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Over the past decade, multiple trials, including the precision medicine trial National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH, EAY131, NCT02465060) have sought to determine if treating cancer based on specific genomic alterations is effective, irrespective of the cancer histology. Although many therapies are now approved for the treatment of cancers harboring specific genomic alterations, most patients do not respond to therapies targeting a single alteration. Further, when antitumor responses do occur, they are often not durable due to the development of drug resistance. Therefore, there is a great need to identify rational combination therapies that may be more effective. To address this need, the NCI and National Clinical Trials Network have developed NCI-ComboMATCH, the successor to NCI-MATCH. Like the original trial, NCI-ComboMATCH is a signal-seeking study. The goal of ComboMATCH is to overcome drug resistance to single-agent therapy and/or utilize novel synergies to increase efficacy by developing genomically-directed combination therapies, supported by strong preclinical in vivo evidence. Although NCI-MATCH was mainly comprised of multiple single-arm studies, NCI-ComboMATCH tests combination therapy, evaluating both combination of targeted agents as well as combinations of targeted therapy with chemotherapy. Although NCI-MATCH was histology agnostic with selected tumor exclusions, ComboMATCH has histology-specific and histology-agnostic arms. Although NCI-MATCH consisted of single-arm studies, ComboMATCH utilizes single-arm as well as randomized designs. NCI-MATCH had a separate, parallel Pediatric MATCH trial, whereas ComboMATCH will include children within the same trial. We present rationale, scientific principles, study design, and logistics supporting the ComboMATCH study.

PURPOSE The National Cancer Institute–Children's Oncology Group Pediatric MATCH trial aimed to facilitate evaluation of molecular-targeted therapies in biomarker-selected cohorts of childhood and young adult patients with cancer by screening tumors for actionable alterations. PATIENTS AND METHODS Tumors from patients age 1-21 years with refractory solid tumors, lymphomas, or histiocytic disorders were subjected to cancer gene panel sequencing and limited immunohistochemistry to identify actionable alterations for assignment to phase II treatment arms. The rates of treatment arm assignment and enrollment were compared between clinical and demographic groups. RESULTS Testing was completed for 94.7% of tumors submitted. Actionable alterations were detected in 31.5% of the first 1,000 tumors screened, with treatment arm assignment and enrollment occurring in 28.4% and 13.1% of patients, respectively. Assignment rates varied by tumor histology and were higher for patients with CNS tumors or enrolled at Pediatric Early Phase Clinical Trials Network sites. A reported history of prior clinical molecular testing was associated with higher assignment and enrollment rates. Actionable alterations in the mitogen-activated protein kinase signaling pathway were most frequent (11.2%). The most common reasons provided for not enrolling on treatment arms were patients receiving other treatment or poor clinical status. CONCLUSION The Pediatric MATCH trial has proven the feasibility of a nationwide screening Protocol for identification of actionable genetic alterations and assignment of pediatric and young adult patients with refractory cancers to trials of molecularly targeted therapies. These data support the early use of tumor molecular screening for childhood patients with cancer whose tumors have not responded to standard treatments.

PURPOSE The NCI-COG Pediatric MATCH trial assigns patients age 1-21 years with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase II studies of molecularly targeted therapies on the basis of detection of predefined genetic alterations. Patients with tumors harboring mutations or fusions driving activation of the mitogen-activated protein kinase (MAPK) pathway were treated with the MEK inhibitor selumetinib. METHODS Patients received selumetinib twice daily for 28-day cycles until disease progression or intolerable toxicity. The primary end point was objective response rate; secondary end points included progression-free survival and tolerability of selumetinib. RESULTS Twenty patients (median age: 14 years) were treated. All were evaluable for response and toxicities. The most frequent diagnoses were high-grade glioma (HGG; n = 7) and rhabdomyosarcoma (n = 7). Twenty-one actionable mutations were detected: hotspot mutations in KRAS (n = 8), NRAS (n = 3), and HRAS (n = 1), inactivating mutations in NF1 (n = 7), and BRAF V600E (n = 2). No objective responses were observed. Three patients had a best response of stable disease including two patients with HGG ( NF1 mutation, six cycles; KRAS mutation, 12 cycles). Six-month progression-free survival was 15% (95% CI, 4 to 34). Five patients (25%) experienced a grade 3 or higher adverse event that was possibly or probably attributable to study drug. CONCLUSION A national histology-agnostic molecular screening strategy was effective at identifying children and young adults eligible for treatment with selumetinib in the first Pediatric MATCH treatment arm to be completed. MEK inhibitors have demonstrated promising responses in some pediatric tumors (eg, low-grade glioma and plexiform neurofibroma). However, selumetinib in this cohort with treatment-refractory tumors harboring MAPK alterations demonstrated limited efficacy, indicating that pathway mutation status alone is insufficient to predict response to selumetinib monotherapy for pediatric cancers.

Background NCI-COG Pediatric MATCH assigns patients aged 1-21 years with refractory solid tumors, brain tumors, lymphomas, and histiocytic disorders to phase II trials of molecularly targeted therapies based on detection of pre-defined genetic alterations. Patients whose tumors harbored EZH2 mutations or loss of SMARCB1 or SMARCA4 by immunohistochemistry were treated with EZH2 inhibitor tazemetostat. Methods Patients received tazemetostat for 28-day cycles until disease progression or intolerable toxicity (max 26 cycles). The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS) and tolerability of tazemetostat. Results Twenty patients (median age, 5 years) enrolled, all evaluable for response and toxicities. The most frequent diagnoses were atypical teratoid rhabdoid tumor (ATRT; n = 8) and malignant rhabdoid tumor (MRT; n = 4). Actionable alterations consisted of SMARCB1 loss (n = 16), EZH2 mutation (n = 3), and SMARCA4 loss (n = 1). One objective response was observed in a patient with non-Langerhans cell histiocytosis with SMARCA4 loss (26 cycles, 1200 mg/m2/dose twice daily). Four patients with SMARCB1 loss had a best response of stable disease: epithelioid sarcoma (n = 2), ATRT (n = 1), renal medullary carcinoma (n = 1). Six-month PFS was 35% (95% CI: 15.7%, 55.2%) and six-month OS, 45% (95% CI 23.1, 64.7%). Treatment-related adverse events were consistent with prior tazemetostat reports. Conclusion Although tazemetostat did not meet its primary efficacy endpoint in this population of refractory pediatric tumors (ORR: 5%, 90% CI 1%, 20%), 25% of patients with multiple histologic diagnoses experienced prolonged stable disease of > 6 months (range: 9-26 cycles), suggesting a potential effect of tazemetostat on disease stabilization.

Over the past decade, multiple trials, including the precision medicine trial National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH, EAY131, NCT02465060) have sought to determine if treating cancer based on specific genomic alterations is effective, irrespective of the cancer histology. Although many therapies are now approved for the treatment of cancers harboring specific genomic alterations, most patients do not respond to therapies targeting a single alteration. Further, when antitumor responses do occur, they are often not durable due to the development of drug resistance. Therefore, there is a great need to identify rational combination therapies that may be more effective. To address this need, the NCI and National Clinical Trials Network have developed NCI-ComboMATCH, the successor to NCI-MATCH. Like the original trial, NCI-ComboMATCH is a signal-seeking study. The goal of ComboMATCH is to overcome drug resistance to single-agent therapy and/or utilize novel synergies to increase efficacy by developing genomically-directed combination therapies, supported by strong preclinical in vivo evidence. Although NCI-MATCH was mainly comprised of multiple single-arm studies, NCI-ComboMATCH tests combination therapy, evaluating both combination of targeted agents as well as combinations of targeted therapy with chemotherapy. Although NCI-MATCH was histology agnostic with selected tumor exclusions, ComboMATCH has histology-specific and histology-agnostic arms. Although NCI-MATCH consisted of single-arm studies, ComboMATCH utilizes single-arm as well as randomized designs. NCI-MATCH had a separate, parallel Pediatric MATCH trial, whereas ComboMATCH will include children within the same trial. We present rationale, scientific principles, study design, and logistics supporting the ComboMATCH study.

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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.

3035 Background: The National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) multi-arm phase II clinical trial tested tumor tissue from 5,954 patients with advanced refractory cancer to assign treatment based on the molecular profile. Molecular profiling was successful for 93% of patients. For 267 of the patients who were not enrolled because molecular profiling was not successful, plasma cfDNA was evaluated to provide insight into the potential utility of blood-based testing in a broad spectrum of histologies when tissue is not evaluable. Methods: Cell-free DNA was extracted from plasma collected from Streck blood tubes and quantitated. Libraries were constructed using ³ 15 ng cfDNA into the Illumina TruSight Oncology 500 ctDNA RUO Assay, including unique molecular identifiers and duplex barcodes for error correction. Libraries were sequenced on the NovaSeq 6000 with S4 XP flow cells. Results: Of the 267 samples, 250 samples (94%) were evaluable, representing 72 histologies, including colorectal cancer (N = 36), lung adenocarcinoma (N = 15), pancreatic adenocarcinoma (N = 14), and invasive breast carcinoma (N = 12). Of these, 231 (92%) had ³ 1 OncoKB annotated mutation, with 208 patients (83%) having putative somatic mutations detected in genes not commonly associated with clonal hematopoiesis. The most common somatic mutations were in TP53, KRAS, APC, and PIK3CA, reported in 51%, 20%, 12%, and 12% of patients respectively. A total of 109 patients (44%) had ³ 1 actionable mutation of interest (aMOI) reported that could have been used for treatment assignment in the NCI-MATCH clinical trial. After applying histology and molecular exclusions, 75 patients (30%) had ³ 1 aMOI. The most common assignable treatment arms were Z1B/Z1BX1 (palbociclib with CCND1/2/3, N = 13), Z1F (copanlisib with PIK3CA Mutations, N = 13), S1/S1X1 (trametinib with NF1 mutation, N = 12), and Z1C/Z1CX1 (palbociclib with CDK4/CDK6 Amplification and Rb Expression by IHC, N = 10). Mutations in genes commonly associated with clonal hematopoiesis (CH) were prevalent in this population. Along with the expected high frequency of DNMT3A (21% of patients) and TET2 (11%) mutations, PPM1D mutations were the highest amongst CH genes, with 61 patients (24%) having ³ 1 PPM1D mutation, likely due to the heavily pre-treated nature of these patients. Conclusions: Variants observed in the blood are consistent with what is reported in the tissue. Using liquid biopsy when tissue is not evaluable can expand the ability of patients to obtain mutation information that can inform treatment compared to using tumor tissue only. Cell-free DNA provided valuable mutation information for these patients and could have resulted in up to an additional 75 patients being eligible for treatment selection based on their mutation profile. These results indicate that blood-based screening could be a tool for future NCI-sponsored clinical studies.

e17617 Background: NCI-MATCH, a signal-finding precision medicine trial, centrally screened tumors from ̃6000 patients age > 18 with refractory/relapsed cancer using Oncomine Comprehensive Assay (OCA) targeted gene panel. Screened cohort included a subset of patients with ovarian cancer age 18-39 yrs, overlapping adolescent and young adult (AYA) range (NCI consensus definition: 15-39 yrs). Objective of this study was to compare tumor genomic features of AYA to non-AYA ovarian cancers. Methods: Patient clinicopathologic, demographic, and tumor mutation (SNVs, Indels, CNVs by central OCA) data from NCI-MATCH were available. Analyses were restricted to mutation profiles generated by OCA version 2 (OCA v2), which assessed 143 genes and was used for most samples. Proportions of cases with mutations in each gene were compared for AYA and non-AYA groups by 2-sided Fisher’s exact tests. For each gene, association between age (continuous independent variable) and presence of mutation (binary dependent variable) was assessed using logistic regression. Benjamini-Hochberg adjusted p-values were computed; false discovery rate (FDR) was controlled at 10%. Results: Data from 455 ovarian cancers (437 epithelial, 18 stromal), including 21 AYA and 434 non-AYA cases, were included in this analysis. Among the 28 genes most frequently (in > 6 patient tumors) mutated and altered, CTNNB1 was mutated in 9.5% of AYA patients compared to 0.9% in non-AYA (unadj. p=0.027) but failed to meet 10% FDR criterion (FDR-adj. p=0.7). KRAS mutation was more frequent in AYA than non-AYA but not significantly after adjustment (FDR-adj. p=0.7). Logistic regression results showed TP53 mutation was significantly associated with older age (FDR-adj. p

3009 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 J evaluated the ERK1/2 inhibitor ulixertinib (BVD-523FB) in patients whose tumors harbored activating alterations in the MAPK pathway ( ARAF, BRAF, HRAS, KRAS, NRAS, MAPK1, MAP2K1, GNA11, GNAQ hotspot mutations; NF1inactivating mutations; BRAF fusions). Methods: As there were no prior pediatric data, ulixertinib was initially tested in a dose escalation cohort using a rolling 6 design to establish the recommended phase 2 dose (RP2D) before proceeding with enrollment to the phase 2 cohort. Ulixertinib was administered at 260 mg/m2/dose PO BID (dose level 1, DL1, n = 15) or 350 mg/m2/dose PO BID (dose level 2, DL2, n = 5). Patients were treated on continuous 28-day cycles for up to 2 years, until disease progression or intolerable toxicity; response assessment occurred every 2-3 cycles. The primary endpoint was objective response rate; secondary endpoints included safety/tolerability and progression-free survival (PFS). Results: Twenty patients (median age 12 years; range 5-20) were enrolled between November 2018 and March 2021. All patients were evaluable for response. High-grade glioma (HGG, n = 7) was most common, with CNS tumors comprising 55% (11/20) of diagnoses; all CNS tumors except one (HGG with KRAS and NF1 mutations) harbored BRAF fusions or V600 mutations. Rhabdomyosarcoma (n = 5) was the most frequent non-CNS diagnosis, with NRAS mutations detected in 4 tumors. DL1 was declared the RP2D after first-cycle dose limiting toxicities (DLTs) occurred in 1/6 DLT-evaluable patients at DL1 and 2/5 patients at DL2 in the dose escalation cohort. Any-cycle DLTs in 8 patients in the dose escalation and primary cohorts included fatigue, anorexia, rash, nausea, vomiting, diarrhea, dehydration, increased creatinine, hypoalbuminemia, hypernatremia, and hip fracture. No objective responses were observed. Six-month PFS was 37% (95% CI: 17%, 58%). Three patients with CNS tumors achieved stable disease > 6 months (HGG with BRAF fusion, 15 cycles; glioneuronal tumor with BRAF V600E, 9 cycles; low-grade glioma with BRAF fusion, 7 cycles). Analyses of correlative studies, including pharmacokinetics and circulating tumor DNA, are ongoing. Conclusions: The pediatric RP2D of ulixertinib was established as 260 mg/m2/dose PO BID. There were no objective responses in this cohort of children and young adults with treatment-refractory tumors with activating MAPK alterations. Clinical benefit of prolonged disease control was observed in 3 patients with BRAF-altered gliomas and glioneuronal tumors. Clinical trial information: NCT03698994.

10009 Background: The NCI-Children’s Oncology Group (COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial assigns patients, age 1-21 years, with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase 2 treatment arms based on genetic alterations detected in their tumor. Arm C evaluated the EZH2 inhibitor tazemetostat in patients whose tumors harbored EZH2 hotspot mutations or SMARCB1 or SMARCA4 loss by immunohistochemistry. Methods: Tazemetostat 1200 mg/m2/dose PO BID was administered to the first 13 patients; after study amendment due to second malignancy noted in the pediatric phase 1 trial, the dose for patients with non-CNS tumors was reduced to 520 mg/m2/dose PO BID. Patients were treated for 28-day cycles until PD or intolerable toxicity (max 26 cycles); response assessments occurred every 2-3 cycles. Primary and secondary endpoints were ORR and PFS, respectively. Results: Twenty eligible and evaluable patients (median age 5 years; range 1-21) were enrolled between Nov 2017 and Sept 2020. SMARCB1 loss was detected in 16/20 (80%) tumors: atypical teratoid rhabdoid tumor (ATRT, n = 8), malignant rhabdoid tumor (MRT, n = 4), epithelioid sarcoma (ES, n = 2), renal medullary carcinoma (RMC, n = 1) and hepatocellular carcinoma (HCC, n = 1). EZH2 mutations were identified in 3/20 (15%) tumors: Ewing sarcoma (n = 2), ependymoma (n = 1). One patient with Langerhans cell histiocytosis (LCH) had SMARCA4 loss. Centrally reviewed, one objective response (PR) was observed (LCH [SMARCA4], 26 cycles at 1200 mg/m2/dose BID). Five other patients had a best response of stable disease (ES [SMARCB1], 26 cycles, 520 mg/m2/dose BID; ATRT [SMARCB1], 13 cycles,1200 mg/m2/dose BID; RMC [SMARCB1], 12 cycles, 520 mg/m2/dose BID; ES [SMARCB1], 9 cycles,1200 mg/m2/dose BID; ATRT [SMARCB1], 6 cycles, 1200 mg/m2/dose BID). No other patients received > 2 cycles. Six-month PFS was 35% (95% CI 15.7%, 55.2%); OS was 45% (95% CI 23.1%, 64.7%). Treatment-related adverse events were consistent with AEs previously reported with tazemetostat, including anemia, thrombocytopenia, elevated LFTs, abdominal pain, dyspnea, infection, and intracranial hemorrhage. Three patients had bromide elevations. Conclusions: In this cohort of children with relapsed tumors harboring EZH2 mutations or loss of SMARCB1 or SMARCA4, tazemetostat did not produce significant objective responses (ORR: 5%, 90% CI 1%, 20%). However, we observed prolonged stable disease of > 6 months (range: 6-26 cycles) in 33% of patients across different histologic diagnoses, including two patients who received the full two years of study therapysuggesting a potential effect of tazemetostat on disease stabilization. Future studies will incorporate tazemetostat in combination with chemotherapy or immunologic agents for patients with these aggressive and difficult to treat tumors. Clinical trial information: NCT03213665.

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.

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. Our current understanding of the unique biological/genomic characteristics of AYA cancers is limited. However, there has been some progress that has provided clues about the biology of AYA cancers. We here review the latest findings in the area of AYA cancer biology and discuss what is required to advance the field for the more effective treatment of this patient population.

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.

The US National Cancer Institute (NCI), in collaboration with scientists representing multiple areas of expertise relevant to 'omics'-based test development, has developed a checklist of criteria that can be used to determine the readiness of omics-based tests for guiding patient care in clinical trials. The checklist criteria cover issues relating to specimens, assays, mathematical modelling, clinical trial design, and ethical, legal and regulatory aspects. Funding bodies and journals are encouraged to consider the checklist, which they may find useful for assessing study quality and evidence strength. The checklist will be used to evaluate proposals for NCI-sponsored clinical trials in which omics tests will be used to guide therapy.

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.

Investigating the potential biological basis of age-related differences in outcome for AYA with cancer could lead to a better understanding of the biology, facilitate the development of new diagnostic and predictive markers, and identify novel therapeutic targets and treatment approaches for AYA patients. The evidence that cancers in AYA patients may differ biologically from those in older and younger populations includes data from numerous laboratories. However, much of this evidence is preliminary, and large comprehensive studies to confirm and validate these findings are only now beginning to get underway. Indeed, there may be substantial differences in biological and molecular features between different age groups even within the population of AYA patients with a specific cancer type. If age is a good surrogate for a unique tumor biology associated with AYA cancers, then studies of cancers in AYA patients will almost certainly illuminate alternative tumorigenic pathways and will also likely benefit patients in other age groups whose tumors exhibit similar biological/molecular features. The biologic, molecular, and clinical features of five AYA cancers (colon, breast, acute lymphoblastic leukemia, melanoma, and sarcoma) are highlighted in this chapter, and the current state of research for each of them is examined. What will be required to better diagnose, treat, and predict response in patients with AYA cancer is also discussed.

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...

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.

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 introduction of novel technologies that can be applied to the investigation of the molecular underpinnings of human cancer has allowed for new insights into the mechanisms associated with tumor development and progression. They have also advanced the diagnosis, prognosis and treatment of cancer. These technologies include microarray and other analysis methods for the generation of large-scale gene expression data on both mRNA and miRNA, next-generation DNA sequencing technologies utilizing a number of platforms to perform whole genome, whole exome, or targeted DNA sequencing to determine somatic mutational differences and gene rearrangements, and a variety of proteomic analysis platforms including liquid chromatography/mass spectrometry (LC/MS) analysis to survey alterations in protein profiles in tumors. One other important advancement has been our current ability to survey the methylome of human tumors in a comprehensive fashion through the use of sequence-based and array-based methylation analysis (Bock et al., Nat Biotechnol 28:1106-1114, 2010; Harris et al., Nat Biotechnol 28:1097-1105, 2010). The focus of this chapter is to present and discuss the evidence for key genes involved in prostate tumor development, progression, or resistance to therapy that are regulated by methylation-induced silencing.

The introduction of novel technologies that can be applied to the investigation of the molecular underpinnings of human cancer has allowed for new insights into the mechanisms associated with tumor development and progression. They have also advanced the diagnosis, prognosis and treatment of cancer. These technologies include microarray and other analysis methods for the generation of large-scale gene expression data on both mRNA and miRNA, next-generation DNA sequencing technologies utilizing a number of platforms to perform whole genome, whole exome, or targeted DNA sequencing to determine somatic mutational differences and gene rearrangements, and a variety of proteomic analysis platforms including liquid chromatography/mass spectrometry (LC/MS) analysis to survey alterations in protein profiles in tumors. One other important advancement has been our current ability to survey the methylome of human tumors in a comprehensive fashion through the use of sequence-based and array-based methylation analysis (Bock et al., Nat Biotechnol 28:1106-1114, 2010; Harris et al., Nat Biotechnol 28:1097-1105, 2010). The focus of this chapter is to present and discuss the evidence for key genes involved in prostate tumor development, progression, or resistance to therapy that are regulated by methylation-induced silencing.

A change in Y chromosome number is but one of the many cytogenetic abnormalities reported in human prostate tumors. However, reports in the literature have varied regarding the frequency of Y loss or gain, whether it is restricted to the cancerous tissue, and its relation to the biology of the disease. The most frequently used materials for analysis of Y enumeration have been metaphase spreads from short-term cell cultures of prostate tumor tissue and paraffin-embedded tissue sections. Analysis of Y chromosome number by using metaphase spreads on short-term cultures can be misleading owing to clonal cell selection during the establishment of these cultures. This may result in an incomplete representation of the loss / gain pattern in the tumor as a whole. Studies using paraffin-embedded tissue sections can be complicated by apparent chromosome loss due to nuclear truncation as a result of tumor sectioning. In an attempt to circumvent these problems, we have used touch preparations from human prostate tumors to search for Y chromosome loss. Fluorescence in situ hybridization analysis was conducted by using a whole chromosome Y paint, with an α-satellite chromosome 3 probe as a control, on tumor samples from 42 patients ages 40–75. The results demonstrated a gain of Y in a single prostate tumor sample, with no convincing evidence for loss of the entire Y chromosome in any of the other 41 samples examined. The results suggest that loss of the entire Y chromosome is an infrequent event in prostate cancer.

BACKGROUND Overexpression of cyclin D1 has been documented in a number of human cancers. Increased expression of cyclin D1 can contribute to cellular transformation and abnormal proliferation. METHODS Quantitative RT-PCR and/or Western blot analysis were used to determine the level of cyclin D1 expression in 96 human prostate tumors, 15 benign prostate hyperplasias, 4 prostate cancer cell lines, and 3 xenografts. RESULTS Our results demonstrate that 4.2% of the prostate tumors examined overexpressed cyclin D1 trasnscripts. In the cell lines, expression was normal, with the exception that reduced levels of cyclin D1 transcript and protein were observed in the DU145 cell line, as expected from cells with mutant RB. Normal levels of cyclin D1 were found in all xenograft tumors and BPH specimens examined. CONCLUSIONS These data show that overexpression of cyclin D1 occurs rarely in human prostate tumors. However, when overexpression of cyclin D1 does occur, it may identify a subset of tumors with a different molecular biology. Prostate 38:40–45, 1999. © 1999 Wiley-Liss, Inc.

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.

The loss or mutational inactivation of the RB1 tumor suppressor gene has been implicated in the development of a diverse group of human malignancies. However, the contribution of the RB1 gene alteration to human prostatic carcinogenesis has been poorly understood. Thus far, deletion of the promoter sequence and exon 21 from one primary tumor specimen and the alterations found in the cell line DU-145, are the only cases of RB1 mutations reported in human carcinoma of the prostate. This study was designed to determine whether alterations in the structure or expression of the RB1 gene occur in human prostate carcinoma, and to determine the nature of these changes and the frequency with which they occur. One hundred twelve primary prostate tumor tissues and four metastatic lesions were obtained immediately after surgical resection. The RB1 gene was characterized in 68 tumor DNA samples using Southern analysis and the PG3.8M or H3-8 probes. Band profiles were analyzed by scanning densitometry. Sixty-three tumor DNA samples were analyzed for defects in the RB1 promoter using polymerase chain reaction (PCR) and heteroduplex analysis. Alterations in the expression of exons 1-27 were analyzed in 79 primary and four metastatic tumor RNAs using RT-PCR. Three of 68 tumors were identified to have gross rearrangement of the RB1 gene or deletion of one allele. One of four stage D tumor specimens showed truncated RT-PCR products indicating an internal deletion of RB1 transcripts. In all, 14 of 83 (17%) specimens displayed abnormally low levels of RB1 mRNA expression. Furthermore, these alterations of RB1 expression showed a correlation with increasing tumor stage and grade. These results suggest alterations of RB1 mRNA expression occur more frequently in higher stages and grades of prostate cancer and, thus, may be contributing to the malignant progression of a subset of human prostate cancer.

The human sex-region Y (SRY) gene maps to Yp 11.3 and encodes a protein that shares significant sequence homology with a conserved DNA binding motif found in the nonhistone high-mobility group (HMG) proteins. In the mouse, Sry is required for normal testicular development and is expressed in the developing male gonadal ridge as well as in the adult testis. In man, SRY expression has been observed in the adult testis, but not in other adult male tissues. We have analyzed samples from human prostate adenocarcinoma and benign prostatic hypertrophy (BPH) for the expression of the SRY gene. We found expression of SRY in 60% of malignant prostate tumors and in three of six samples of BPH. We did not find expression in male or female colon mucosa, or in tissue from a cystic ovary. Malignant and atrophic testicular tissue both contained SRY transcript and served as positive controls in these experiments. We also found SRY transcript in the DU-145 prostate adenocarcinoma cell line. Interestingly, SRY expression is absent in the Tera-2 teratocarcinoma cell line. The potential for the SRY gene product to bind HMG core response elements in vitro suggests that SRY could participate in the cascade of gene regulatory events that result in aberrant cell growth or malignancy. © 1993 Wiley-Liss, Inc.

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