Publications by authors named "Katherine A Janeway"

84 Publications

Patterns of Translocation Testing in Patients Enrolling to a Cooperative Group Trial for Newly Diagnosed Metastatic Ewing Sarcoma: A Report From the Children's Oncology Group.

Arch Pathol Lab Med 2021 Mar 26. Epub 2021 Mar 26.

the Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York (Glade-Bender).

Context.—: Molecular diagnostics play an increasing role in the diagnosis of Ewing sarcoma. The type of molecular testing used in clinical practice has been poorly described.

Objective.—: To describe patterns of translocation testing for newly diagnosed Ewing sarcoma.

Design.—: Children's Oncology Group (COG) trial AEWS1221 was a phase III randomized trial enrolling patients with newly diagnosed metastatic Ewing sarcoma from 2014 to 2019. Patients were required to have a histologic diagnosis of Ewing sarcoma, but translocation testing was not required. Sites provided types and results of any molecular diagnostics performed.

Results.—: Data from 305 enrolled patients were available. The most common type of molecular testing was fluorescence in situ hybridization (FISH) performed on the primary tumor (236 of 305 patients; 77.4%), with positive testing for an EWSR1 or FUS translocation in 211 (89.4%). Reverse transcription-polymerase chain reaction (RT-PCR) on the primary tumor was performed in 61 of 305 (20%), with positive results in 48 of 61 patients (78.7%). Next-generation sequencing was reported in 7 patients on primary tumor and in 3 patients on metastatic sites. Evaluating all types of testing on either primary or metastatic tumor, 16 of 305 patients (5.2%) had no reported translocation testing. Evaluating all results from all testing, 44 of 305 patients (14.4%) lacked documentation of an abnormality consistent with a molecular diagnosis of Ewing sarcoma.

Conclusions.—: COG sites enrolling in a Ewing sarcoma trial have high rates of testing by FISH or PCR. A small proportion of patients have no translocation testing on either primary or metastatic sites. Next-generation sequencing techniques are not yet commonly used in this context.
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http://dx.doi.org/10.5858/arpa.2020-0671-OADOI Listing
March 2021

Retrospective evaluation of single patient investigational new drug (IND) requests in pediatric oncology.

Cancer Med 2021 Mar 9. Epub 2021 Mar 9.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA.

Background: Single patient Investigational New Drug (IND) applications are one mechanism through which experimental therapies are accessed for children with cancer. The landscape of use, outcomes, and toxicity from single patient INDs remains unknown in pediatric oncology.

Methods: We performed a retrospective analysis of all single patient INDs requested and prescribed at a single institution between 1/1/2007 and 5/1/2019. We report aggregate data from the US Food and Drug Administration (FDA) on single patient IND applications over the final two years of the study (2017-2019). We report an overview of all IND applications, as well as clinical descriptions of patients, treatments, outcomes, and toxicity.

Results: Over the 2-year period, the FDA approved all 171 submitted single patient IND requests for pediatric oncology. We identified 56 requests from our center during the 12-year study period, and all were approved (median time from FDA submission to approval: 1 day (range 0-12)). 71% of requests were based on disease histology. Lack of pediatric clinical trial (65%) was the most common reason for use. 48 approved requests were ultimately administered. The median duration of treatment was 84 days (range: 4-1590), with 3 patients remaining on treatment at time of analysis. Only 7% discontinued treatment due to toxicity. Three-year overall survival was 50% (95% CI, 35-64).

Conclusions: Single patient INDs in pediatric oncology were universally approved in our national and single-center analysis. In our cohort, single patient INDs were primarily utilized based on disease histology, rather than genomics, for agents that lacked a clinical trial.
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http://dx.doi.org/10.1002/cam4.3791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982629PMC
March 2021

Matched Targeted Therapy for Pediatric Patients with Relapsed, Refractory or High-risk Leukemias: A Report from the LEAP Consortium.

Cancer Discov 2021 Feb 9. Epub 2021 Feb 9.

Department of Pediatrics and The Center for Childhood Cancer Research, Children's Hospital of Philadelphia.

Despite a remarkable increase in the genomic profiling of cancer, integration of genomic discoveries into clinical care has lagged behind. We report the feasibility of rapid identification of targetable mutations in 153 pediatric patients with relapsed/refractory or high-risk leukemias enrolled on a prospective clinical trial conducted by the LEAP Consortium. Eighteen percent of patients had a high confidence, Tier 1 or 2, recommendation. We describe clinical responses in the 14% of patients with relapsed/refractory leukemia who received the matched targeted therapy. Further, in order to inform future targeted therapy for patients, we validated variants of uncertain significance (VUS), performed ex vivo drug sensitivity testing in patient leukemia samples, and identified new combinations of targeted therapies in cell lines and patient-derived xenograft models. These data and our collaborative approach should inform the design of future precision medicine trials.
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http://dx.doi.org/10.1158/2159-8290.CD-20-0564DOI Listing
February 2021

Survey of Paediatric Oncologists and Pathologists regarding Their Views and Experiences with Variant Translocations in Ewing and Ewing-Like Sarcoma: A Report of the Children's Oncology Group.

Sarcoma 2020 5;2020:3498549. Epub 2020 Dec 5.

Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Advances in molecular diagnostics have identified subsets of Ewing and Ewing-like sarcomas driven by variant translocations with unique biology. It is likely that patients with these tumours will have different clinical features and therapeutic outcomes. Nevertheless, the management of these patients both locally and within cooperative group trials depends on the local pathological diagnosis. It is not known what molecular diagnostic approaches are employed by local pathologists or if the exact translocation is commonly determined. In addition, it is not known what therapeutic approaches are employed for these patients or what cooperative trials are deemed appropriate for these patients by expert consensus. To answer these questions, we performed an international survey of oncologists and pathologists to better understand the diagnostic approaches used to identify variant translocations and the influence the findings have on therapy and clinical trial eligibility. An online survey was distributed to oncologists and pathologists primarily in North America. A total of 141 surveys were completed, representing a 28% response rate. The majority of respondents considered EWSR1-ETS gene family translocations (range 61-96%) to be Ewing sarcoma and would include them on the primary arm of a Ewing sarcoma clinical trial. There was a lack of consensus on how to classify and stratify BCOR-CCNB3, CIC-DUX4, and EWSR1+ with non-ETS partner fusions. Most respondents were either unsure how their institution tested, or their institution did not perform the test. In cases with atypical Ewing morphology, most respondents favoured additional fusion transcript testing. There is a lack of consensus regarding the classification and stratification of rare molecular subtypes in Ewing sarcoma. It is not clear how these alternative translocations have impacted outcomes for past clinical studies. This suggests a need for molecular confirmation of diagnoses and centralized or minimum standardization of testing for future trial enrolment.
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http://dx.doi.org/10.1155/2020/3498549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787769PMC
December 2020

A case of metastatic adenocarcinoma of unknown primary in a pediatric patient: Opportunities for precision medicine.

Pediatr Blood Cancer 2021 Apr 12;68(4):e28780. Epub 2020 Dec 12.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Dana-Farber Cancer Institute, Boston, Massachusetts.

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http://dx.doi.org/10.1002/pbc.28780DOI Listing
April 2021

Phase I/II Study of Stereotactic Body Radiation Therapy for Pulmonary Metastases in Pediatric Patients.

Adv Radiat Oncol 2020 Nov-Dec;5(6):1267-1273. Epub 2020 Sep 23.

Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

Purpose: Pulmonary metastases are common in many pediatric solid tumors; however, little is known about safety and efficacy of lung stereotactic body radiation therapy (SBRT) for pediatric patients. We conducted a phase I/II study to investigate the minimum effective dose level of SBRT with an acceptable safety profile in pediatric patients.

Methods And Materials: Patients with sarcoma and metastatic pulmonary lesions ≤3 cm in diameter and ≤21 years of age were enrolled. Dose levels 1, 2, and 3 were 24, 30, and 36 Gy in 3 fractions, respectively. Enrolled patients with metastases from primary renal tumors and sarcoma histologies were to begin at dose level 1 and 2, respectively. Exclusion criteria included receipt of whole-lung/hemi-thorax irradiation >12 Gy within 6 months of consent. Primary endpoints were tolerability and safety per Common Terminology Criteria for Adverse Events grading and disease response at 6 weeks post-SBRT per response evaluation criteria in solid tumors (RECIST) 1.1 criteria. Secondary endpoints included rates of local control and distant failure within the lung, but outside of the treatment volume.

Results: Five patients with median age of 13 years (range, 7-21) received SBRT at dose level 2. Primary tumor histologies included Ewing sarcoma (n = 3), anaplastic chordoma (n = 1), and osteosarcoma (n = 1). No grade ≥3 adverse events were observed. At 6 weeks after SBRT, 7/8 (87.5%) lesions achieved partial response. With median follow-up of 2.1 years (range, 1.4-2.5), 2-year local control and distant failure-free survival were 60% (n = 8) and 40% (n = 5), respectively. One patient developed widespread metastases and succumbed to disease 1.4 years after SBRT.

Conclusions: SBRT for pulmonary metastases produces responses in pediatric patients with sarcoma at 6 weeks with acceptable toxicity; however, patients remain at risk of local and distant failure within the lung. Future prospective studies are needed to investigate whether higher doses of SBRT, possibly in combination with other therapies, are safe and provide more durable response.
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http://dx.doi.org/10.1016/j.adro.2020.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718514PMC
September 2020

Desmoid tumors of the head and neck in the pediatric population: Has anything changed?

Int J Pediatr Otorhinolaryngol 2021 Jan 18;140:110511. Epub 2020 Nov 18.

Department of Otolaryngology & Communication Enhancement, Boston Children's Hospital, Boston, MA, United States; Department of Otolaryngology, Harvard Medical School, Boston, MA, United States. Electronic address:

Introduction: Pediatric head and neck desmoid tumors are rare neoplasms that can cause significant morbidity due to infiltration of vital anatomic structures. The goal of this study is to review presentation, evaluation, and management of these tumors.

Methods: Retrospective study of children with head and neck desmoid tumors treated from 1999 to 2018 and literature review.

Results: 11 patients (5 boys, 6 girls) were included. Presentation included firm neck mass (n = 8), trismus (n = 2) and tongue lesion (n = 1). All patients had preoperative imaging with CT (n = 2), MRI (n = 1) or both (n = 8). Five patients underwent needle biopsy, five had open biopsy and one was diagnosed on pathology from primary excision. Seven patients were treated by primary surgical resection, with positive surgical margins in six cases due to proximity to vital neurovascular structures. None needed chemotherapy, had disease recurrence or progression. Three patients with unresectable disease were treated with chemotherapy. One patient was monitored with imaging without any treatment and did not have disease progression. Follow-up ranged from 6 months to 6 years (median 21 months). Ten patients (7 surgical, 2 chemotherapy, 1 observation) were either disease-free or had stable disease at last follow-up.

Conclusion: Pediatric head and neck desmoid tumors, though rare and histologically benign, are locally infiltrative and aggressive. When feasible, surgical treatment results in good disease control despite positive margins. A balance between achieving negative margins and minimizing functional deficits should be considered. Chemotherapy can be successfully utilized in patients where surgery entails a high risk of morbidity and mortality.
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http://dx.doi.org/10.1016/j.ijporl.2020.110511DOI Listing
January 2021

Derivation and validation of risk groups in patients with osteosarcoma utilizing regression tree analysis.

Pediatr Blood Cancer 2021 Mar 30;68(3):e28834. Epub 2020 Nov 30.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, Massachusetts.

Background: For patients with osteosarcoma, apart from stage and primary site, we lack reliable prognostic factors for risk stratification at diagnosis. There is a need for further defined, discrete prognostic groups using presenting clinical features.

Methods: We analyzed a cohort of 3069 patients less than 50 years of age, diagnosed with primary osteosarcoma of the bone between 1986 and 2013 from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were randomly split into test and validation cohorts. Optimal cut points for age, tumor size, and grade were identified using classification and regression tree analysis. Manual recursive partitioning was used to identify discrete prognostic groups within the test cohort. These groups were applied to the validation cohort, and overall survival was analyzed using Cox models, Kaplan Meier methods, and log-rank tests.

Results: After applying recursive partitioning to the test cohort, our initial model included six groups. Application of these groups to the validation cohort resulted in four final groups. Key risk factors included presence of metastases, tumor site, tumor grade, age, and tumor size. Patients with localized axial tumors were identified as having similar outcomes to patients with metastases. Age and tumor size were only prognostically important in patients with extremity tumors when assessed in the validation cohort.

Conclusions: This analysis supports prior reports that patients with axial tumors are a high-risk group, and demonstrates the importance of age and tumor size in patients with appendicular tumors. Biologic and genetic markers are needed to further define subgroups in osteosarcoma.
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http://dx.doi.org/10.1002/pbc.28834DOI Listing
March 2021

Safety and efficacy of gamma-secretase inhibitor nirogacestat (PF-03084014) in desmoid tumor: Report of four pediatric/young adult cases.

Pediatr Blood Cancer 2020 10 6;67(10):e28636. Epub 2020 Aug 6.

Division of Hematology/Oncology, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.

Systemic therapy for pediatric desmoid tumors has been challenged by a lack of high-quality clinical evidence and potential adverse effects. The gamma-secretase inhibitor nirogacestat has shown promising efficacy in adults. We report four cases of pediatric and young adult desmoid tumor patients (three with familial adenomatous polyposis [FAP] syndrome) who received nirogacestat on compassionate use. After a median of 13.5 months (range 6-18), three had durable benefit: a complete response (Case 1); a partial response (Case 2); stable disease (Case 3). The fourth had disease progression after a partial response. No patient experienced grade 3 or 4 adverse events.
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http://dx.doi.org/10.1002/pbc.28636DOI Listing
October 2020

The use of interval-compressed chemotherapy with the addition of vincristine, irinotecan, and temozolomide for pediatric patients with newly diagnosed desmoplastic small round cell tumor.

Pediatr Blood Cancer 2020 10 19;67(10):e28559. Epub 2020 Jul 19.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, Massachusetts.

Background: Desmoplastic small round cell tumor (DSRCT) is a rare aggressive sarcoma that affects children and young adults, and portends poor outcomes despite intensive multimodal treatment approaches. We report toxicity, response, and outcomes of patients with DSRCT treated with the addition of vincristine, irinotecan, and temozolomide (VIT) to interval-compressed chemotherapy as per Children's Oncology Group ARST08P1.

Methods: All newly diagnosed pediatric patients with DSRCT treated at Dana-Farber Cancer Institute and Boston Children's Hospital between 2014 and 2019 as per ARST08P1, Arm P2 with replacement of VAC cycles with VIT, were identified. Medical records were reviewed for clinical and disease characteristics, and treatment response and outcomes.

Results: Six patients were treated as per the above regimen. Median age at diagnosis was 15.1 years (range 3.2-16.4) and five patients were male. Five patients had abdominal primary tumors, of which one had exclusively intraabdominal and four had extraabdominal metastases. Two initial cycles of VIT were well tolerated with nausea, vomiting, diarrhea, and constipation as the most common adverse events. Overall response rate defined as partial or complete response after two initial cycles of VIT was 50%. For local control, all patients had surgical resection followed by radiotherapy, and two patients received hyperthermic intraperitoneal chemotherapy at the time of surgery. Of the four patients who have completed therapy to date, three remain disease-free with median follow-up time of 46.7 months.

Conclusions: The addition of VIT to interval-compressed chemotherapy is tolerable and active in DSRCT, with activity warranting additional investigation.
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http://dx.doi.org/10.1002/pbc.28559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721987PMC
October 2020

Making the most of small samples: Optimization of tissue allocation of pediatric solid tumors for clinical and research use.

Pediatr Blood Cancer 2020 09 15;67(9):e28326. Epub 2020 Jul 15.

Department of Pathology, Boston Children's Hospital, Boston, Massachusetts.

Introduction: Tissue from pediatric solid tumors is in high demand for use in high-impact research studies, making the allocation of tissue from an anatomic pathology laboratory challenging. We designed, implemented, and assessed an interdepartmental process to optimize tissue allocation of pediatric solid tumors for both clinical care and research.

Methods: Oncologists, pathologists, surgeons, interventional radiologists, pathology technical staff, and clinical research coordinators participated in the workflow design. Procedures were created to address patient identification and consent, prioritization of protocols, electronic communication of requests, tissue preparation, and distribution. Pathologists were surveyed about the value of the new workflow.

Results: Over a 5-year period, 644 pediatric solid tumor patients consented to one or more studies requesting archival or fresh tissue. Patients had a variety of tumor types, with many rare and singular diagnoses. Sixty-seven percent of 1768 research requests were fulfilled. Requests for archival tissue were fulfilled at a significantly higher rate than those for fresh tissue (P > .001), and requests from resection specimens were fulfilled at a significantly higher rate than those from biopsies (P > .0001). In an anonymous survey, seven of seven pathologists reported that the process had improved since the introduction of the electronic communication model.

Conclusions: A collaborative and informed model for tissue allocation is successful in distributing archival and fresh tissue for clinical research studies. Our workflows and policies have gained pathologists' approval and streamlined our processes. As clinical and research programs evolve, a thoughtful tissue allocation process will facilitate ongoing research.
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http://dx.doi.org/10.1002/pbc.28326DOI Listing
September 2020

DICER1-associated central nervous system sarcoma in children: comprehensive clinicopathologic and genetic analysis of a newly described rare tumor.

Mod Pathol 2020 10 14;33(10):1910-1921. Epub 2020 Apr 14.

Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

The spectrum of neoplasms associated with DICER1 variants continues to expand, with the recent addition of primary "DICER1-associated central nervous system sarcoma" (DCS). DCS is a high-grade malignancy predominantly affecting pediatric patients. Six pediatric DCS were identified through a combination of clinical diagnostic studies, archival inquiry, and interinstitutional collaboration. Clinical, histologic, immunohistologic, and molecular features were examined. Genomic findings in the 6 DCS were compared with those in 14 additional DICER1-associated tumors sequenced with the same assay. The six patients presented at ages 3-15 years with CNS tumors located in the temporal (n = 2), parietal (n = 1), fronto-parietal (n = 1), and frontal (n = 2) lobes. All underwent surgical resection. Histologic examination demonstrated high-grade malignant spindle cell tumors with pleuropulmonary blastoma-like embryonic "organoid" features and focal rhabdomyoblastic differentiation; immature cartilage was seen in one case. Immunohistochemically, there was patchy desmin and myogenin staining, and patchy loss of H3K27me3, and within eosinophilic cytoplasmic globules, alfa-fetoprotein staining. Biallelic DICER1 variants were identified in all cases, with germline variants in two of five patients tested. DCS demonstrated genomic alterations enriched for Ras pathway activation and TP53 inactivation. Tumor mutational burden was significantly higher in the 6 DCS tumors than in 14 other DICER1-associated tumors examined (mean 12.9 vs. 6.8 mutations/Mb, p = 0.035). Postoperative care included radiation (n = 5) and chemotherapy (n = 3); at the last follow-up, three patients were alive without DCS, and three had died of disease. Our analysis expands the clinical, histologic, immunohistological, and molecular spectrum of DCS, identifying distinctive features that can aid in the diagnosis, multidisciplinary evaluation, and treatment of DCS.
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http://dx.doi.org/10.1038/s41379-020-0516-1DOI Listing
October 2020

Effects of dexrazoxane on doxorubicin-related cardiotoxicity and second malignant neoplasms in children with osteosarcoma: a report from the Children's Oncology Group.

Cardiooncology 2019 28;5:15. Epub 2019 Oct 28.

6Department of Pediatrics, University at Buffalo, Oishei Children's Hospital, Roswell Park Comprehensive Cancer Center, Buffalo, NY USA.

Background: Dexrazoxane protects from lower-cumulative-dose doxorubicin cardiotoxicity, but the effect of dexrazoxane in children with sarcoma treated with higher-cumulative-dose doxorubicin is unknown.

Methods: We evaluated children with osteosarcoma (OS) on two Children's Oncology Group trials with higher dose doxorubicin (375-600 mg/m) preceded by dexrazoxane (10:1 dexrazoxane:doxorubicin dosing). They were evaluated after the minimum expected treatment time (METT), defined as 28 weeks. Cardiotoxicity was identified by echocardiography and serum N-terminal pro-brain natriuretic peptide (NT-proBNP). Second malignant neoplasm (SMN) data was collected.

Results: All children had normal left ventricular (LV) systolic function as measured by LV fractional shortening and no heart failure. The end-diastolic septal thickness scores ( < 0.01) and LV mass scores ( < 0.01) were significantly smaller than normal for body-surface area in both sexes. The average LV mass scores were significantly smaller for girls ( < 0.01) and marginally smaller for boys ( = 0.06). Girls had significantly smaller LV end-diastolic dimension scores normalized to BSA ( < 0.01) compared to healthy controls and had significant increases in NT-proBNP. Four children developed SMNs as first events, a rate similar to historical controls.

Conclusions: Dexrazoxane prevented LV dysfunction and heart failure in children with OS receiving higher dose doxorubicin. However, LV structural changes were not fully prevented, especially in girls. As a result, hearts become abnormally small for body size, resulting in higher LV stress. Dexrazoxane did not increase the risk of SMN. Dexrazoxane should be used in this population, particularly for girls, to mitigate anthracycline-induced cardiotoxicity.

Trial Registrations: ClinicalTrials.gov: NCT00003937 (P9754) registered 1 Nov 1999, and NCT00023998 (AOST0121) registered 13 Sept 2001.
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http://dx.doi.org/10.1186/s40959-019-0050-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048050PMC
October 2019

Genomic and Immunologic Characterization of INI1-Deficient Pediatric Cancers.

Clin Cancer Res 2020 06 2;26(12):2882-2890. Epub 2020 Mar 2.

Department of Pediatric Hematology/Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, Massachusetts.

Purpose: Several aggressive pediatric cancers harbor alterations in , including rhabdoid tumors, epithelioid sarcoma, and chordoma. As tumor profiling has become more routine in clinical care, we investigated the relationship between genetic variants identified by next-generation sequencing (NGS) and INI1 protein expression. Therapeutic approaches for INI1-deficient tumors are limited. Early reports suggest a potential role for immune checkpoint inhibition in these patients. Thus, we also investigated PD-L1 and CD8 expression in INI1-negative pediatric brain and solid tumors.

Experimental Design: We performed immunohistochemistry (IHC) for INI1 and immune markers (PD-L1, CD8, and CD163) and NGS on tumor samples from 43 pediatric patients who had tumors with INI1 loss on previous IHC or genomic alterations on prior somatic sequencing.

Results: two-copy deletions and inactivating mutations on NGS were associated with loss of INI1 protein expression. Single-copy deletion of was not predictive of INI1 loss in tumor histologies not known to be INI1-deficient. In the 27 cases with INI1 loss and successful tumor sequencing, 24 (89%) had a alteration detected. In addition, 47% (14/30) of the patients with INI1-negative tumors had a tumor specimen that was PD-L1 positive and 60% (18/30) had positive or rare CD8 staining. We report on 3 patients with INI1-negative tumors with evidence of disease control on immune checkpoint inhibitors.

Conclusions: A significant proportion of the INI1-negative tumors express PD-L1, and PD-L1 positivity was associated with extracranial tumor site. These results suggest that clinical trials of immune checkpoint inhibitors are warranted in INI1-negative pediatric cancers.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3089DOI Listing
June 2020

PD-1 and PD-L1 Expression in Osteosarcoma: Which Specimen to Evaluate?

J Pediatr Hematol Oncol 2020 11;42(8):482-487

Department of Pathology, Boston Children's Hospital.

There is a growing interest in immunotherapy in childhood cancers. Osteosarcoma is a compelling potential target as there are few targeted options available for this aggressive cancer. We provide a description of the landscape of programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1) and relevant immune markers in serial samples from 15 osteosarcoma patients. PD-1 and PD-L1 expression was present in biopsy samples (47% and 53%, respectively), absent in resections, and present in metastases (40% and 47%). Both decalcified and nondecalcified specimens demonstrated expression of PD-1 and PD-L1. The results suggest that biopsy or metastatic specimens maybe most valuable in assessing expression of PD-1 and PD-L1.
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http://dx.doi.org/10.1097/MPH.0000000000001685DOI Listing
November 2020

Linsitinib (OSI-906) for the Treatment of Adult and Pediatric Wild-Type Gastrointestinal Stromal Tumors, a SARC Phase II Study.

Clin Cancer Res 2020 04 2;26(8):1837-1845. Epub 2019 Dec 2.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: Most gastrointestinal stromal tumors (GIST) have activating mutations of , or uncommonly . Fifteen percent of adult and 85% of pediatric GISTs are wild type (WT), commonly having high expression of IGF-1R and loss of succinate dehydrogenase (SDH) complex function. We tested the efficacy of linsitinib, an oral TKI IGF-1R inhibitor, in patients with WT GIST.

Patients And Methods: A multicenter phase II trial of linsitinib was conducted. The primary endpoint was objective response rate. Secondary endpoints were clinical benefit rate: complete response, partial response, and stable disease (SD) ≥ 9 months, and quantitative 2[18F]fluoro-2-deoxy-D-glucose (FDG) metabolic response (MR) at week 8. Serum levels for glucose, insulin, IGF-1R ligand IGF1, and binding proteins were obtained to explore correlations to patient outcomes and FDG-PET results.

Results: Twenty patients were accrued in a 6-month period. Grade 3-4 toxicities possibly related to linsitinib were uncommon (8.5%). No objective responses were seen. Clinical benefit rate (CBR) at 9 months was 40%. Intense FDG uptake was observed at baseline, with partial MR of 12% and stable metabolic disease of 65% at week 8; these patients had RECIST 1.1 SD as their best response. Progression-free survival (PFS) and overall survival Kaplan-Meier estimates at 9 months were 52% and 80%, respectively. SDHA/B loss determined by IHC was seen in 35% and 88% of cases, respectively.

Conclusions: Linsitinib is well tolerated in patients with WT GIST. Although the 9-month CBR was 40%, and PFS at 9 months was 52%, no objective responses were observed. Rapid accrual to this study demonstrates that clinical trials of experimental agents in selected subtypes of GIST are feasible.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856429PMC
April 2020

Pediatric Trials for Cancer Therapies With Targets Potentially Relevant to Pediatric Cancers.

J Natl Cancer Inst 2020 03;112(3):224-228

Pediatric Therapeutics and Regulatory Science Initiative, Computational Health Informatics Program, Boston Children's Hospital, Boston, MA.

The Research to Accelerate Cures and Equity (RACE) for Children Act was enacted in 2017 to authorize the US Food and Drug Administration (FDA) to require pediatric studies for new cancer drugs that have a molecular target relevant to the growth or progression of a pediatric cancer. To assess the possible scope of this new policy, we examined all 78 adult cancer drugs approved by the FDA from 2007 to 2017. Only 17 (21.8%) drugs received any pediatric labeling information. Based on the FDA's Pediatric Molecular Target List, we found that the RACE Act could have increased the proportion of cancer drugs potentially subject to pediatric study requirements from 0% to 78.2%. However, the actual effect of the legislation will depend on how often regulators require pediatric trials and on timely completion of such trials.
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http://dx.doi.org/10.1093/jnci/djz207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073929PMC
March 2020

A Novel Fusion in Pediatric Medullary Thyroid Carcinoma.

Thyroid 2019 11;29(11):1704-1707

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, Massachusetts.

Medullary thyroid carcinoma (MTC) is most commonly associated with gene mutations. fusions have rarely been described, although not previously in pediatrics and not previously partnered with in MTC or any other cancer. A 10-year-old boy with progressive stridor was found to have metastatic MTC, including lung, lymph node, and adrenal metastases. Baseline calcitonin was 6703 pg/mL. While molecular testing was pending, he was treated empirically with the investigational selective RET inhibitor, LOXO-292, without improvement. Molecular testing revealed a novel - fusion. His therapy was changed to crizotinib and then to alectinib for improved tolerability. Calcitonin decreased to 663 pg/mL after 6 days of ALK inhibition. He remains on alectinib with ongoing response. A novel - fusion has now been implicated in a pediatric case of metastatic MTC. This fusion has profound clinical sensitivity to ALK inhibitors. This report expands the spectrum of fusions seen in MTC, including the first pediatric case of translocated MTC. This novel fusion with has not previously been reported in other human cancers. Given the dramatic response to ALK inhibition in this case, identifying patients with fusion MTC has important therapeutic implications.
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http://dx.doi.org/10.1089/thy.2019.0041DOI Listing
November 2019

Phase II trial of the glycoprotein non-metastatic B-targeted antibody-drug conjugate, glembatumumab vedotin (CDX-011), in recurrent osteosarcoma AOST1521: A report from the Children's Oncology Group.

Eur J Cancer 2019 11 3;121:177-183. Epub 2019 Oct 3.

Pediatric Hematology-Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA.

Background: The prognosis is poor for children and adolescents with recurrent osteosarcoma (OS). Glycoprotein non-metastatic B (gpNMB) is a glycoprotein highly expressed in OS cells. We conducted a phase II study of glembatumumab vedotin (GV), a fully human IgG2 monoclonal antibody (CR011) against gpNMB conjugated to the microtubule inhibitor, monomethyl auristatin E.

Patients And Methods: Patients aged ≥12 years and <50 years with relapsed or refractory OS were eligible. GV 1.9 mg/kg/dose was administered on day 1 of each 21 day cycle. Pharmacokinetics were mandatory in patients aged <15 years. gpNMB expression was measured by immunohistochemistry. The primary end-point was disease control at 4 months and Response Evaluation Criteria in Solid Tumours response. A 2-stage design was used to determine efficacy.

Results: Twenty-two patients were enrolled, and all were evaluable for response. Antibody-drug conjugate levels were detectable in patients, although small numbers limit comparison to adult data. The toxicities observed were similar to the previous studies with GV. The most common grade III adverse event was rash. One death from end organ failure occurred possibly related to GV. Of the 22 patients, one patient had a partial response, and two had stable disease. There was no correlation between gpNMB expression and response to GV.

Conclusions: GV was well tolerated in this population. Although there was some antitumour activity, the extent of disease control in stage I did not meet the level required to proceed to stage II.

Trial Registration Numbers: NCT02487979.
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http://dx.doi.org/10.1016/j.ejca.2019.08.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952063PMC
November 2019

A Distinctive Genomic and Immunohistochemical Profile for NOTCH3 and PDGFRB in Myofibroma With Diagnostic and Therapeutic Implications.

Int J Surg Pathol 2020 Apr 29;28(2):128-137. Epub 2019 Sep 29.

Boston Children's Hospital, Boston, MA, USA.

. Myofibromas are rare tumors of pericytic lineage, typically affecting children, and are sometimes aggressive. A subset of sporadic and familial myofibromas have activating variants in . The relationship of myofibroma and PDGFRB to the NOTCH pathway has not yet been described. . Ten myofibroma cases were sequenced with a targeted panel of 447 genes, including copy number variation and selected fusions. Immunohistochemical analysis of total NOTCH3 and activated NOTCH3 was assessed for all 10 myofibroma cases, and a series of histologic mimics (n = 20). . Alterations identified by next-generation sequencing included sequence variants in 8/10 cases (80%), a variant in 1/10 cases (10%), and a variant in 1/10 cases (10%). All 10 cases also showed a pattern of low-amplitude (1.5- to 2-fold) copy number alterations including gains in and . Ten of 10 myofibromas (100%) showed cytoplasmic staining for total NOTCH3 and 9 of 10 cases (90%) showed nuclear staining for activated NOTCH3. Within the control cohort of histologic mimics, 3 of 3 nodular fasciitis cases (100%) were positive for activated and total NOTCH3, and the remaining 17 cases were negative for pan NOTCH3, while 3 of 3 desmoid-type fibromatosis cases (100%) showed patchy weak nuclear staining for activated NOTCH3. . Our findings suggest a common pathway of PDGFRB/NOTCH3 activation in myofibromas, even in cases that lack sequence variants. These results support the pericytic lineage of myofibroma. Identification of the characteristic genomic alterations or immunohistochemical staining pattern may facilitate a difficult pathologic diagnosis, and support the use of targeted treatments.
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http://dx.doi.org/10.1177/1066896919876703DOI Listing
April 2020

Provocative questions in osteosarcoma basic and translational biology: A report from the Children's Oncology Group.

Cancer 2019 10 29;125(20):3514-3525. Epub 2019 Jul 29.

Dana-Farber Cancer Institute, Boston, and Broad Institute of Harvard and MIT, Cambridge, Massachusetts.

Patients who are diagnosed with osteosarcoma (OS) today receive the same therapy that patients have received over the last 4 decades. Extensive efforts to identify more effective or less toxic regimens have proved disappointing. As we enter a postgenomic era in which we now recognize OS not as a cancer of mutations but as one defined by p53 loss, chromosomal complexity, copy number alteration, and profound heterogeneity, emerging threads of discovery leave many hopeful that an improving understanding of biology will drive discoveries that improve clinical care. Under the organization of the Bone Tumor Biology Committee of the Children's Oncology Group, a team of clinicians and scientists sought to define the state of the science and to identify questions that, if answered, have the greatest potential to drive fundamental clinical advances. Having discussed these questions in a series of meetings, each led by invited experts, we distilled these conversations into a series of seven Provocative Questions. These include questions about the molecular events that trigger oncogenesis, the genomic and epigenomic drivers of disease, the biology of lung metastasis, research models that best predict clinical outcomes, and processes for translating findings into clinical trials. Here, we briefly present each Provocative Question, review the current scientific evidence, note the immediate opportunities, and speculate on the impact that answered questions might have on the field. We do so with an intent to provide a framework around which investigators can build programs and collaborations to tackle the hardest problems and to establish research priorities for those developing policies and providing funding.
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http://dx.doi.org/10.1002/cncr.32351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948723PMC
October 2019

Canine osteosarcoma genome sequencing identifies recurrent mutations in and the histone methyltransferase gene .

Commun Biol 2019 19;2:266. Epub 2019 Jul 19.

2Translational Genomics Research Institute, Phoenix, AZ 85004 USA.

Osteosarcoma (OS) is a rare, metastatic, human adolescent cancer that also occurs in pet dogs. To define the genomic underpinnings of canine OS, we performed multi-platform analysis of OS tumors from 59 dogs, including whole genome sequencing ( = 24) and whole exome sequencing (WES;  = 13) of primary tumors and matched normal tissue, WES ( = 10) of matched primary/metastatic/normal samples and RNA sequencing ( = 54) of primary tumors. We found that canine OS recapitulates features of human OS including low point mutation burden (median 1.98 per Mb) with a trend towards higher burden in metastases, high structural complexity, frequent (71%), PI3K pathway (37%), and MAPK pathway mutations (17%), and low expression of immune-associated genes. We also identified novel features of canine OS including putatively inactivating somatic (42%) and (50%) aberrations. These findings set the stage for understanding OS development in dogs and humans, and establish genomic contexts for future comparative analyses.
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http://dx.doi.org/10.1038/s42003-019-0487-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642146PMC
May 2020

Duality of purpose: Participant and parent understanding of the purpose of genomic tumor profiling research among children and young adults with solid tumors.

JCO Precis Oncol 2019 22;3. Epub 2019 Jan 22.

Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.

Purpose: Increasing use of genomic tumor profiling may blur the line between research and clinical care. We aimed to describe research participants' perspectives on the purpose of genomic tumor profiling research in pediatric oncology.

Methods: We surveyed 45 participants (response rate 85%) in a pilot study of genomic profiling in pediatric solid tumors at four academic cancer centers following return of sequencing results. We defined understanding according to a one-item ("basic") definition (recognizing that the primary purpose was not to improve the patient's treatment) and a four-item ("comprehensive") definition (primary purpose was not to improve patient's treatment; primary purpose was to improve treatment of future patients; there may not be direct medical benefit; most likely result of participation was not increased likelihood of cure).

Results: Sixty-eight percent of respondents (30/44) demonstrated basic understanding of the study purpose; 55% (24/44) demonstrated comprehensive understanding. Understanding was more frequently seen in those with higher education and greater genetic knowledge according to basic (81% vs 50%, p=0.05; and 82% vs 46%, p=0.03, respectively) and comprehensive definitions (73% vs 28%, p=0.01; 71% vs 23%, p=0.01). Ninety-three percent of respondents who believed the primary purpose was to improve the patient's care simultaneously stated that the research also aimed to benefit future patients.

Conclusions: Most participants in pediatric tumor profiling research understand that the primary goal of this research is to improve care for future patients, but many express dual goals when participating in sequencing research. Some populations demonstrate increased rates of misunderstanding. Nuanced participant views suggest further work is needed to assess and improve participant understanding, particularly as tumor sequencing moves beyond research into clinical practice.
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http://dx.doi.org/10.1200/po.18.00176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592430PMC
January 2019

Sunitinib in pediatric patients with advanced gastrointestinal stromal tumor: results from a phase I/II trial.

Cancer Chemother Pharmacol 2019 07 20;84(1):41-50. Epub 2019 Apr 20.

Pediatrics, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA.

Background: Sunitinib is approved for treatment of adults with imatinib-resistant gastrointestinal stromal tumor (GIST) or imatinib intolerance.

Methods: This single-arm, multicenter, multinational phase I/II clinical trial (NCT01396148) enrolled eligible patients aged 6 to < 18 years with advanced, unresectable GIST with non-mutant KIT, or who demonstrated disease progression or intolerance to imatinib. Patients received sunitinib 15 mg/m per day, 4-weeks-on/2-weeks-off (schedule 4/2), for ≤ 18 cycles over 24 months. Intra-patient dose escalation to 22.5 and subsequently 30 mg/m were permitted based on individual patient tolerability and supported by real-time pharmacokinetics (PK). Primary objective was PK characterization. Secondary objectives included safety, antitumor activity and PK/pharmacodynamic relationships.

Results: Six patients were enrolled with median (range) age of 14 (13-16) years. All six patients completed at least three treatment cycles, with one completing all 18 cycles. Five patients had a dose increase to 22.5 mg/m; two of them had a further dose increase to 30 mg/m. The average daily dose at cycle 3 was 21.1 mg/m (n = 6). Steady-state plasma concentrations were reached by day 15, cycle 1. No tumor responses were observed, but three patients had stabilization of the disease (50%). Median progression-free survival was 5.8 months (95% CI 2.3-not reached). There were no serious adverse events.

Conclusions: The tolerable dose of sunitinib in chemotherapy-naïve pediatric patients is at least 20 mg/m on schedule 4/2. The safety profile and PK of sunitinib in pediatric patients with GIST are comparable to those in adults.
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http://dx.doi.org/10.1007/s00280-019-03814-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561985PMC
July 2019

Correction: Detection of circulating tumour DNA is associated with inferior outcomes in Ewing sarcoma and osteosarcoma: a report from the Children's Oncology Group.

Br J Cancer 2019 Apr;120(8):869

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA.

The authors have noticed that the final paragraph of the Results section contains errors in the number of patients involved. The correct number of patients is included in the text below. These errors do not affect the Figure referenced.In osteosarcoma, we focused on 8q gain as a specific biological feature of interest. Among the 41 patients with detectable ctDNA in the osteosarcoma cohort, 8q gain was detected in 73.2% (30/41). The 3-year EFS for patients with 8q gain (n = 30) in ctDNA was 60.0% (95% CI 40.5-75.0) compared to 80.8 (95% CI 42.4-94.9) in patients without 8q gain (n = 11) in ctDNA (p = 0.18; Fig. 3).
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http://dx.doi.org/10.1038/s41416-019-0424-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474275PMC
April 2019

Ushering in the next generation of precision trials for pediatric cancer.

Science 2019 Mar;363(6432):1175-1181

Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.

Cancer treatment decisions are increasingly based on the genomic profile of the patient's tumor, a strategy called "precision oncology." Over the past few years, a growing number of clinical trials and case reports have provided evidence that precision oncology is an effective approach for at least some children with cancer. Here, we review key factors influencing pediatric drug development in the era of precision oncology. We describe an emerging regulatory framework that is accelerating the pace of clinical trials in children as well as design challenges that are specific to trials that involve young cancer patients. Last, we discuss new drug development approaches for pediatric cancers whose growth relies on proteins that are difficult to target therapeutically, such as transcription factors.
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http://dx.doi.org/10.1126/science.aaw4153DOI Listing
March 2019

Renal medullary carcinomas depend upon loss and are sensitive to proteasome inhibition.

Elife 2019 03 12;8. Epub 2019 Mar 12.

Broad Institute of Harvard and MIT, Cambridge, United States.

Renal medullary carcinoma (RMC) is a rare and deadly kidney cancer in patients of African descent with sickle cell trait. We have developed faithful patient-derived RMC models and using whole-genome sequencing, we identified loss-of-function intronic fusion events in one allele with concurrent loss of the other allele. Biochemical and functional characterization of these models revealed that RMC requires the loss of for survival. Through integration of RNAi and CRISPR-Cas9 loss-of-function genetic screens and a small-molecule screen, we found that the ubiquitin-proteasome system (UPS) was essential in RMC. Inhibition of the UPS caused a G2/M arrest due to constitutive accumulation of cyclin B1. These observations extend across cancers that harbor loss, which also require expression of the E2 ubiquitin-conjugating enzyme, . Our studies identify a synthetic lethal relationship between -deficient cancers and reliance on the UPS which provides the foundation for a mechanism-informed clinical trial with proteasome inhibitors.
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http://dx.doi.org/10.7554/eLife.44161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436895PMC
March 2019

Survival and prognosis with osteosarcoma: outcomes in more than 2000 patients in the EURAMOS-1 (European and American Osteosarcoma Study) cohort.

Eur J Cancer 2019 03 25;109:36-50. Epub 2019 Jan 25.

CDC MRC Clinical Trials Unit at UCL, London, UK.

Background: High-grade osteosarcoma is a primary malignant bone tumour mainly affecting children and young adults. The European and American Osteosarcoma Study (EURAMOS)-1 is a collaboration of four study groups aiming to improve outcomes of this rare disease by facilitating randomised controlled trials.

Methods: Patients eligible for EURAMOS-1 were aged ≤40 years with M0 or M1 skeletal high-grade osteosarcoma in which case complete surgical resection at all sites was deemed to be possible. A three-drug combination with methotrexate, doxorubicin and cisplatin was defined as standard chemotherapy, and between April 2005 and June 2011, 2260 patients were registered. We report survival outcomes and prognostic factors in the full cohort of registered patients.

Results: For all registered patients at a median follow-up of 54 months (interquartile range: 38-73) from biopsy, 3-year and 5-year event-free survival were 59% (95% confidence interval [CI]: 57-61%) and 54% (95% CI: 52-56%), respectively. Multivariate analyses showed that the most adverse factors at diagnosis were pulmonary metastases (hazard ratio [HR] = 2.34, 95% CI: 1.95-2.81), non-pulmonary metastases (HR = 1.94, 95% CI: 1.38-2.73) or an axial skeleton tumour site (HR = 1.53, 95% CI: 1.10-2.13). The histological subtypes telangiectatic (HR = 0.52, 95% CI: 0.33-0.80) and unspecified conventional (HR = 0.67, 95% CI: 0.52-0.88) were associated with a favourable prognosis compared with chondroblastic subtype. The 3-year and 5-year overall survival from biopsy were 79% (95% CI: 77-81%) and 71% (95% CI: 68-73%), respectively. For patients with localised disease at presentation and in complete remission after surgery, having a poor histological response was associated with worse outcome after surgery (HR = 2.13, 95% CI: 1.76-2.58). In radically operated patients, there was no good evidence that axial tumour site was associated with worse outcome.

Conclusions: In conclusion, data from >2000 patients registered to EURAMOS-1 demonstrated survival rates in concordance with institution- or group-level osteosarcoma trials. Further efforts are required to drive improvements for patients who can be identified to be at higher risk of adverse outcome. This trial reaffirms known prognostic factors, and owing to the large numbers of patients registered, it sheds light on some additional factors to consider.
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http://dx.doi.org/10.1016/j.ejca.2018.11.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506906PMC
March 2019

Rationale and Design of the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.

JCO Precis Oncol 2018 11;2018. Epub 2018 Jul 11.

American Society of Clinical Oncology, Alexandria, VA.

Purpose: Case reports and small prospective trials suggest that administering targeted therapies to patients with advanced cancer and an identified genomic target may be associated with clinical benefit. The TAPUR Study, a phase II, prospective, non-randomized, multi-basket, pragmatic clinical trial aims to identify signals of drug activity when Food and Drug Administration (FDA) approved drugs are matched to pre-specified genomic targets in patients with advanced cancer, outside of approved indications.

Methods: Patients eligible to participate in TAPUR are ages 12 years and older, with advanced, measurable or evaluable solid tumors, multiple myeloma or B cell non-Hodgkin lymphoma. Eligible participants are matched to any of the sixteen FDA approved study drugs based on protocol specified genomic inclusion and exclusion criteria. Genomic profiling from any Clinical Laboratory Improvement Amendments certified, College of American Pathologists accredited laboratory is acceptable. The treating physician selects the treatment from the available study therapies, or consults with the TAPUR Molecular Tumor Board. Participants are placed into multiple parallel cohorts defined by tumor type, genomic alteration and drug. The primary study endpoint within each cohort is objective response or stable disease of at least 16 weeks duration. Secondary endpoints include safety, progression-free survival and overall survival.

Results: More than 1000 participants have thus far been registered and more than 800 treated with a TAPUR study drug. Two study cohorts have permanently closed to enrollment due to lack of anti-tumor activity and 12 have expanded to the second stage of enrollment due to promising preliminary activity.

Conclusion: The TAPUR Study will describe the efficacy and toxicity of the targeted drugs used outside of their approved indications when matched to a somatic genomic variant.
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http://dx.doi.org/10.1200/PO.18.00122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312096PMC
July 2018

A Combination CDK4/6 and IGF1R Inhibitor Strategy for Ewing Sarcoma.

Clin Cancer Res 2019 02 5;25(4):1343-1357. Epub 2018 Nov 5.

Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts.

Purpose: Novel targeted therapeutics have transformed the care of subsets of patients with cancer. In pediatric malignancies, however, with simple tumor genomes and infrequent targetable mutations, there have been few new FDA-approved targeted drugs. The cyclin-dependent kinase (CDK)4/6 pathway recently emerged as a dependency in Ewing sarcoma. Given the heightened efficacy of this class with targeted drug combinations in other cancers, as well as the propensity of resistance to emerge with single agents, we aimed to identify genes mediating resistance to CDK4/6 inhibitors and biologically relevant combinations for use with CDK4/6 inhibitors in Ewing.

Experimental Design: We performed a genome-scale open reading frame (ORF) screen in 2 Ewing cell lines sensitive to CDK4/6 inhibitors to identify genes conferring resistance. Concurrently, we established resistance to a CDK4/6 inhibitor in a Ewing cell line.

Results: The ORF screen revealed as a gene whose overexpression promoted drug escape. We also found elevated levels of phospho-IGF1R in our resistant Ewing cell line, supporting the relevance of IGF1R signaling to acquired resistance. In a small-molecule screen, an IGF1R inhibitor scored as synergistic with CDK4/6 inhibitor treatment. The combination of CDK4/6 inhibitors and IGF1R inhibitors was synergistic and active in mouse models. Mechanistically, this combination more profoundly repressed cell cycle and PI3K/mTOR signaling than either single drug perturbation.

Conclusions: Taken together, these results suggest that IGF1R inhibitors activation is an escape mechanism to CDK4/6 inhibitors in Ewing sarcoma and that dual targeting of CDK4/6 inhibitors and IGF1R inhibitors provides a candidate synergistic combination for clinical application in this disease.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498855PMC
February 2019