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Background Tumor molecular profiling from patients experiencing exceptional responses to systemic therapy may provide insights into cancer biology and improve treatment tailoring. This pilot study evaluates the feasibility of identifying exceptional responders retrospectively, obtaining pre-exceptional response treatment tumor tissues, and analyzing them with state-of-the-art molecular analysis tools to identify potential molecular explanations for responses. Methods Exceptional response was defined as partial (PR) or complete (CR) response to a systemic treatment with population PR or CR rate less than 10% or an unusually long response (eg, duration >3 times published median). Cases proposed by patients’ clinicians were reviewed by clinical and translational experts. Tumor and normal tissue (if possible) were profiled with whole exome sequencing and, if possible, targeted deep sequencing, RNA sequencing, methylation arrays, and immunohistochemistry. Potential germline mutations were tracked for relevance to disease. Results Cases reflected a variety of tumors and standard and investigational treatments. Of 520 cases, 476 (91.5%) were accepted for further review, and 222 of 476 (46.6%) proposed cases met requirements as exceptional responders. Clinical data were obtained from 168 of 222 cases (75.7%). Tumor was provided from 130 of 168 cases (77.4%). Of 117 of the 130 (90.0%) cases with sufficient nucleic acids, 109 (93.2%) were successfully analyzed; 6 patients had potentially actionable germline mutations. Conclusion Exceptional responses occur with standard and investigational treatment. Retrospective identification of exceptional responders, accessioning, and sequencing of pretreatment archived tissue is feasible. Data from molecular analyses of tumors, particularly when combining results from patients who received similar treatments, may elucidate molecular bases for exceptional responses.

While the incidence of colorectal cancer (CRC) in the US has declined at a pace of 3% annually between 2003 and 2012, there has been an increase in the incidence of early-onset colorectal cancer (EOCRC). The reasons for this increase are unclear. Diet, the environment, the microbiome and alcohol consumption have all been proposed as contributing factors. There is the possibility that EOCRC has a unique biology. Overlapping with the EOCRC age range is CRC in adolescent and young adults (AYA) that share many molecular characteristics with EOCRC. The purpose of this review is to cover current progress in our understanding of the biology of CRC in the context of adolescent and young adult CRC and EOCRC and discuss future directions.

The incidence rates of sporadic early-onset colorectal cancer (EO-CRC) are increasing rapidly in the USA and globally. Birth cohort analyses strongly suggest that changes in early life exposures to known or unknown risk factors for CRC may be driving EO disease, but the etiology of EO-CRC remains poorly understood. To address the alarming rise in sporadic EO-CRC, the National Cancer Institute and National Institute of Environmental Health Sciences convened a virtual meeting that featured presentations and critical discussions from EO-CRC experts that examined emerging evidence on potential EO-CRC risk factors, mechanisms and translational opportunities in screening and treatment.

Background It is possible that the relative lack of progress in treatment outcome among the adolescent and young adult (AYA) group of cancer patients is due to a difference in disease biology compared to the corresponding diseases in younger and older individuals. There is evidence that colon cancer is more aggressive, and has a poorer prognosis in AYA patients than that observed in older adult patients.

With the use of high-throughput molecular profiling technologies, precision medicine trials are ongoing for adults with cancer. Similarly, there is an interest in how these techniques can be applied to tumors in children and adolescents to expand our understanding of the biology of pediatric cancers and evaluate the clinical implications of genomic testing for these patients. This article reviews the early studies in pediatric oncology showing the feasibility of this approach, describe the future plans to evaluate the clinical implications in a multicenter clinical trial and identify the challenges of applying genomics in this patient population.

Background: Although genomic changes identified by clinical tumor sequencing may be present in the germline, precision oncology trials have generally not incorporated germline testing and reporting. We describe our experience with clinical reporting of matched tumor and germline results from the NCI-COG Pediatric Molecular Analysis for Therapy Choice (MATCH) trial (NCT03155620). Design/Method: Patients age 1 to 21 years old with treatment-refractory solid tumors, non-Hodgkin lymphomas, or histiocytic disorders were eligible. DNA and RNA extracted from FFPE tumors were sequenced using Oncomine Assay v.3 with reporting of potentially actionable fusions, amplifications, and mutations, including loss of function variants in tumor suppressor genes. Germline reporting focused on 36 genes from the same DNA panel that convey adult or pediatric cancer susceptibility but does not include all cancer susceptibility genes (e.g. APC, DICER1). Deletions and splice site variants were not reported. Results: As of June 2020, 1009 patients had been enrolled from 132 COG sites, with tumor and germline testing complete for 868 patients to date. Overall, 62 (7.1%) germline reports included a pathogenic or likely pathogenic germline variant (termed germline findings) in 18 cancer susceptibility genes. This frequency was similar in patients with solid tumors (46/633, 7.3%), CNS tumors (14/204, 6.9%), and lymphomas/histiocytoses (2/31, 6.5%). Variant(s) of potential germline significance were identified in 25% of tumor reports; of these, 74% (163/221) had no germline findings. The proportion of germline findings for genes with >10 reported tumor variants varied: 32% (7/22) in NF1, 25% (3/12) in RB1, 16% (17/108) in TP53 and 0% in ALK (0/21) and PTEN (0/12). Of note, 82% (14/17) of tumor variants in breast cancer susceptibility genes (BRCA1/2, CHEK2 and PALB2) had germline findings. On study intake forms, 25% of patients with germline findings had a “known genetic disease” reported. Oncologists caring for patients with a germline finding were then queried about prior knowledge of a genetic diagnosis. Of 24 respondents, 13 (54%) reported no prior molecular diagnosis of the identified condition. Conclusions: Coordinated germline and tumor testing revealed clinically relevant cancer susceptibility variants across a spectrum of genes in 7% of pediatric patients with treatment-refractory cancers. This is likely an underestimate of germline findings given test limitations. The parallel tumor/normal reporting approach minimized the need for targeted reflex genetic testing in 19% of study participants and provided new information on cancer susceptibility in germline positive patients to half of the responding oncologists. The NCI-COG Pediatric MATCH trial reporting process can serve as a model for precision oncology trials and clinical tumor profiling. Citation Format: Sarah Scollon, Sharon E. Plon, Steven Joffe, Jaclyn A. Biegel, Shashikant Kulkarni, George Miles, David Patton, Brent Coffey, Paul M. Williams, Gregory J. Tsongalis, Mark J. Routbort, Julie M. Gastier-Foster, Lauren Saguilig, Jin Piao, Todd A. Alonzo, Katherine A. Janeway, Peter C. Adamson, Margaret Mooney, James V. Tricoli, Nita L. Seibel, Donald W. Parsons. Germline cancer predisposition results from the National Cancer Institute - Children's Oncology Group (NCI-COG) Pediatric MATCH Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 631.

10007 Background: The NCI-Children’s Oncology Group (COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial assigns patients age 1 to 21 years with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase 2 treatment arms of molecularly-targeted therapies based on the genetic alterations detected in their tumor. Treatment arm assignments and enrollment decisions have now been made for 1000 study participants: we report here match and enrollment data and factors affecting treatment protocol enrollment. Methods: Patients enrolled in the Pediatric MATCH screening protocol were assigned to an open treatment protocol if an actionable mutation (aMOI) was detected by tumor DNA and RNA-based cancer gene panel sequencing. After a match, treatment protocol enrollment must occur within 8-12 weeks. Patient demographic data, reasons for not enrolling on treatment protocol (if applicable), and prior history of molecular testing were reported by study sites. The Fisher exact test was used to compare protocol enrollment rates between groups. Results: Results were analyzed for the first 1000 patients with testing completed (enrolled between July 2017 and October 2020). At least one tumor aMOI was detected in 310 (31%) patients and treatment protocol slots were available for 284 patients (28%). A total of 131 patients (46% of those matched) enrolled on a treatment arm. No difference in treatment protocol match or enrollment rate was observed for gender, race, or ethnicity. Both treatment protocol match rate (105/275, 38% vs 86/394, 22%) and enrollment rate (56/275, 20% vs 33/394, 8%) were significantly more frequent in patients with a reported history of prior molecular testing (p

10008 Background: The NCI-Children’s Oncology Group (COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial assigns patients age 1 to 21 years with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase 2 treatment arms of molecularly-targeted therapies based on genetic alterations detected in their tumor. Arm E evaluated the MEK inhibitor selumetinib (ARRY-142886) in patients whose tumors harbored activating alterations in the MAPK pathway ( ARAF, BRAF, HRAS, KRAS, NRAS, MAP2K1, GNA11, GNAQ hotspot mutations; NF1 inactivating mutations; BRAF fusions). Methods: Patients received selumetinib 25 mg/m2/dose (max 75 mg/dose) PO BID for 28-day cycles until disease progression or intolerable toxicity with response assessments obtained every 2-3 cycles. The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS). Patients with low grade glioma were excluded. Results: A total of 21 patients (median age 14 years; range 5-21) were enrolled between 10/2017 and 8/2019, with 20 patients evaluable for response. Diagnoses were high grade glioma (HGG; n = 8), rhabdomyosarcoma (n = 7), adenocarcinoma (n = 2), and one each of MPNST, endodermal sinus/yolk sac tumor, plexiform neurofibroma (PN), and neuroblastoma. MAPK pathway alterations detected consisted of inactivating NF1 mutations (n = 8), hotspot mutations in KRAS (n = 8), NRAS (n = 3), and HRAS (n = 1), and BRAF V600E (n = 2). No objective responses were observed. Three patients had a best response of stable disease (HGG with NF1 mutation, 6 cycles; HGG with KRAS mutation, 12 cycles; PN with NF1 mutation, 13 cycles prior to removal for dose-limiting toxicity). Six-month PFS was 15% (95% CI: 4%, 34%). Adverse events that were deemed possibly, probably, or definitely attributable to study drug included one case each of grade 3 uveitis, lymphopenia, and thromboembolic event; one grade 4 CPK elevation; and one grade 5 thromboembolic event. Conclusions: Selumetinib did not result in tumor regression in this cohort of children and young adults with treatment-refractory tumors with activating MAPK pathway alterations. Of note, two patients with HGG initially had stable disease, but ultimately progressed after 6 and 12 cycles, respectively. Selumetinib has previously demonstrated activity in low grade glioma and PN and is now FDA-approved for PN. The results of our study indicate that MAPK pathway mutation status alone is insufficient to predict response to selumetinib monotherapy. It is likely that selumetinib and other MEK inhibitors will require combination with targeted or cytotoxic agents for optimal efficacy in children with persistent or progressive cancers after front-line chemotherapy. Clinical trial information: NCT03213691. Clinical trial information: NCT03155620.

Introduction: In aggregate, about 20% of all cancers can be considered rare. In addition, molecularly defined subsets of more common cancers are generally rare. Many rare cancers urgently need development of efficacious therapeutics, yet their rarity makes it difficult to conduct standard clinical trials. The advent of molecular profiling of cancers, however, may offer an opportunity for more thoughtful and successful development of new effective treatments.Areas covered: This manuscript describes instances in which drugs have been approved for rare cancers, and describes the potential value and challenges of new policies and research that may lead to more broad development of drugs based on the molecular characterization of a patient’s tumor.Expert opinion: Although challenges in use of any methods for development of therapeutics for rare cancers exist, international collaboration, broad molecular profiling for research, and new trial designs such as basket designs and tumor agnostic designs, hav...

A small fraction of cancer patients with advanced disease survive significantly longer than patients with clinically comparable tumors. Molecular mechanisms for exceptional responses to therapy have been identified by genomic analysis of tumor biopsies from individual patients. Here, we analyzed tumor biopsies from an unbiased cohort of 111 exceptional responder patients using multiple platforms to profile genetic and epigenetic aberrations as well as the tumor microenvironment. Integrative analysis uncovered plausible mechanisms for the therapeutic response in nearly a quarter of the patients. The mechanisms were assigned to four broad categories���DNA damage response, intracellular signaling, immune engagement, and genetic alterations characteristic of favorable prognosis���with many tumors falling into multiple categories. These analyses revealed synthetic lethal relationships that may be exploited therapeutically and rare genetic lesions that favor therapeutic success, while also providing a wealth of testable hypotheses regarding oncogenic mechanisms that may influence the response to cancer therapy. Profiling multi-platform genomics of 110 cancer patients with an exceptional therapeutic response, Wheeler et al. identify putative molecular mechanisms explaining this survival phenotype in ���23% of cases. Therapeutic success is related to rare molecular features of responding tumors, exploiting synthetic lethality and oncogene addiction.

The importance of circulating free DNA (cfDNA) in cancer clinical research was recognized in 1994 when a mutated RAS gene fragment was detected in a patient's blood sample. Up to 1% of the total circulating DNA in patients with cancer is circulating tumor DNA (ctDNA) that originates from tumor cells. As ctDNA is rapidly cleared from the blood stream and can be obtained by minimally invasive methods, it can be used as a dynamic cancer biomarker for cancer early detection, diagnosis, and treatment monitoring. Despite the potential for clinical use, few ctDNA assays have been cleared or approved by the US Food and Drug Administration. As tools for clinical and translational research, current ctDNA assays face some challenges, and more research is needed to advance use of these assays. On September 29-30, 2016, the Division of Cancer Treatment and Diagnosis at the National Cancer Institute convened a workshop entitled "Circulating Tumor DNA Assays in Clinical Cancer Research" to garner input from industry experts, academia, and government research and regulatory agencies to understand and promote the translation of ctDNA assays to clinical research, with potential to advance to use in clinical practice. This Commentary presents the topics of the workshop covered in the presentations and points made in the discussions that followed: 1) background on ctDNA, 2) potential clinical utility of ctDNA assays, 3) assay technology, 4) assay clinical and analytical validation, and 5) industry perspectives. Additional relevant information that has come to light since the workshop has been included.

Each year, 70,000 adolescents and young adults (AYAs) between ages 15 and 39 years in the United States are diagnosed with cancer. In 2006, a National Cancer Institute (NCI) Progress Review Group (PRG) examined the state of science associated with cancer among AYAs. To assess the impact of the PRG and examine the current state of AYA oncology research, the NCI, with support from the LIVESTRONG Foundation, sponsored a workshop entitled "Next Steps in Adolescent and Young Adult Oncology" on September 16 and 17, 2013, in Bethesda, Maryland. This report summarizes the findings from the workshop, opportunities to leverage existing data, and suggestions for future research priorities. Multidisciplinary teams that include basic scientists, epidemiologists, trialists, biostatisticians, clinicians, behavioral scientists, and health services researchers will be essential for future advances for AYAs with cancer.

Adolescent and young adult (AYA) patients with cancer have not attained the same improvements in overall survival as either younger children or older adults. One possible reason for this disparity may be that the AYA cancers exhibit unique biologic characteristics, resulting in differences in clinical and treatment resistance behaviors. This report from the biologic component of the jointly sponsored National Cancer Institute and LiveStrong Foundation workshop entitled “Next Steps in Adolescent and Young Adult Oncology” summarizes the current status of biologic and translational research progress for 5 AYA cancers; colorectal cancer breast cancer, acute lymphoblastic leukemia, melanoma, and sarcoma. Conclusions from this meeting included the need for basic biologic, genomic, and model development for AYA cancers as well as translational research studies to elucidate any fundamental differences between pediatric, AYA, and adult cancers. The biologic questions for future research are whether there are mutational or signaling pathway differences (for example, between adult and AYA colorectal cancer) that can be clinically exploited to develop novel therapies for treating AYA cancers and to develop companion diagnostics. Cancer 2016;122:1017–1028. © 2016 American Cancer Society

Many cancers evolve from benign precancerous lesions and have a natural history of progression that provides a window of opportunity for intervention. The biological mechanisms underlying this evolutionary trajectory can only be truly understood through an extensive characterization of the molecular, cellular, and non-cellular properties of premalignant and malignant tumors, and must also recognize how the microenvironment (stromal cells, immune cells, and other types of cells) contributes to this evolution. We describe here the need to develop comprehensive molecular and cellular atlases for organ-specific premalignant lesions while capturing the spatial, structural, and functional changes over time that will provide a greater understanding of how premalignancy transitions to malignancy. The PreCancer Atlas (PCA) initiative, described in this Opinion, will address this need and aims to overcome the many challenges that currently plague the field. The hope is that PCAs will lead to the development of effective and timely interventions to prevent the development of invasive cancers.

Introduction: NCI-MATCH, developed by ECOG-ACRIN & NCI, is the largest precision medicine study for pts with refractory malignancy. Over 1100 clinical sites in the National Clinical Trials Network enrolled pts. The purpose of the study is to identify potentially beneficial targeted treatments across tumor types with similar molecular abnormalities. Methods: The NCI Central IRB approved NCI-MATCH. Pts with refractory/no treatment available solid tumors, lymphomas or myelomas had a fresh biopsy profiled by next generation sequencing (143 genes, > 4000 single nucleotide variants, indels, amplifications & targeted fusions). Pts are assigned by a defined algorithm to treatments with evidence of activity against tumors with the relevant molecular alteration. Pts are excluded if a treatment is FDA approved or known to be ineffective for their malignancy. After successfully sequencing fresh biopsies from 5540 pts, subprotocols with extremely rare variants lacked sufficient accrual. To address actionable variants with a prevalence of < 1.5%, we decided to accept clinical sequencing results from 30 commercial and academic laboratories vetted by NCI-MATCH to address relevant variants. These labs notify clinicians participating in NCI-MATCH if their pt’s tumor contains an actionable variant. Treatment continues until tumors became refractory, pt intolerance or withdrawal of consent. An objective response rate (ORR by RECIST) of > 16% among 31 eligible patients is considered a positive signal. Results: After screening 5540 pts, 37.6% had an actionable variant. After histology and treatment-specific exclusions, 17.8% were assigned and 69.5% enrolled on the assigned subprotocol. 11 of the initial 30 subprotocols reached completion with adequate follow-up. Of the first 11 evaluable subprotocols, 3 addressing rare variants had a positive signal: Nivolumab in pts with loss of expression of MLH1 or MSH2 (ORR 36%), capivasertib in pts with AKT mutations (ORR 23%), and dabrafenib + trametinib in pts with BRAF V600 mutations (ORR 33%). These molecular variants were found in 2%, 1.2% and 1.9% respectively, of screened pts. Two other subprotcocols (afatinib in ERBB2 mutations and AZD4547 in FGFR abnormalities) showed responses in rare tumors or specific variant subsets, respectively. As of July 15, 2019, an additional 378 of 432 (88%) pts have been assigned to a treatment with a clinical sequencing assay; 83% of these pts enrolled to 1 of 24 subprotocols, allowing completion of an additional 9 of the original 30 subprotocols and complete accrual to 2 of 5 recently added subprotocols. Four of 35 subprotocols closed for lack of accrual, 10 continue accruing and 4 are planned. Conclusions: Platform precision medicine trials can identify potentially useful targeted treatments for diverse malignancies in pts with uncommon tumors & rare actionable variants, an unmet need. In a population of pts with refractory cancers, lymphomas and myelomas, 30-40% will have an actionable variant for targeted treatment (investigational or standard). Of the first 11 subprotocols with adequate follow-up, 3 (27%) showed a positive signal and an additional 2 showed responses in rare tumors or in a molecular subset, suggesting that the NCI-MATCH trial approach identifies useful targets for further exploration. Citation Format: Lyndsay N Harris, Robert J Gray, Barbara A Conley, Alice P Chen, Keith T Flaherty, Stanley R Hamilton, Paul M Williams, Chris Karlovich, David Patton, Shuli Li, Lisa M McShane, Larry V Rubinstein, Edith P Mitchell, James V Tricoli, Richard F Little, Carlos L Arteaga, Peter J O'Dwyer, NCI-MATCH team. National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH): A successful precision medicine signal-seeking trial in patients (pts) with rare variants and refractory malignancies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A079. doi:10.1158/1535-7163.TARG-19-A079

Background: Over the last 30 years, adolescent and young adult (AYA, 15-39 years of age) patients (pts) with cancer have experienced smaller improvements in 5-year survival compared to younger and older pts. One reason is their historically lower rate of participation in clinical trials (~3% AYA vs. 10% in pts > 40 years of age in adult cancer centers). A histology-agnostic trial provides greater opportunity for the AYA population and may improve accrual. The National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH; NCT0246506), a phase II precision medicine trial evaluating targeted therapy in adult pts (3 18 years old) based on molecular abnormalities in a tumor-agnostic fashion, has been open since 2015. Jointly developed and coordinated by NCI and ECOG-ACRIN and open through the NCI National Clinical Trials Network and the NCI Community Oncology Research Program at more than 1100 academic and community sites, this trial screened 6801 pts for 39 independently-accruing targeted treatment subprotocols. We reviewed the AYA data from the NCI-MATCH trial, which, due to eligibility criteria, does not include pts age 15-17. Materials and Methods: AYA pts age 18-39 with treatment-refractory malignancies (solid tumor, lymphoma, or myeloma) who were (a) eligible for a screening biopsy on the NCI-MATCH trial (screening cohort [SC]) or (b) had an actionable mutation previously identified through clinically indicated sequencing at a CLIA-approved and NCI-MATCH–accepted laboratory (outside assay cohort [OAC]) were eligible for MATCH AYA analysis. Results: Of the 6801 pts screened for NCI-MATCH, 373 were AYA pts age 18-39 (5.5%). Within the SC, 93.5% (300/321) of AYA pts were successfully biopsied, vs. 92.9% of those age 40+ (5240/5640); 35.7% of the SC AYA vs. 39.6% of the 40+ pts had a study-eligible actionable mutation, and 17% (51/300) of AYA pts vs. 17.8% (934/5240) of those 40+ were subsequently assigned to treatment. Of the 401 pts in the OAC, 30 (7.1%) were AYA; 24/30 (80.0%) of AYA OAC pts were assigned to treatment vs. 87.6% (332/379) of OAC pts age 40+. Screening enrollment data show that at Lead Academic Participating Sites (LAPS), a higher percentage of AYA pts were enrolled compared to pts age 40+ (32.8% [113/344] vs. 24.3% [1472/6047], respectively). In contrast, at NCORP sites, a higher percentage of 40+ pts was enrolled relative to AYA pts (43.8% [2647/6047] vs. 35.8% [123/344], respectively). Among the top histologies enrolled (aside from colon, breast, ovarian) were soft tissue sarcoma other than rhabdomyosarcoma, primary CNS tumors, and liver and hepatobiliary, cervical, and neuroendocrine cancers. Conclusions: There were no statistically significant differences between AYA and older (40+) pts in the number who underwent successful biopsies, the prevalence of tumor actionable mutations, or the number of pts assigned to or who received study treatment. AYA pts were more likely to have been enrolled at a LAPS than a NCORP site, consistent with the AYA population being referred to LAPS upon progression from first-line treatment. Enrollment of the AYA in adult cancer centers in the NCI-MATCH trial was higher than the historical 3%: 5.5% in the SC and 7.1% in the OAC. As more tissue-agnostic studies become available in nationwide trials, AYA participation in clinical trials may increase. Citation Format: Alice P Chen, Shuli Li, Brent Coffey, James V Tricoli, Stanley R Hamilton, Mickey P Williams, Edith P Mitchell, David Patton, Robert J Gray, Lisa M McShane, Lawrence V Rubinstein, Carlos L Arteaga, Peter J O'Dwyer, Lyndsay N Harris, Barbara A Conley, Keith T Flaherty. Adolescent and young adult (AYA) cohort of the NCI MATCH clinical trial (EAY131) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A089. doi:10.1158/1535-7163.TARG-19-A089

10011 Background: The screening protocol for the NCI-Children’s Oncology Group (COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial detects tumor alterations that are used to assign patients with treatment-refractory or recurrent cancers to phase 2 treatment arms of molecularly-targeted therapies. Methods: Patients age 1 to 21 years old with treatment-refractory or recurrent solid tumors, non-Hodgkin lymphomas, or histiocytic disorders treated at U.S. based COG sites are eligible. DNA and RNA extracted from FFPE tumor samples are sequenced using an Oncomine cancer gene panel for detection of mutations, amplifications, and fusions. Loss of SMARCB1, SMARCA4, and PTEN expression is detected by immunohistochemistry. Lists of actionable mutations (aMOIs) based upon available clinical and pre-clinical data are used a priori to determine eligibility for treatment arms. Results: Between 7/24/17 and 12/31/18, 422 patients with a median age of 13 years (range 1-21) were enrolled from 93 COG sites. Solid tumors comprised 71% (n = 300) of diagnoses, CNS tumors 24% (n = 101) and lymphomas/histiocytoses 5% (n = 21). A tumor sample was submitted for 390 patients, sequencing was attempted for 370 (95%), and results were confirmed for 357 (92%). Median turn-around time was 15 days. An aMOI for at least one of the 10 current treatment arms was identified in 112 patients (29%, 95% CI 24%-33%); 95 patients (24%, 95% CI 20%-29%) were assigned to a treatment arm with 39 patients (10%, 95% CI 7%-13%) enrolled to date. The aMOI rate was similar in patients less than 12 years of age (35%) compared to patients 12 years and older (25%). Actionable MAPK pathway alterations were found in 11% of patients (n = 41), most often HRAS/ KRAS/ NRAS mutations (n = 16), BRAF mutations or fusions (n = 14), or NF1 mutations (n = 11). Other genes with recurrent aMOIs included SMARCB1 (n = 14), ALK (n = 8), CDK4 (n = 8), PIK3CA (n = 7), PTEN (n = 7), FGFR1 (n = 5), and BRCA1/BRCA2 (n = 5). Conclusions: Approximately one-quarter of patients with tumor submitted for Pediatric MATCH screening have been assigned to an investigational therapy, facilitating the evaluation of molecularly-targeted agents in biomarker-positive pediatric cohorts through a collaborative nationwide study. Clinical trial information: NCT03155620.

3016 Background: NCI-MATCH is a precision medicine trial that assigns treatment to refractory cancer patients by tumor mutation profile rather than by histology. After screening fresh tumor biopsies from nearly 6000 patients many treatment arms did not meet accrual due to the low prevalence of the eligible variants. NCI MATCH developed an approach to identify patients for the remaining arms utilizing a network of academic and commercial CLIA-certified labs that perform NGS assays as routine care at MATCH participating sites. Methods: Candidate labs were recruited through a notice in the Federal Register and posted on the NCI and ECOG ACRIN web sites. Twenty-seven labs (17 academic/10 commercial) submitted applications. After acceptance each lab analyzed a common set of 10 DNAs extracted from 8 cell lines and 2 clinical samples for concordance with the central NCI-MATCH NGS assay. Results: For the 17 labs with concordance results, a median of 8 (range 2 – 58) copy number variants (CNVs) were evaluated by the NGS assay of each DL, with the number evaluated depending on each lab’s clinical assay panel content. CNV concordance between central and DL assays, as measured by positive percent agreement (PPA), averaged 98.7% (range 87.5% - 100%) with the central assay as referent and 94.1% (range 77.8% – 100%) with the DL assay as referent. For single nucleotide variants (SNVs) and Insertion/deletions (Indels) combined, a median of 19 variants (range 11 – 26) were evaluated by each DL for concordance. PPA between central and DL assays averaged 98.0% (range 87.5% – 100%) and 98.6% (range 90.0% – 100%) with central and DL assay as referents, respectively. Strong correlations were observed between central and DL assays for both CNVs (median r = 0.93; 0.33 – 1.00) and SNV/Indels (median r = 0.98; 0.67 – 0.99). Conclusions: Our results suggest that different NGS assay platforms using diverse strategies for target enrichment and data analysis may still achieve high concordance if pre-analytical variables are minimized and the common genomic regions interrogated by each assay are well-understood. The designated lab network allows for a wider search for rare variants in tumors and provides a model for conducting future clinical trials. Clinical trial information: NCT02465060.

SUMMARY Colorectal carcinoma (CRC) in children, adolescents and young adults under 30 years of age is rare. When it occurs in these young people, is this just an ‘adult’ cancer occurring in a young patient or is it a different disease? How should these patients be managed? Here, we review what is known about the epidemiology and clinical presentation of CRC in children, adolescents and young adults, as well as the current model for CRC development to provide a framework for questioning whether CRC in these young patients is the same disease as that seen in their older adult counterparts. In addition, we will summarize the clinical options described in the peer-reviewed literature to provide a basis for management decisions of these young patients.

Cancers of the lower gastrointestinal (GI) tract are a major cause of morbidity and mortality and among the most common cancers affecting men and women alike. Adenocarcinoma of the colon and rectum and anal squamous cell carcinoma (SCC) are the predominant diseases in this category. Colorectal cancer (CRC) is the third most common malignancy in the US population with nearly 140,000 new cases diagnosed and over 50,000 deaths from CRC in 2014 [1]. The incidence of CRC in adolescents and young adults (AYAs) has been increasing in recent years. Anal SCC is less common, but its incidence is also increasing. Malignancy of the lower GI tract in the AYA population will be reviewed in this chapter.

Each year in the United States, nearly 70 000 individuals between the ages of 15 and 40 years are diagnosed with cancer. Although overall cancer survival rates among pediatric and older adult patients have increased in recent decades, there has been little improvement in survival of adolescent and young adult (AYA) cancer patients since 1975 when collected data became adequate to evaluate this issue. In 2006, the AYA Oncology Progress Review Group made recommendations for addressing the needs of this population that were later implemented by the LIVESTRONG Young Adult Alliance. One of their overriding questions was whether the cancers seen in AYA patients were biologically different than the same cancers in adult and/or pediatric patients. On June 9–10, 2009, the National Cancer Institute (NCI) and the Lance Armstrong Foundation (LAF) convened a workshop in Bethesda, MD, entitled “Unique Characteristics of AYA Cancers: Focus on Acute Lymphocytic Leukemia (ALL), Breast Cancer and Colon Cancer” that aimed to examine the current state of basic and translational research on these cancers and to discuss the next steps to improve their prognosis and treatment.

2503Background: MATCH is a histology-agnostic signal finding trial targeting pathways in cancer. AZD4547 is a selective inhibitor of the fibroblast growth factor receptor (FGFR) 1-3 kinases. Method...

Carcinoma of the prostate is the second leading cause of male cancer-related death in the United States. Better indicators of prostate cancer presence and progression are needed to avoid unnecessary treatment, predict disease course, and develop more effective therapy. Numerous molecular markers have been described in human serum, urine, seminal fluid, and histological specimens that exhibit varying capacities to detect prostate cancer and predict disease course. However, to date, few of these markers have been adequately validated for clinical use. The purpose of this review is to examine the current status of these markers in prostate cancer and to assess the diagnostic potential for future markers from identified genes and molecules that display loss, mutation, or alteration in expression between tumor and normal prostate tissues. In this review we cite 91 molecular markers that display some level of correlation with prostate cancer presence, disease progression, cancer recurrence, prediction of response to therapy, and/or disease-free survival. We suggest criteria to consider when selecting a marker for further development as a clinical tool and discuss five examples of markers (chromogranin A, glutathione S-transferase π 1, prostate stem cell antigen, prostate-specific membrane antigen, and telomerase reverse transcriptase) that fulfill some of these criteria. Finally, we discuss how to conduct evaluations of candidate prostate cancer markers and some of the issues involved in the validation process.

Introduction: NCI-MATCH (EAY131), a national signal-finding trial, assigns targeted treatments to patients (pts) with relapsed/refractory solid tumors, lymphomas and myelomas based on molecular abnormalities in tumors. We screened 4901 pts for dMMR, an eligibility criterion. Methods: Immunohistochemical expression (IHC) of MLH1 and MSH2 was performed at the CLIA-accredited MD Anderson Clinical IHC Laboratory. Loss of nuclear expression of MLH1 or MSH2 predicted microsatellite instability resulting from sporadic alterations or germline mutations. Assays were validated for FFPE tissue and used under an FDA abbreviated investigational device exemption. IHC was performed on 4 μm deparaffinized and rehydrated FFPE tissue sections. Antigen retrieval was performed at 100°C for 20 minutes with Tris-EDTA buffer solution, pH 6.0 & blocking of endogenous peroxidase with 3% peroxide for 5 minutes. Primary MLH1 antibody (Cell MarqueTM, clone G168-728) at 1:300 dilution and primary MSH2 antibody (Calbiochem®, clone FE11) at 1:100 dilution were applied. Primary antibody detection used a commercial polymer system (Bond Polymer Refine Detection, Leica) with stain development using incubation with DAB and DAB Enhancer (Leica). Loss of nuclear expression (required for dMMR eligibility): Complete loss of nuclear expression by tumor cells and retention of staining in non-neoplastic cells (internal control). Intact nuclear expression: Nuclear expression of any intensity within tumor cells. Cannot be determined: Insufficient specimen, technically inadequate IHC assay, or cytoplasmic staining without definite nuclear staining. Results: 4901 pts had MLH1/MSH2 IHC assay, of whom 37 had both MLH1 and MSH2 indeterminate. Of 4864 cases with valid MLH1/MSH2 results, 2% had dMMR (Table–histologies combined to fit allowed space). The most frequent dMMR was in the few thyroid/parathyroid tumors, followed by various gynecologic tumors. Conclusion: 2% of 4864 cases with valid MLH1/MSH2 results in NCI-MATCH had dMMR by IHC; prevalence varied across histologies. Many tumors lacking expression of MLH1 or MSH2 are not prominently associated with Lynch syndrome or frequent somatic dMMR. The NCI-MATCH screen for dMMR adds to information on the potential benefit of screening advanced/refractory tumor types for this abnormality as a standard practice for determining eligibility for PD-1 inhibitors. Pecent tumor categories lacking MLH1/MSH2 expressionHistologyLoss of nuclear MLH1 expressionLoss of nuclear MSH2 expression# screenedPercent of screenedGastrointestinal cancer29413252.5%Gynecological cancer28330110.3%Brain cancer02523.8%Sarcoma (various)601065.7%Thyroid/Parathyroid02366.7%Prostate071225.7%Breast715661.4%Neuroendocrine231922.6%Other303260.9% Citation Format: Barbara A. Conley, Stanley R. Hamilton, Shuli Li, Robert J. Gray, David R. Patton, Peter J. O'Dwyer, Robert L. Comis, Jeffrey S. Abrams, Nilofer S. Azad, Michael J. Overman, Jonathan D. Schoenfeld, Paul M. Williams, James V. Tricoli, Elad Sharon, Howard Streicher, Lyndsay N. Harris, Alice P. Chen, Keith T. Flaherty. Prevalence of mismatch repair deficiency (dMMR) in the NCI Molecular Analysis for Therapy Choice (NCI-MATCH or EAY131) population [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A053.

Cancer therapies can provide substantially improved survival in some patients while other seemingly similar patients receive little or no benefit. Strategies to identify patients likely to respond well to a given therapy could significantly improve health care outcomes by maximizing clinical benefits while reducing toxicities and adverse effects. Using a glycan microarray assay, we recently reported that pretreatment serum levels of IgM specific to blood group A trisaccharide (BG-Atri) correlate positively with overall survival of cancer patients on PROSTVAC-VF therapy. The results suggested anti-BG-Atri IgM measured prior to treatment could serve as a biomarker for identifying patients likely to benefit from PROSTVAC-VF. For continued development and clinical application of serum IgM specific to BG-Atri as a predictive biomarker, a clinical assay was needed. In this study, we developed and validated a Luminex-based clinical assay for measuring serum IgM specific to BG-Atri. IgM levels were measured with the Luminex assay and compared to levels measured using the microarray for 126 healthy individuals and 77 prostate cancer patients. This assay provided reproducible and consistent results with low %CVs, and tolerance ranges were established for the assay. IgM levels measured using the Luminex assay were found to be highly correlated to the microarray results with R values of 0.93-0.95. This assay is a Laboratory Developed Test (LDT) and is suitable for evaluating thousands of serum samples in CLIA certified laboratories that have validated the assay. In addition, the study demonstrates that discoveries made using neoglycoprotein-based microarrays can be readily migrated to a clinical assay.

The Cancer Diagnosis Program of the National Cancer Institute sponsored a workshop entitled “MicroRNA: Potential for Cancer Detection, Diagnosis, and Prognosis” in Rockville, Maryland on November 28 and 29, 2006. The purpose of this workshop was to bring together leaders in the microRNA (miRNA)

High-throughput 'omics' technologies that generate molecular profiles for biospecimens have been extensively used in preclinical studies to reveal molecular subtypes and elucidate the biological mechanisms of disease, and in retrospective studies on clinical specimens to develop mathematical models to predict clinical endpoints. Nevertheless, the translation of these technologies into clinical tests that are useful for guiding management decisions for patients has been relatively slow. It can be difficult to determine when the body of evidence for an omics-based test is sufficiently comprehensive and reliable to support claims that it is ready for clinical use, or even that it is ready for definitive evaluation in a clinical trial in which it may be used to direct patient therapy. Reasons for this difficulty include the exploratory and retrospective nature of many of these studies, the complexity of these assays and their application to clinical specimens, and the many potential pitfalls inherent in the development of mathematical predictor models from the very high-dimensional data generated by these omics technologies. Here we present a checklist of criteria to consider when evaluating the body of evidence supporting the clinical use of a predictor to guide patient therapy. Included are issues pertaining to specimen and assay requirements, the soundness of the process for developing predictor models, expectations regarding clinical study design and conduct, and attention to regulatory, ethical, and legal issues. The proposed checklist should serve as a useful guide to investigators preparing proposals for studies involving the use of omics-based tests. The US National Cancer Institute plans to refer to these guidelines for review of proposals for studies involving omics tests, and it is hoped that other sponsors will adopt the checklist as well.

Introduction: Preliminary data show that up to 10% of patients on early clinical trials have complete (CR) or partial (PR) responses. Exceptional responses (ER) are also observed in certain clinical cases using standard chemotherapy. The ERI Pilot study is evaluating the molecular alterations found in tumors from cancer patients who respond to a systemic treatment (standard or investigational) that is ineffective in at least 90% of patients. The study is available through the Cancer Trials Support Unit (www.ctsu.org). Experimental Procedures Cases of patients who achieve a CR or PR > 6 months are proposed by email at NCIExceptionalResponders@mail.nih.gov. Once provisionally approved, the proposer sends tissue to a central repository, where the tissue is evaluated for percent tumor &necrosis; nucleic acids are isolated & sent for whole exome, mRNA & deep targeted sequencing. Tissue may be frozen or formalin fixed paraffin embedded but must be at least an entire core biopsy. Data will be correlated with mechanism of action of the treatment given. The ERI pilot study will characterize > 100 ERs. If sufficient tissue is available, whole genome sequencing &other molecular analysis may be done. We anticipate that some specimens will not be of sufficient quality/quantity; thus many more tumors will need to be submitted to obtain these results. Six months after the genomic data are generated they will be released to a publicly available, controlled access database to facilitate research by qualified investigators. The ERI study accepts all types of malignant disease in adults or children if adequate tissue obtained prior to the ER exists. The ER could have been to an approved or investigational, targeted, or non-targeted systemic treatment. The feasibility of retrospectively collecting tumor tissue & clinical data for genomic analysis is a goal of the ERI study. Results: The ER study was activated on September 24, 2014. As of December 2, > 80 cases have been proposed, 46 are provisionally approved & 26 cases were not ERs or were withdrawn. Accepted Cases: solid & hematologic tumors (2 brain, 4 breast, 2 colon, 6 gastric, 1 hepatocellular, 7 head/neck, 2 renal, 2 lung cancer, 1 melanoma, 2 ovarian, 6 pancreatic, 2 prostate and 4 sarcomas; 2 acute leukemia, 2 lymphoma, 1 myeloma). Approximately 75% involved standard & 25% involved targeted drugs or combinations. Tissue analysis is ongoing & results will be presented. Conclusions: Collection of archived tissue from ERs for genomic evaluation is feasible. Efficient ER case identification occurs through expert review and consensus-based case selection. Citation Format: Barbara A. Conley, S Percy Ivy, James V. Tricoli, Jean-Claude Zenklusen, Roy Tarnuzzer, Irina Lubensky, Naoko Takebe, Paul M. Williams, JoAnne Zujewski, Richard Little, Jeffrey White, Elise Kohn, Shakun Malik, Ben Kim, Erin Souhan, Lou Staudt. The NCI exceptional responders initiatives: Initial feasibility result. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 612. doi:10.1158/1538-7445.AM2015-612

Objectives. To further investigate the relationship between the plasma levels of insulin-like growth factor-1 (IGF-1), insulin-like growth factor-2 (IGF-2), insulin-like growth factor binding protein-3 (IGFBP-3), growth hormone, testosterone, and demographic factors, particularly race, within a group of men at increased risk of prostate cancer development. Methods. Enzyme-linked immunosorbent assays or an immunosorbent assay was used to quantitate the plasma levels of IGF-1, IGF-2, IGFBP-3, growth hormone, and testosterone. The study group consisted of 169 men (85 African-American, 84 white) aged 35 to 69 years, with no personal history of prostate cancer, but having at least one first-degree relative diagnosed with the disease, unless they were African-American. The relationships between the plasma levels and the categorical covariates were assessed using the nonparametric Wilcoxon test and between the continuous variables using Spearman’s correlation coefficient. Results. The mean plasma levels of IGFBP-3 were significantly lower in African-American (2657 ng/mL) than in white (2965 ng/mL) men ( P = 0.0062). The plasma levels of IGF-2 were also lower in the African-American (503.5 ng/mL) than in the white (549.1 ng/mL) men ( P = 0.0084). Overall, the IGF-1 plasma levels correlated positively with the IGF-2, IGFBP-3, and growth hormone levels and the IGF-2 plasma levels correlated negatively with the testosterone levels. Conclusions. Our results demonstrate that lower plasma levels of IGFBP-3 and IGF-2 are associated with race in a population of men at increased risk of developing prostate cancer. The ability of these markers to predict earlier disease onset is currently under investigation.

Objectives. To test the hypothesis that increasing levels of hypoxia are associated with increased expression of vascular endothelial growth factor (VEGF) in prostate cancer by correlating the level of median tissue oxygenation in human prostate tumors with the immunohistochemically determined level of VEGF expression. Methods. Custom-made Eppendorf oxygen microelectrodes were used to quantitate the pO2 levels in prostate tumors of 13 men undergoing radical prostatectomy. All pO2 measurements were performed under fluorine-based general anesthesia. Paraffin-embedded tumor tissue from these men was analyzed to measure the level of VEGF expression by immunohistochemical staining. The significance of the associations between the pO2 levels and VEGF staining were determined by the Pearson correlations. Results. The range of the median pO2 levels (based on between 97 and 129 individual measurements) among 13 prostate tumors was 0.5 to 44.9 mm Hg. The blinded comparison of pO2 levels and VEGF staining intensity demonstrated a significant correlation between increasing hypoxia and the percentage of cells staining positive for VEGF (r = −0.721, P = 0.005). This correlation was also significant when pO2 levels were compared with the overall immunoreactive score, which takes into account staining intensity (r = −0.642, P = 0.018). Conclusions. To our knowledge, this is the first study demonstrating a significant association between increasing levels of hypoxia and increased expression of the angiogenesis marker VEGF in human prostate carcinoma. The results of our study further support the exploration of antiangiogenesis strategies for the treatment of human prostate cancer.

Objectives. To determine the overall plasma levels of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) in a group of men at higher risk of prostate cancer development and to investigate the relationships between demographics and these levels, particularly with regard to race. Methods. An enzyme-linked immunosorbant assay was used to quantitate plasma levels of IGF-1 and IGFBP-3. The study group consisted of 105 men (63 African American [AA], 42 white), aged 35 to 69 years, with no personal history of prostate cancer, but having at least one first-degree relative diagnosed with the disease, unless they were AA. Differences in plasma levels and categorical covariates were assessed using the nonparametric Wilcoxon test. Associations between plasma levels and the continuous variables were quantified using the nonparametric Spearman correlation coefficient. Results. The mean plasma level of IGF-1 was not significantly different between AA (162.3 ng/mL) and white (172.1 ng/mL) men (P = 0.415). However, the mean plasma level of IGFBP-3 was lower in AA (2789 ng/mL) than in white (3216 ng/mL) men, and this decrease was highly significant (P = 0.0045). No correlation between IGFBP-3 plasma level and age was detected in the group as a whole, but an inverse relationship between IGF-1 plasma level and age was evident (P = 0.0079). Conclusions. Our results demonstrate that IGFBP-3 plasma levels are lower in AA men than in white men. Since IGFBP-3 can control IGF-1 bioavailability, the lowered IGFBP-3 could explain in part the increased risk of prostate cancer in AA men.

58 Background: High-throughput omics technologies (e.g., genomics, epigenomics, proteomics, metabolomics) offer exciting opportunities for new biological insights into cancer. The IOM report on translational omics defined omics as the study of related sets of biological molecules in a comprehensive fashion. (IOM (Institute of Medicine) 2012. Evolution of Translational Omics: Lessons Learned and the Path Forward. Washington, DC: The National Academic Press.) The promise of omics technologies has proven problematic to translate into clinically useful tests. Difficulty obtaining biospecimens, unrecognized preanalytical influences, and suboptimal assay analytical performance can lead to unreliable results and conflicting reports. Poor reporting of study details and limited access to data and computer code can thwart efforts to replicate published results or to detect flaws in study design and analysis methods. Methods: NCI held an interactive workshop for a wide variety of stakeholders to explore better approaches to omics-based test development and validation. This workshop heavily informed the ideas presented here. Recommendations are stated concisely, then explained. Results: A checklist of items to consider when evaluating the evidence for clinical use of an omics-based predictor, including in a trial where it will guide therapy, is presented. It covers specimen and assay requirements, the predictor model development process, clinical study design and conduct, and regulatory, ethical, and legal issues. The list applies to any trial involving investigational use of an omics test that will alter the clinical management of patients. The criteria also largely apply to situations in which the test will be evaluated retrospectively on specimens collected from patients who were prospectively enrolled on clinical studies. Conclusions: The proposed checklist should serve as a useful guide to investigators planning to submit proposals for NCI-funded studies involving use of an omics-based test. Ideally, this checklist will be consulted in the assay planning and development phases so that the necessary evidence will have been collected in a well-documented fashion by the time definitive evaluation of the test is desired.