Comprehensive genomic profiling of parathyroid carcinoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 6088-6088 ◽  
Author(s):  
Hyunseok Kang ◽  
Adrian Daniel Schubert ◽  
Paul Ladenson ◽  
Douglas Wilmot Ball ◽  
Jon Chung ◽  
...  
Keyword(s):  
Parathyroid Carcinoma ◽  
Cell Cycle Progression ◽  
Stage Iv ◽  
Genomic Profiling ◽  
Genomic Alterations ◽  
Initial Surgery ◽  
Mutation Burden ◽  
Number Of Patients ◽  
Comprehensive Genomic Profiling ◽  
Life Threatening

6088 Background: Parathyroid carcinoma (PC) is a rare endocrine malignancy, which can cause life-threatening hypercalcemia. Initial surgery is often noncurative, and adjunctive radiotherapy and previous chemotherapies have not been shown to be effective. Previous studies identified recurring mutations in CDC73 and PRUNE2in a limited number of patients. We queried whether comprehensive genomic profiling (CGP) would have potential to discover novel targets of therapy. Methods: DNA was extracted from 40 microns of FFPE sections from 13 consecutive cases of relapsed/metastatic PC. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 672x for up to 315 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. Genomic alterations (GA) included base substitutions (SUB), INDELs, copy number alterations (CNA) and fusions/rearrangements. Clinically relevant GA (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: Total of 13 specimens were identified from 7 male and 6 female patients. The mean age of the patients in this study was 54 years (range 38 to 76 years). All (100%) cases were Stage IV at the time of CGP. Tumor mutation burden was generally low - median mutation load per mega base was 1.8. There were 58 total GA (4.5 GA/sample) and 10 CRGA (0.8 CRGA/sample). The most frequent GA were non-CRGA mutations in TP53 (31%) and CDC73 (31%). MEN1 mutations were identified in 23% of cases. Frequent alterations in genes controlling cell cycle progression at G1 including CDKN1B, CDKN2A, CDKN2B and CDKN2C were identified (30%). The most frequent CRGA involved PTEN (23%), NF1 (23%) and KDR (15%). No alterations in BRAF or RETwere identified. A patient with KDR mutation treated with cabozantinib experienced > 50% drop in PTH level and radiographic partial response in 3 months. Conclusions: CGP identified previously unreported TP53 mutations in PCs and potentially actionable genomic alterations including PTEN, NF1 and KDR. Clinical benefit and response observed in a patient treated with VEGFR targeted therapy suggest that patients with this rare tumor may be candidates for targeted therapies.

Comprehensive genomic profiling of neuroendocrine carcinoma of the prostate.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 187-187
Author(s):  
Sumanta K. Pal ◽  
Matthew I. Milowsky ◽  
Julia Andrea Elvin ◽  
Siraj Mahamed Ali ◽  
Jean H. Hoffman-Censits ◽  
...  
Keyword(s):  
Neuroendocrine Carcinoma ◽  
Stage Iv ◽  
Mtor Inhibitors ◽  
Mtor Pathway ◽  
Tumor Type ◽  
Genomic Profiling ◽  
Genomic Alterations ◽  
Carcinoma Of The Prostate ◽  
Comprehensive Genomic Profiling ◽  
Metastatic Sites

187 Background: Neuroendocrine carcinoma of the prostate (NCAP) is an aggressive high grade malignancy that often presents as metastatic disease. Current treatments of this tumor have only modest benefit leading investigators to query whether comprehensive genomic profiling (CGP) would have potential to discover novel targets of therapy. Methods: DNA was extracted from 40 microns of FFPE sections from 37 consecutive cases of relapsed/metastatic NCAP. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 583X for up to 315 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. Genomic alterations (GA) included base substitutions (SUB), INDELs, copy number alterations (CNA) and fusions/rearrangements. Clinically relevant GA (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: The median age of the men in this study was 65.1 years (range 43 to 83 years). All (100%) cases were positive for neuroendocrine markers on immunohistochemical staining and were Stage IV at the time of CGP. Samples used for sequencing were obtained from the primary tumor in 9 (24%) of NCAP and from metastatic sites in 28 (76%) of NCAP (12 liver, 6 LN, 2 each from bladder, pelvis and soft tissue, and 1 each from rectum, bone, urethra and ureter. There were 213 total GA (5.8 GA/sample) and 47 CRGA (1.3 CRGA/sample). The most frequent GA were non-CRGA mutations in TP53 (68%) and RB1 (51%). TMPRSS:ERG fusions were identified in 32% of cases whereas AR was altered in 8% (1 mutation and 2 amplifications). The most frequent CRGA involved PTEN (32%), BRCA2 (14%), FGFR1 (5%), PIK3CA (5%) and AKT2 (3%). No alterations in BRAF were identified. Clinical responses to MTOR inhibitors in patients with MTOR pathway alterations will be presented. Conclusions: NCAP has distinctive genomic alterations from classic acinar CAP including reduced frequencies of alterations in TMPRSS:ERG and AR and frequent RB1 mutations. Multiple alterations in the MTOR pathway identified in this infrequent tumor type suggest that these patients may be candidates for MTOR inhibitors and other targeted therapies.

Comprehensive Genomic Profiling of Central Giant Cell Lesions Identifies Clinically Relevant Genomic Alterations

2017 ◽  
Vol 75 (5) ◽  
pp. 955-961 ◽  
Author(s):  
Brett Bezak ◽  
Heidi Lehrke ◽  
Julia Elvin ◽  
Laurie Gay ◽  
David Schembri-Wismayer ◽  
...  
Keyword(s):  
Giant Cell ◽  
Genomic Profiling ◽  
Genomic Alterations ◽  
Comprehensive Genomic Profiling

scholarly journals OA03.05 Characterization of Genomic Alterations in Chinese LCNEC and SCLC via Comprehensive Genomic Profiling

2019 ◽  
Vol 14 (10) ◽  
pp. S212-S213
Author(s):  
L. Wu ◽  
L. Cao ◽  
L. Chen ◽  
B. Zhu ◽  
X. Hu ◽  
...  
Keyword(s):  
Genomic Profiling ◽  
Genomic Alterations ◽  
Comprehensive Genomic Profiling

FoundationOne as a relevant tool for comprehensive genomic profiling and assessment of tumor mutation burden in the era of precision oncology in India.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23096-e23096
Author(s):  
Amit Verma ◽  
Nitesh Rohatgi ◽  
Pramod Kumar Julka ◽  
Meenu Walia ◽  
Ankur Bahl ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Mutation Frequency ◽  
Unknown Primary ◽  
Precision Oncology ◽  
Tumor Type ◽  
Genomic Profiling ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Comprehensive Genomic Profiling ◽  
Tumor Types

e23096 Background: Comprehensive genomic profiling (CGP) is gaining acceptability globally, but clinical experience in developing countries like India is limited. CGP identifies genomic alterations (GA), with tumor mutation burden (TMB) and microsatellite status (MSI), revealing therapeutic options such as targeted inhibitors and immunotherapies. We sought to evaluate the mutation frequency and actionability across tumors. Methods: Metastatic and/or refractory patients (referred to Personalized Cancer Medicine Clinic) underwent CGP analysis, including calculation of TMB and MSI, using a targeted NGS panel (FoundationOne, 53 samples; FoundationOne Heme, 4 samples). This panel detects all relevant classes of GA: base substitutions, small indels, rearrangements and copy number changes. Mutation frequencies were compared with the larger Foundation database. TMB status was reported as low (≤5 mutations/Mb), intermediate (6-19 mut/Mb) or high (≥20 mut/Mb). Results: The most common tumor types were lung (23%), breast (14%) and sarcoma (12%); other tumor types, including unknown primary constituted the rest (51%). Most samples were from metastatic sites (60%). Oncogenic GA were found in 131 genes across all tumor subtypes and affected major pathways: apoptosis/cell cycle (31%), PI3K (14%), transcriptional regulation (13%), and receptor tyrosine kinases (10%). Among these GA, 38 were considered actionable and were distributed across 43 (75%) samples. Therapies with FDA approval for the tumor type analyzed were indicated for 18 samples; an additional 25 samples had GA associated with therapies FDA approved for another indication. More than 1 actionable GA was identified in 24/43 (56%). TMB status was low in 36 (63%), intermediate in 19 (33%) and high in 2 (3.5%). High TMB status correlated with high MSI status (p < 0.001). Trend observed in the mutation frequency was comparable with the larger Foundation database. Conclusions: This is the first study in India showing CGP identified actionable targets associated with FDA approved therapies in approx. 32% of cases. TMB status identified 2/57 samples with high mutation burden for whom immunotherapy might be relevant.

PD-L1 genomic alterations (GA) in solid tumors and hematologic malignancies: A comprehensive genomic profiling (CGP) study.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. 12092-12092
Author(s):  
Laurie M. Gay ◽  
David Fabrizio ◽  
Garrett Michael Frampton ◽  
Lee A. Albacker ◽  
Ethan Sokol ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Hematologic Malignancies ◽  
Genomic Profiling ◽  
Genomic Alterations ◽  
Comprehensive Genomic Profiling

Comprehensive genomic profiling of ctDNA in patients with colon cancer and its fidelity to the genomics of the tumor biopsy.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 569-569 ◽  
Author(s):  
Jeffrey P. Gregg ◽  
Gerald Li ◽  
Dean Pavlick ◽  
Jon Chung ◽  
Matthew Cooke ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Stage Iv ◽  
Prospective Clinical Study ◽  
Genomic Profiling ◽  
Blood Draw ◽  
Tumor Biopsy ◽  
Comprehensive Genomic Profiling ◽  
Tumor Types ◽  
Ct Dna ◽  
Clinical Trial Information

569 Background: The liquid biopsy offers the ability to non-invasively analyze the genome of a tumor through circulating tumor (ct) DNA to identify targetable and prognostic genomic alterations. Few studies have rigorously analyzed ctDNA results and determined the fidelity with which they recapitulate the genomics of the tumor. The clinical utility study (CUS) for FoundationACT (Foundation Medicine, Cambridge, MA; NCT02620527) is a large multi-center prospective clinical study to validate this ctDNA assay for multiple solid tumor types. In this subset of the CUS study, paired specimens from 98 patients with colon cancer were analyzed with comprehensive genomic profiling of the tumor (FoundationOne) and a blood sample (FoundationACT). Methods: Maximum somatic allele fraction (MSAF) was used to estimate the fraction of ctDNA in the sample. The set of genes and targeted regions common to both FoundationOne and FoundationACT were compared for each subject. Results: 60% were male; 73 had stage IV, 17 had stage III, and 8 had stage II disease. 16% of cases had an MSAF value of 0, indicating that no ctDNA were in these samples. For the cases with MSAF > 0, 153 insertion/deletions (indels)/substitutions were identified in the tumor, and 73% of these identical alterations were also identified in the ctDNA samples. As robust analytical performance for FoundationACT has been demonstrated at MSAF > 0.5% for indel/subs, further analysis was conducted using this threshold. 83% of the alterations identified with FoundationOne were identified with FoundationACT. Further, 90% of NRAS/KRAS and 75% BRAF alterations (NCCN guideline genes) were concordant between the two assays. Lastly, there were 11 patients with tumor biopsy and blood draw taken within 30 days of each other, and in these there was 100% concordant. Association of the genomics results with other clinical variables will be presented for the available subset of patients. Conclusions: In cases where tumor profiling is not possible, these results provide compelling evidence that comprehensive molecular profiling of ctDNA in colon cancer can be used to identify most clinically relevant alterations and has fidelity to the genomics of the tumor. Clinical trial information: NCT02620527.

Efficacy of systemic treatment for metastatic renal cell carcinoma (mRCC) guided by comprehensive genomic profiling (CGP).

2019 ◽  
Vol 37 (27_suppl) ◽  
pp. 63-63
Author(s):  
Paulo Gustavo Bergerot ◽  
Cristiane Decat Bergerot ◽  
Nazli Dizman ◽  
Nicholas Salgia ◽  
Joann Hsu ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Cox Regression ◽  
Clinical Care ◽  
Genomic Profiling ◽  
Genomic Alterations ◽  
Comprehensive Genomic Profiling

63 Background: Comprehensive genomic profiling (CGP) has been used to guide treatment selection in metastatic renal cell carcinoma (mRCC). This study sought to determine if genomic alterations guided treatment and contributed to improved outcomes. Methods: From a single institution, patients (pts) diagnosed with mRCC who had CGP in the course of clinical care were identified. Pts were tested on a CLIAA-certified platform (FoundationOne; Cambridge, MA). Pts who died/initiated hospice within the 30 days after the test was performed or who were lost to follow-up were excluded. Duration of therapy (DOT) was measured as months between first and last day of therapy following CGP test. The Kaplan-Meier method was undertaken to estimate the association of CGP-directed therapy with overall survival (OS). Cox regression was also performed and adjusted for histologic subgroup. Results: A total of 64 patients underwent CGP between February 2014 and August 2018. From this group, 15 patients were excluded due to death/hospice within 30 d (n = 10) and lack of follow-up (n = 5). Median age at diagnosis was 60 years (range, 24-84), and 79% were male. Most patients (69%) were diagnosed with clear cell RCC. The median identified genomic alterations (GAs) was 3 (range, 0-7). The most common GAs were VHL (54%), PBRM1 (28%), TERT (21%), TP53 (15%), BAP1 (13%), and SETD2 (13%). Of the 49 patients included in this analysis, 47% had actionable mutations based on their CGP results. Of those, 13 patients received directed-therapy of whom 57% had stable disease, 28% had partial response, and 14% had progressive disease. The median time from CGP test to treatment was 1 month (range, 0-17). The median duration of directed-therapy was 12 months (range, 1-28) and of non-directed therapy was 4 months (range, 1-40) (P = 0.04). Directed-therapy was significantly associated with better OS (adjusted HR, 0.32 [95% CI, 0.13 to 0.82]; P = 0.018) compared to non-directed therapy. Conclusions: This study provides preliminary evidence to justify CGP-guided therapy in mRCC. Forthcoming studies should prospectively explore the use of CGP in treatment allocation for mRCC to validate these findings.

Cyclin pathway genomic alterations across 5,356 prostate cancers.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 179-179
Author(s):  
Denis Leonardo Fontes Jardim ◽  
Sherri Z. Millis ◽  
Michele Sue-Ann Woo ◽  
Jeffrey S. Ross ◽  
Siraj Mahamed Ali ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Genomic Profiling ◽  
Genomic Alterations ◽  
Resistance Pathway ◽  
Lower Likelihood ◽  
Ccnd1 Amplification ◽  
Comprehensive Genomic Profiling ◽  
Prostate Cancers ◽  
Copy Number Changes ◽  
Generation Sequencing

179 Background: The cyclin pathway is comprised of possible targetable alterations as well as resistant alterations that affect treatment, including hormonal agents. We describe the landscape of cyclin genomic alterations in prostate cancer. Methods: Consecutive samples were analyzed in a CLIA-certified laboratory using comprehensive genomic profiling (CGP) performed by next-generation sequencing (315 genes, >500X coverage). We describe alterations in activating genes (Table) and co-alterations in resistant genes ( RB1 and CCNE1) (related to cyclin inhibition) and androgen receptor ( AR). Results: Alterations in any cyclin pathway genes were found in 9.7% of the 5,356 tumors analyzed. Frequent alterations included CCND1 amplification (4.2%) and CDKN2A and B loss (2.4% each). Frequencies were substantially different according to prostate cancer histology (Table). The majority of alterations were copy number changes. Alterations in possible resistance genes, RB1 and CCNE1 were detected in 9.7% (up to 54.6% in neuroendocrine) and 1.2% of cases, respectively, while AR alterations were seen in 20.9% (up to 27.3% in anaplastic). Co-occurrence analysis demonstrated a lower likelihood of concomitant vs. isolated alterations in cyclin activating and resistance pathway (odds ratio (OR), 0.44, p<0.001). Conversely, we detected a higher likelihood of co-occurrence between AR and cyclin alterations (OR 1.79, p<0.001). Conclusions: Cyclin pathway genomic abnormalities were observed in about 10% of prostate cancer tumors, and are more frequently associated with concomitant AR alterations and absence of co-alterations associated with resistance to cyclin inhibition.[Table: see text]

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