular determinants other than genetic aberrations may emerge that will contribute to treatment decisions. The next 5 years will decide if personalized medicine will become standard practice across all tumor types and if this will revolutionize treatment options for greater survival benefit for patients with cancer.
Conception and design: J.M. Jürgensmeier, J.P. Eder, R.S. Herbst
Development of methodology: J.M. Jürgensmeier, R.S. Herbst
Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): R.S. Herbst
Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): J.M. Jürgensmeier, R.S. Herbst
Writing, review, and/or revision of the manuscript: J.M. Jürgensmeier, J.P. Eder, R.S. Herbst
Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): J.M. Jürgensmeier, R.S. Herbst
Study supervision: J.M. Jürgensmeier, J.P. Eder, R.S. Herbst
This work was supported by the NIH (2P30CA016359-34; to J.P. Eder, through his institution) and the NIH/NCI (1R01CA155196; to R.S. Herbst).
- Received March 18, 2014.
- Revision received June 11, 2014.
- Accepted June 12, 2014.
- ©2014 American Association for Cancer Research.