New Strategies in Personalized Medicine for Solid Tumors: Molecular Markers and Clinical Trial Designs

Clinical Cancer CCR New Strategies Research

Juliane M. Jurgensmeier,€ Joseph P. Eder, and Roy S. Herbst

Abstract 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. Jurgensmeier€ 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.

Learning Objectives 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.

Background "-omics" approaches, have facilitated the discovery and Over the past decade, the delineation of signaling development of novel targeted anticancer therapeutics, or pathways to understand tumor biology has laid the foun- at least provided the scientific rationale for their devel- dation for the discovery of novel targets and development opment. This increased molecular understanding of of multiple therapies for cancer. The identification tumors has led to a new era of personalized medicine of driver mutations and critical pathway dependencies, that has begun to influence common practice for oncol- as well as genomic sequencing and other large-scale ogists beyond academic institutions. The National Cancer Institute (NCI) defines "personalized medicine," often also called "precision medicine," Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut. as "a form of medicine that uses information about a Corresponding Author: Roy S. Herbst, Yale School of Medicine, 333 person’s genes, proteins, and environment to prevent, Cedar Street, WWW221, P.O. Box 208028, New Haven, CT 06520-8028. diagnose, and treat disease." Personalized medicine uses Phone: 203-785-6879; Fax: 203-737-5698; E-mail: [email protected] specific markers in patients’ tumors to diagnose partic- doi: 10.1158/1078-0432.CCR-13-0753 ular cancers or make treatment decisions. A specific 2014 American Association for Cancer Research. marker may have prognostic significance for biologic

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behavior or predict therapeutic outcome with a particular Antihormonal agents such as tamoxifen have been used anticancer agent. This review focuses on predictive mar- for decades, initially without molecular profiling. Studies kers associated with tumors but does not discuss host later correlated outcome with the expression of estrogen genetic factors that also can determine treatment and receptor (ER), progesterone receptor (PR), and androgen prognosis. receptor (AR). The presence of ER, PR, and AR not only Traditionally, the site of tumor origin, together with categorizes breast and prostate cancers into different prog- histology, was used to make treatment decisions. This nostic groups, but also determines treatment. Trastuzumab, approach has been changed to include molecular tumor a monoclonal antibody targeting human epithelial growth parameters. Markers presently used to guide decisions factor receptor-2 (HER-2), was approved for patient popu- for personalized medicine treatment with targeted agents lations with a specific molecular profile: HER-2–overexpres- are either protein based [immunohistochemistry (IHC)] sing breast and gastric cancer (3–5). The first agent targeting or based on detection of genetic aberrations and are sum- a chromosomal translocation, imatinib, was originally marized in Table 1. For genetic aberrations, a range of approved for the treatment of Philadelphia chromosome þ methods, including fluorescence in situ hybridization positive (Ph ) chronic myelogenous leukemia, based on (FISH) tests, polymerase chain reaction (PCR), sequenc- inhibiting the Bcr–Abl tyrosine kinase (6). In 2008, based ing—nowadays often next-generation sequencing (NGS) of on the additional activity of imatinib to inhibit c-Kit, either multiple selected genes in parallel or whole exome approval by the FDA for the treatment of adult patients sequencing—are used, in particular in early clinical trials or with c-Kit (CD117)–positive unresectable and/or metastat- for exploratory purposes. These large panels of genes offer ic gastrointestinal stromal tumors (GIST) followed (7, 8). the opportunity not only to detect aberrations for which Other recent successes in targeting molecularly defined tu- treatment options already exist but also to generate data on mor subtypes include the development of vemurafenib for additional driver mutations or resistance pathways (1, 2). advanced BRAFV600-mutated melanoma (9), and of crizo- Treatment decisions may be based on the data when tests tinib for patients with non–small cell lung cancer (NSCLC) have been performed in Clinical Laboratory Improvement with ALK translocations (10). Molecular profiling can also Amendment (CLIA)–certified laboratories. lead to a negative selection, as the retrospective studies

Table 1. Molecular selection markers for approved anticancer agents

Target Cancer Variation type Marker Drug Test EGFR Lung cancer Mutation Predict benefitto Erlotinib DNA EGFR TKIs Gefitinib ALK Lung cancer Rearrangement Predict response to Crizotinib FISH ALK inhibitors ROS Lung cancer Rearrangement Predict response to Crizotinib FISH TKIs RET Lung cancer Rearrangement Predict response to Vandetanib FISH TKIs BRAF Melanoma Mutation Predict response to Vemurafenib DNA BRAF inhibitors Dabrafenib KRAS Colorectal cancer Mutation Predict lack of response to Panitumumab DNA anti-EGFR antibodies Cetuximab HER2 Breast cancer Amplification Predict response to anti-HER2 Trastuzumab FISH, IHC Gastric cancer Overexpression antibodies Lapatinib Pertuzumab KIT GIST Mutation Predict response to c-Kit Imatinib IHC inhibitors Estrogen receptor Breast cancer Overexpression Predict response Examestane IHC Fulvestrant Letrozole Tamoxifen Progesterone receptor Breast cancer Overexpression Predict response Examestane IHC Letrozole

4426 Clin Cancer Res; 20(17) September 1, 2014 Clinical Cancer Research

showing consistent lack of benefit from the anti-EGFR feedback loop that increases EGFR expression (34). Multi- antibodies cetuximab or panitumumab in patients with ple ongoing studies are testing these hypotheses. Encour- colorectal cancer with KRAS codon 12/13 mutations led to aging preliminary results have come from studies of PI3K/ the recommendation to restrict the use of these antibodies AKT/mTOR inhibitors in PIK3CAmt-deficient or PTEN- to patients with wild-type KRAS tumors (11–14). deficient cancers (35). Lung cancer has become the prototype for genetically tailored cancer therapy. The remarkable advances in under- On the Horizon standing molecular drivers in NSCLC, together with the Many cancer centers now profile patients by genetic development of targeted agents, allow classification of testing, RNA expression profiling, or protein analyses and NSCLC on a molecular basis, and molecular profiling has use the obtained data to direct patients to clinical trials at become routine practice in thoracic oncology. EGFR muta- their centers or elsewhere (36, 37). Genetic profiling is tions were discovered in 2004 in parallel to the develop- booming, and molecular profiling is discussed in multi- ment of gefitinib, an EGFR tyrosine kinase inhibitor (TKI), disciplinary tumor boards and contributes to treatment when retrospective studies revealed that patients with recommendations. Some academic cancer centers now responses harbor exon 19 deletions or exon 21 point holdaweeklyprecisiontumorboardmeetinginwhich mutations (15, 16). These findings led to the use of the oncologists together with radiologists and molecular EGFR TKIs gefitinib and erlotinib as initial treatment for pathologists present cases. The multidisciplinary team, patients with these mutations. The discovery of EGFR muta- which also includes basic and translational scientists, tions and the large benefit of targeted treatment have surgeons, and nurses, discusses the cases and potential boosted profiling and the search for novel targets. The treatment options. Presently, molecular profiling is most- development of crizotinib to treat patients with ALK ly limited to genetic aberrations [mutations, transloca- fusions, detected by a FISH assay, highlights one of the tions, fusions, copy number variation (CNV)], but it is outstanding successes in lung cancer with rapid develop- planned to extend the profiling to include RNA and ment of a treatment (17). More recently, the additional immune profiling (Fig. 1). Although currently genetic activity of crizotinib in patients with ROS fusions (18, 19) profiling is only performed for patients for whom addi- was discovered, and patients with RET fusions are beginning tional data are critical to guide treatment, it is envisioned to be treated with the RET inhibitors vandetanib and car- that in the near future all patients treated at academic bozantinib (20–24). cancer centers will have a diagnostic tumor sample ana- Although these targeted therapies have brought signifi- lyzed for genetic aberrations, and with repeat-biopsy cant improvements, all patients eventually develop thera- programs in place, ideally also at progression. The ulti- peutic resistance. Multiple resistance mechanisms have mate goal of the profiling is to find the best available been characterized, such as secondary mutations preventing treatment for the patient, mostly by enrollment in a inhibitor binding, EGFR or HER2 gene amplifications, clinical trial, if such a trial exists. There is an urgent need HGF/Met pathway activations as well as PI3K and BRAF for more studies with molecularly targeted agents that are mutations (25, 26). Multiple resistance mechanisms have open for patients across tumor types to investigate if these also been identified in patients with ALK fusions who treatments can benefit other patient populations. progress on crizotinib. These include ALK mutations, copy Several institutions and companies have launched trials gain number, and mutations in alternative pathways, that assign patients based on molecular profiling of tumors including EGFR mutations. Second- and third-generation in specific cancer types (BATTLE I and II; ref. 38), but also inhibitors of EGFR and ALK, such as AZD9291 with activity independent of cancer type. These investigations include against EGFRT790M and alectinib or ceritinib, especially observational studies as well as nonrandomized and ran- active against the L11986M ALK mutation that confers domized studies (2, 39–41). Nonrandomized studies build- resistance to crizotinib, are now in development with initial ing on the ability of academic cancer centers to perform promising data (17, 27–32). molecular profiling in CLIA-certified laboratories have been Multiple deregulated pathways have been identified initiated in 2013 by pharmaceutical companies making a across a range of tumor types, which could potentially be number of agents available for use in molecularly defined targeted by novel agents (summarized in Table 2). However, patient populations. These include agents for which safety often several genetic aberrations are found in the same data already exist and a phase II dose is defined, and exclude tumor and it is not always clear which are driver mutations, patient populations for which the drugs are either already which are secondary changes, and which are the determi- registered or for which dedicated randomized studies exist nants of inherent or acquired resistance. Moreover, muta- or populations for which a lack of benefit for the agent was tions that clearly act as driver mutations in one tumor type already observed. For example, the Novartis SIGNATURE may not be of similar relevance in another tumor. For studies offer independent trials with investigational agents example, patients with malignant melanoma with BRAF from a pharmaceutical company for patients with a specific V600E mutations respond to treatment with vemurafenib, molecular profile (42). These agents would otherwise not be (33), whereas patients with colorectal cancer that harbor available for patients with many tumor types, as specific the same mutation seem to derive little benefit from BRAF studies in all tumor types do not exist. The NCI plans to inhibitors because of complex mechanisms that include a open a similar study in 2014, NCI-MATCH, which is

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Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2014 American Association for Cancer Research. 4428 lnCne e;2(7 etme ,2014 1, September 20(17) Res; Cancer Clin J Downloaded from resee tal. et urgensmeier € Table 2. Genetic aberrations as putative predictive biomarkers for anticancer agents

Examples for Aberration type Putative or proven drugs in clinical Target/pathway in solid tumors Disease examples drugs development References

clincancerres.aacrjournals.org EGFR Mutation Lung cancer EGFR inhibitors Erlotinib (15, 16, 25, 26, 30) Amplification GBM Gefitinib Afatinib AZD9291 HER2 (ERB2) Mutation Breast cancer ERB2/ERB3 inhibitors Lapatinib (4, 5) Amplification Gastric cancer Neratinib Lung cancer Trastuzumab Trastuzumab-emtansine ALK Rearrangement Lung cancer ALK inhibitors Crizotinib (10, 22, 28, 29, 65, 66) Mutation Neuroblastoma Ceritinib Colorectal cancer Alectinib on September 23, 2021. © 2014American Association for Cancer RET Rearrangement Thyroid cancer RET inhibitors Vandetanib (19–21, 23) Research. Mutation Lung cancer Carbozantinib ROS1 Rearrangement Lung cancer ROS1 inhibitors Crizotinib (18, 19) DDR2 Mutation Lung cancer DDR2 inhibitors Dasatinib (67, 68) Nilotinib FGFR1-4 Amplification Lung cancer FGFR inhibitors Ponatinib (69, 70) Mutation Gastric cancer Dovitinib Breast cancer BGJ398 Bladder cancer AZD4547 MET/HGF Mutation Lung cancer Met inhibitors Onartuzumab (71–73) Amplification Gastric cancer Crizotinib Colorectal cancer Foretinib HCC INC280 RCC lnclCne Research Cancer Clinical KIT Mutation GIST Kit inhibitors Imatinib (7, 8) Mastocytosis Nilotinib Melanoma Sunitinib Dasatinib Ponatinib

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Downloaded from Table 2. Genetic aberrations as putative predictive biomarkers for anticancer agents (Cont'd )

Examples for Aberration type Putative or proven drugs in clinical Target/pathway in solid tumors Disease examples drugs development References PDGFRA and PDGFRB Mutation GIST PDGFR inhibitors Imatinib (8, 74) Translocation Sarcoma Sunitinib clincancerres.aacrjournals.org GBM Ponatinib Leukemia Dermatoﬁbrosarcoma protuberans KRAS, NRAS, HRAS Mutation Most cancers, including Mek inhibitors Trametinib (75) (RAS-RAF-MEK) colorectal cancer, Selumetinib lung cancers BRAF Mutation Melanoma Braf inhibitors Vemurafenib (75, 76) (RAS-RAF-MEK) Colorectal cancer Mek inhibitors Dabrafenib HCC Trametinib

Research. PI3KCA Mutation Multiple, including: PI3K inhibitors BKM-120 (77, 78) (PTEN/PI3K/AKT/mTOR) Ampliﬁcation Breast cancer AKT inhibitors BEZ235 Colorectal cancer, GBM BYL719 Lung cancer GDC0941 Endometrial GDC0032 MLN1117 AKT inhibitors (see below) PIK3R1 Mutation Endometrial cancer PI3K inhibitors PI3K inhibitors (see above) (78)

(PTEN/PI3K/AKT/mTOR) Colorectal cancer Medicine Personalized for Markers Molecular lnCne e;2(7 etme ,2014 1, September 20(17) Res; Cancer Clin AKT1-3 Mutation Breast cancer PI3K inhibitors GDC0086 (77–79) (PTEN/PI3K/AKT/mTOR) Ampliﬁcation Colorectal cancer AKT inhibitors MK2206 Meningeal cancer AZD5363 Urinary tract cancers PI3K inhibitors (see above) Endometrial cancer PTEN Deletion Most cancers, including PI3K inhibitors PI3K and AKT inhibitors (77–80) (PTEN/PI3K/AKT/mTOR) Mutation breast cancer AKT inhibitors (see above) Lung cancer Colorectal cancer (Continued on the following page) 4429 4430 lnCne e;2(7 etme ,2014 1, September 20(17) Res; Cancer Clin J Downloaded from resee tal. et urgensmeier Table 2. Genetic aberrations as putative predictive biomarkers for anticancer agents (Cont'd ) €

Examples for Aberration type Putative or proven drugs in clinical Target/pathway in solid tumors Disease examples drugs development References mTOR Mutation Endometrial cancer mTOR inhibitors Everolimus (78, 81, 82)

clincancerres.aacrjournals.org (PTEN/PI3K/AKT/mTOR) RCC Temsirolimus Colorectal cancer MLN128 Lung cancer AZD2014 GDC00980 BEZ235

TSC1/2 Mutation Tuberous sclerosis mTOR inhibitors mTOR inhibitors (see above) (78, 83) (PTEN/PI3K/AKT/mTOR) Urinary tract cancers Endometrial cancer Cervical cancer HCC

Research. LKB1 Mutation Cervical cancer mTOR inhibitors mTOR inhibitors (see above) (78) (PTEN/PI3K/AKT/mTOR) Small intestine cancer Lung cancer Skin cancer SMO, PTCH1 Mutation Basal cell carcinoma Hedgehog inhibitors Vismodegib (84, 85) (Hedgehog) Medulloblastoma Meningioma Breast cancer MDM2 Ampliﬁcation GBM MDM2 inhibitors/antagonists RG7388 (53, 54) Sarcoma disrupting p53-MDM2 interaction P53 Mutation Most tumors P53 activators (53, 54) NOTCH Mutation Breast cancer g-secretase inhibitors MK0752 (86, 87) Rearrangement Lung cancer ABs to notch receptors or PF03084014 lnclCne Research Cancer Clinical Ovarian cancer ligands Demcizumab GBM OMP59R5 H&N cancer OMP52M51 Enoticumab CDKS Ampliﬁcation Sarcoma CDK inhibitors Flavopiridol (88) Mutation Melanoma Palbociclib Rearrangement GBM

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Table 2. Genetic aberrations as putative predictive biomarkers for anticancer agents (Cont'd )

Examples for Aberration type Putative or proven drugs in clinical Target/pathway in solid tumors Disease examples drugs development References CHK1/2 Mutation Multiple tumors, including CHK inhibitors RG7741 (88) those listed below: LY2606368 Colorectal cancer Gastric cancer on September 23, 2021. © 2014American Association for Cancer Endometrial cancer Research. Breast cancer AURKA Ampliﬁcation Multiple tumors Aurora kinase inhibitors Alisertib (88, 89) (Aurora kinases) ATR Mutation Gastric cancer ATM inhibitors No ATM inhibitors in clinical development (88, 90) Deletion Breast cancer PARP inhibitors PARP inhibitors (see below) Endometrial cancer ATM Mutation Multiple tumors, including ATR inhibitors VX970 (88, 90) Deletion Breast cancer PARP inhibitors PARP inhibitors (see below) oeua akr o esnlzdMedicine Personalized for Markers Molecular lnCne e;2(7 etme ,2014 1, September 20(17) Res; Cancer Clin BRCA1/2 Mutation Breast cancer PARP inhibitors Olaparib (91, 92) Ovarian cancer Veliparib Rucaparib BMN673

Abbreviations: GBM, glioblastoma multiforme; H&N cancer, head and neck cancer; HCC, hepatocellular carcinoma; RCC, renal cell carcinoma. 4431 Jurgensmeier€ et al.

Protein detection Genetic RNA profiling Immune • Selected markers (e.g., • Expression PTEN, ER, PR, AR, and HER2) profiling • miRNA profiling • Broad profiling

Tumor board treatment decision Figure 1. The academic medical center precision medicine tumor board model.

Clinical trials, Clinical trials, Center-specific Treatment outside NCI studies company A company B studies of institution

expected to include agents from multiple companies (43). tance critical for future direction. Multiplexing also requires For the NCI-MATCH studies, genomic profiling will be less tissue than multiple single tests. The latter is becoming performed by a consortium of NCI-selected CLIA-certified an increasing problem for phase I trials, for which compa- laboratories using NGS of a defined number of genes as the nies require large amounts of tissue for testing to evaluate basis for enrollment. The arms of the NCI-MATCH study are eligibility that exhausts archival diagnostic tissue, resulting still under discussion. It is expected to include agents from in patients requiring new biopsies or even depriving them multiple companies under NCI sponsorship and will val- of enrollment if a new sample cannot be obtained. idate the proposed broad sequencing platform. The SHIVA Advanced technology has revealed intratumor and inter- study randomizes patients with a particular molecular tumor heterogeneity at the protein, genetic, and epigenetic abnormality with any type of cancer between the matched level (44, 45). Genetic analyses, RNA and protein profiling agent and conventional cytotoxic therapy, with crossover of primary carcinomas, and metastases from the same on progression (39). The SHIVA study is different from the patients with renal carcinomas showed a large degree of other two studies mentioned here in that it has system-on- heterogeneity with most detected genetic aberrations not Chip (SoC) comparator arms for each newly tested agent consistent between lesions and tumor regions that confirm and will therefore collect data on the outcome of SoC that multiple clonal subpopulations exist within a single therapies in molecular segments. More studies of this type lesion (46, 47). In contrast, genetic analyses of colorectal with agents in development would be of high interest, but and lung cancer lesions showed more concordant data for a such studies are difficult to initiate and coordinate if they limited gene set (48, 49). Indeed, the effectiveness of avail- involve multiple companies. The results of these ongoing able targeted treatments for patients with advanced cancer studies are likely to identify additional patient populations such as gefitinib in EGFRmt lung cancer and cetuximab or for targeted therapy and hopefully will aid registration for panitumumab in KRASwt colorectal cancer has largely been additional indications. Data collection is critical for the demonstrated in clinical trials that identified the mutations future direction of personalized medicine and may trigger from archival diagnostic biopsies. In light of the heteroge- additional basic research to fully understand the contribu- neity, it is questionable, if a single archival biopsy taken for tions of newly discovered mutations to tumor development diagnostic purposes in early stages of the disease is sufficient and progression. as a sample for molecular profiling to guide treatment. Even Is testing for certain mutations sufficient or should broad if a new biopsy is available for analysis, is one sample testing be applied to all samples? Single mutation or small sufficient, if multiple lesions may have a very different panel testing has the clear advantage of requiring smaller molecular profile? How many areas of a single tumor need amounts of tissue, is less costly, and makes interpretation of to be biopsied to obtain comprehensive information of the data simpler and hence often quicker. Although there are drivers of the tumor in a patient? Answers to these questions only a few tests that clearly direct patient treatment at this are urgently needed. time (see Table 1), broader testing will facilitate better Given the emergence of resistance as described above, it is understanding of tumor drivers and mechanisms of resis- expected that future patients’ tumors will need to be profiled

4432 Clin Cancer Res; 20(17) September 1, 2014 Clinical Cancer Research

at several times during treatment in order to determine the Other areas presently being explored are RNA profiling best treatment options. Indeed, some academic cancer (mRNA and miRNA), epigenetic profiling, and immune centers have repeat-biopsy programs in place, allowing profiling (62–64). RNA analyses will strengthen the them to pursue new biopsies when patients progress on understanding of deregulated signaling pathways in can- targeted treatment, in particular with EGFR or ALK inhibi- cer that genetic profiling alone may not reveal and may tors. How realistic are multiple longitudinal biopsies for a lead to novel hypotheses for targets. Immune profiling majority of patients with cancer across tumor types, and do will become important as new therapies, especially we urgently need to increase our efforts to further explore immune checkpoint therapies, demonstrate striking activ- other technologies that may be able to assess tumor muta- ity in several cancer types. tions without multiple longitudinal biopsies or parallel Although great progress has been made toward molecular biopsies of different lesions? profiling for personalized cancer therapy, it is expected that To minimize invasive procedures, the analysis of cfDNA with rapidly developing technology, molecular determi- or circulating tumor cells should be explored further to nants other than genetic aberrations may emerge that will evaluate if these technologies can replace multiple biopsies contribute to treatment decisions. The next 5 years will for molecular analysis, especially as patients move through decide if personalized medicine will become standard prac- successive lines of treatment. Initial results are promising tice across all tumor types and if this will revolutionize (50–52). Is genetic profiling really enough? How do we treatment options for greater survival benefit for patients approach the many targets for which treatment options do with cancer. not yet exist, including the ones that are presently consid- ered undruggable, like TP53 and KRAS (53–56)? Do we Authors' Contributions need broader molecular profiling that includes other end- Conception and design: J.M. Jurgensmeier,€ J.P. Eder, R.S. Herbst points to strengthen scientific understanding and other Development of methodology: J.M. Jurgensmeier,€ R.S. Herbst selection methods, especially if they can be applied to Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): R.S. Herbst samples other than tumor biopsies? Analysis and interpretation of data (e.g., statistical analysis, biosta- Serum proteins have been established as general prog- tistics, computational analysis): J.M. Jurgensmeier,€ R.S. Herbst € nostic factors, for example PSA levels in patients with Writing, review, and/or revision of the manuscript: J.M. Jurgensmeier, J.P. Eder, R.S. Herbst prostate cancer. Carcinoembryonic antigen (CEA) is mea- Administrative, technical, or material support (i.e., reporting or orga- sured as a tumor marker across multiple tumor types, and nizing data, constructing databases): J.M. Jurgensmeier,€ R.S. Herbst € high levels have been shown to correlate with poor Study supervision: J.M. Jurgensmeier, J.P. Eder, R.S. Herbst prognosis (57–59). Attempts to identify serum proteins as predictors for response to targeted agents so far have Grant Support had limited success (60, 61), but this has not been This work was supported by the NIH (2P30CA016359-34; to J.P. Eder, through his institution) and the NIH/NCI (1R01CA155196; to assessed broadly. Furthermore, serum marker studies in R.S. Herbst). clinical trials should be encouraged, especially if tumor samples are available at the baseline of these trials and Received March 18, 2014; revised June 11, 2014; accepted June 12, 2014; couldbecomparedwithserumassays. published online August 14, 2014.

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