Publications by authors named "Ezra Y Rosen"

9 Publications

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A Performance Comparison of Commonly Used Assays to Detect RET Fusions.

Clin Cancer Res 2021 Mar 3;27(5):1316-1328. Epub 2020 Dec 3.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: Selpercatinib and pralsetinib induce deep and durable responses in patients with advanced fusion-positive lung and thyroid cancer. fusion testing strategies with rapid and reliable results are critical given recent FDA approval. Here, we assess various clinical assays in a large pan-cancer cohort.

Experimental Design: Tumors underwent DNA-based next-generation sequencing (NGS) with reflex to RNA-based NGS if no mitogenic driver or if a structural variant of unknown significance (SVUS) were present. Canonical DNA-level fusions and RNA-confirmed fusions were considered true fusions. Break-apart FISH and IHC performance were assessed in subgroups.

Results: A total of 171 of 41,869 patients with DNA NGS harbored structural variants, including 139 canonical fusions and 32 SVUS. Twelve of 32 (37.5%) SVUS were transcribed into RNA-level fusions, resulting in 151 oncogenic fusions. The most common fusion-positive tumor types were lung (65.6%) and thyroid (23.2%). The most common partners were (45%), (29.1%), and (13.3%). DNA NGS showed 100% (46/46) sensitivity and 99.6% (4,459/4,479) specificity. FISH showed 91.7% (44/48) sensitivity, with lower sensitivity for - (66.7%, 8/12). A total of 87.5% (7/8) of SVUS negative for RNA-level fusions demonstrated rearrangement by FISH. The sensitivity of IHC varied by fusion partner: sensitivity was highest (100%, 31/31), followed by (88.9%, 16/18) and (50%, 6/12). Specificity of RET IHC was 82% (73/89).

Conclusions: Although DNA sequencing has high sensitivity and specificity, RNA sequencing of SVUS is necessary. Both FISH and IHC demonstrated lower sensitivity for - fusions.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3208DOI Listing
March 2021

Overcoming MET-Dependent Resistance to Selective RET Inhibition in Patients with RET Fusion-Positive Lung Cancer by Combining Selpercatinib with Crizotinib.

Clin Cancer Res 2021 Jan 20;27(1):34-42. Epub 2020 Oct 20.

Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: The proto-oncogene encodes a receptor tyrosine kinase that is activated by gene fusion in 1%-2% of non-small cell lung cancers (NSCLC) and rarely in other cancer types. Selpercatinib is a highly selective RET kinase inhibitor that has recently been approved by the FDA in lung and thyroid cancers with activating gene fusions and mutations. Molecular mechanisms of acquired resistance to selpercatinib are poorly understood.

Patients And Methods: We studied patients treated on the first-in-human clinical trial of selpercatinib (NCT03157129) who were found to have amplification associated with resistance to selpercatinib. We validated activation as a targetable mediator of resistance to RET-directed therapy, and combined selpercatinib with the MET/ALK/ROS1 inhibitor crizotinib in a series of single patient protocols (SPP).

Results: amplification was identified in posttreatment biopsies in 4 patients with fusion-positive NSCLC treated with selpercatinib. In at least one case, amplification was clearly evident prior to therapy with selpercatinib. We demonstrate that increased MET expression in fusion-positive tumor cells causes resistance to selpercatinib, and this can be overcome by combining selpercatinib with crizotinib. Using SPPs, selpercatinib with crizotinib were given together generating anecdotal evidence of clinical activity and tolerability, with one response lasting 10 months.

Conclusions: Through the use of SPPs, we were able to offer combination therapy targeting -amplified resistance identified on the first-in-human study of selpercatinib. These data suggest that MET dependence is a recurring and potentially targetable mechanism of resistance to selective RET inhibition in advanced NSCLC.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2278DOI Listing
January 2021

TRK Fusions Are Enriched in Cancers with Uncommon Histologies and the Absence of Canonical Driver Mutations.

Clin Cancer Res 2020 04 23;26(7):1624-1632. Epub 2019 Dec 23.

Department of Medicine, Memorial Sloan Kettering, New York, New York.

Purpose: TRK inhibitors achieve marked tumor-agnostic efficacy in TRK fusion-positive cancers and consequently are now an established standard of care. Little is known, however, about the demographics, outcomes, response to alternative standard therapies, or genomic characteristics of TRK fusion-positive cancers.

Experimental Design: Utilizing a center-wide screening program involving more than 26,000 prospectively sequenced patients, genomic and clinical data from all cases with TRK fusions were extracted. An integrated analysis was performed of genomic, therapeutic, and phenomic outcomes.

Results: We identified 76 cases with confirmed TRK fusions (0.28% overall prevalence) involving 48 unique rearrangements and 17 cancer types. The presence of a TRK fusion was associated with depletion of concurrent oncogenic drivers ( < 0.001) and lower tumor mutation burden ( < 0.001), with the exception of colorectal cancer where TRK fusions cooccur with microsatellite instability (MSI-H). Longitudinal profiling in a subset of patients indicated that TRK fusions were present in all sampled timepoints in 82% (14/17) of cases. Progression-free survival on first-line therapy, excluding TRK inhibitors, administered for advanced disease was 9.6 months [95% confidence interval (CI), 4.8-13.2]. The best overall response rate achieved with chemotherapy containing-regimens across all lines of therapy was 63% (95% CI, 41-81). Among 12 patients treated with checkpoint inhibitors, a patient with MSI-H colorectal cancer had the only observed response.

Conclusions: TRK fusion-positive cancers can respond to alternative standards of care, although efficacy of immunotherapy in the absence of other predictive biomarkers (MSI-H) appears limited. TRK fusions are present in tumors with simple genomes lacking in concurrent drivers that may partially explain the tumor-agnostic efficacy of TRK inhibitors.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7124988PMC
April 2020

NTRK fusion detection across multiple assays and 33,997 cases: diagnostic implications and pitfalls.

Mod Pathol 2020 01 2;33(1):38-46. Epub 2019 Aug 2.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.

With the FDA approval of larotrectinib, NTRK fusion assessment has recently become a standard part of management for patients with locally advanced or metastatic cancers. Unlike somatic mutation assessment, the detection of NTRK fusions is not straightforward, and various assays exist at the DNA, RNA, and protein level. Here, we investigate the performance of immunohistochemistry and DNA-based next-generation sequencing to indirectly or directly detect NTRK fusions relative to an RNA-based next-generation sequencing approach in the largest cohort of NTRK fusion positive solid tumors to date. A retrospective analysis of 38,095 samples from 33,997 patients sequenced by a targeted DNA-based next-generation sequencing panel (MSK-IMPACT), 2189 of which were also examined by an RNA-based sequencing assay (MSK-Fusion), identified 87 patients with oncogenic NTRK1-3 fusions. All available institutional NTRK fusion positive cases were assessed by pan-Trk immunohistochemistry along with a cohort of control cases negative for NTRK fusions by next-generation sequencing. DNA-based sequencing showed an overall sensitivity and specificity of 81.1% and 99.9%, respectively, for the detection of NTRK fusions when compared to RNA-based sequencing. False negatives occurred when fusions involved breakpoints not covered by the assay. Immunohistochemistry showed overall sensitivity of 87.9% and specificity of 81.1%, with high sensitivity for NTRK1 (96%) and NTRK2 (100%) fusions and lower sensitivity for NTRK3 fusions (79%). Specificity was 100% for carcinomas of the colon, lung, thyroid, pancreas, and biliary tract. Decreased specificity was seen in breast and salivary gland carcinomas (82% and 52%, respectively), and positive staining was often seen in tumors with neural differentiation. Both sensitivity and specificity were poor in sarcomas. Selection of the appropriate assay for NTRK fusion detection therefore depends on tumor type and genes involved, as well as consideration of other factors such as available material, accessibility of various clinical assays, and whether comprehensive genomic testing is needed concurrently.
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http://dx.doi.org/10.1038/s41379-019-0324-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437403PMC
January 2020

Real-World Outcomes of an Automated Physician Support System for Genome-Driven Oncology.

JCO Precis Oncol 2019 24;3. Epub 2019 Jul 24.

Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Matching patients to investigational therapies requires new tools to support physician decision making. We designed and implemented Precision Insight Support Engine (PRECISE), an automated, just-in-time, clinical-grade informatics platform to identify and dynamically track patients on the basis of molecular and clinical criteria. Real-world use of this tool was analyzed to determine whether PRECISE facilitated enrollment to early-phase, genome-driven trials.

Materials And Methods: We analyzed patients who were enrolled in genome-driven, early-phase trials using PRECISE at Memorial Sloan Kettering Cancer Center between April 2014 and January 2018. Primary end point was the proportion of enrolled patients who were successfully identified using PRECISE before enrollment. Secondary end points included time from sequencing and PRECISE identification to enrollment. Reasons for a failure to identify genomically matched patients were also explored.

Results: Data were analyzed from 41 therapeutic trials led by 19 principal investigators. In total, 755 patients were accrued to these studies during the period that PRECISE was used. PRECISE successfully identified 327 patients (43%) before enrollment. Patients were diagnosed with 29 tumor types and harbored alterations in 43 oncogenes, most commonly (21.3%), (14.1%), and (8.7%). Median time from sequencing to enrollment was 163 days (interquartile range, 66 to 357 days), and from PRECISE identification to enrollment 87 days (interquartile range, 37 to 180 days). Common reasons for failing to identify patients before enrollment included accrual on the basis of molecular alterations that did not match pre-established PRECISE genomic eligibility (140 [33%] of 428) and external sequencing not available for parsing (127 [30%] of 428).

Conclusion: PRECISE identified 43% of all patients accrued to a diverse cohort of early-phase, genome-matched studies. Purpose-built informatics platforms represent a novel and potentially effective method for matching patients to molecularly selected studies.
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http://dx.doi.org/10.1200/PO.19.00066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446398PMC
July 2019

Tumour lineage shapes BRCA-mediated phenotypes.

Nature 2019 07 10;571(7766):576-579. Epub 2019 Jul 10.

Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Mutations in BRCA1 and BRCA2 predispose individuals to certain cancers, and disease-specific screening and preventative strategies have reduced cancer mortality in affected patients. These classical tumour-suppressor genes have tumorigenic effects associated with somatic biallelic inactivation, although haploinsufficiency may also promote the formation and progression of tumours. Moreover, BRCA1/2-mutant tumours are often deficient in the repair of double-stranded DNA breaks by homologous recombination, and consequently exhibit increased therapeutic sensitivity to platinum-containing therapy and inhibitors of poly-(ADP-ribose)-polymerase (PARP). However, the phenotypic and therapeutic relevance of mutations in BRCA1 or BRCA2 remains poorly defined in most cancer types. Here we show that in the 2.7% and 1.8% of patients with advanced-stage cancer and germline pathogenic or somatic loss-of-function alterations in BRCA1/2, respectively, selective pressure for biallelic inactivation, zygosity-dependent phenotype penetrance, and sensitivity to PARP inhibition were observed only in tumour types associated with increased heritable cancer risk in BRCA1/2 carriers (BRCA-associated cancer types). Conversely, among patients with non-BRCA-associated cancer types, most carriers of these BRCA1/2 mutation types had evidence for tumour pathogenesis that was independent of mutant BRCA1/2. Overall, mutant BRCA is an indispensable founding event for some tumours, but in a considerable proportion of other cancers, it appears to be biologically neutral-a difference predominantly conditioned by tumour lineage-with implications for disease pathogenesis, screening, design of clinical trials and therapeutic decision-making.
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http://dx.doi.org/10.1038/s41586-019-1382-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048239PMC
July 2019

Functional genomic analyses identify pathways dysregulated by progranulin deficiency, implicating Wnt signaling.

Neuron 2011 Sep 21;71(6):1030-42. Epub 2011 Sep 21.

Interdepartmental Program for Neuroscience, University of California Los Angeles, Los Angeles, CA 90095, USA.

Progranulin (GRN) mutations cause frontotemporal dementia (FTD), but GRN's function in the CNS remains largely unknown. To identify the pathways downstream of GRN, we used weighted gene coexpression network analysis (WGCNA) to develop a systems-level view of transcriptional alterations in a human neural progenitor model of GRN-deficiency. This highlighted key pathways such as apoptosis and ubiquitination in GRN deficient human neurons, while revealing an unexpected major role for the Wnt signaling pathway, which was confirmed by analysis of gene expression data from postmortem FTD brain. Furthermore, we observed that the Wnt receptor Fzd2 was one of only a few genes upregulated at 6 weeks in a GRN knockout mouse, and that FZD2 reduction caused increased apoptosis, while its upregulation promoted neuronal survival in vitro. Together, these in vitro and in vivo data point to an adaptive role for altered Wnt signaling in GRN deficiency-mediated FTD, representing a potential therapeutic target.
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http://dx.doi.org/10.1016/j.neuron.2011.07.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3633414PMC
September 2011