Clinical impact of hemizygous deletion detection and panel-size in comprehensive genomic profiling.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15671-e15671
Author(s):  
Kenta Takahashi ◽  
Yasuyuki Gen ◽  
Kousuke Tanimoto ◽  
Atsushi Kudo ◽  
Noriko Oshima ◽  
...  
Keyword(s):  
Copy Number ◽  
Clinical Impact ◽  
Tumor Board ◽  
Genomic Profiling ◽  
Genomic Alterations ◽  
Panel Size ◽  
Drug Candidates ◽  
Hemizygous Deletion ◽  
Comprehensive Genomic Profiling ◽  
The Difference

e15671 Background: Comprehensive genomic profiling (CGP) identified single nucleotide variants (SNVs), copy number alteration (CNA), indels, and rearrangements in cancer-related genes. Only limited CGP detects hemizygous deletion. Also panel size differs among CGPs. Clinical impact of hemizygous deletion and panel-size are not well characterized. Methods: Formalin-fixed paraffin-embedded tissues from 10 cancer patients were analyzed by two CGPs: 1) test A (ACT Onc+) that interrogates SNVs, indels, rearrangement, and CNA including amplification, hemizygous and homozygous deletions in 440 genes, 2) test B that interrogates SNV, indels, rearrangement and CNA including amplification and homozygous deletion in 114 genes, but hemizygous deletion only in limited genes. Result was discussed in molecular tumor board and actionable genes and candidate drug were determined. Primary objective was the number of actionable genomic alterations. Secondary objectives are the number of candidate drugs, SNVs, CAN, and rearrangement. When there was difference of results in two tests, other validation test, such as PCR-based copy number evaluation, was performed. The difference of two tests was statistically evaluated using student t-test. Results: Median age of patients was 56 (range 48 – 70), and 50% were male. Tumor types were neuroendocrine tumor (60%), ovarian cancer (30%) and pancreatic cancer (10%). In 10 patients, actionable genes were found as follows: 39 in test A and 9 in test B (P = 0.0056). Total 64 genomic alterations were found in test A compared 12 in test B. SNV was not statistically different among two tests (10 in test A, 6 in test B; P = 0.269). However, the number of CNA was different: 54 in test A and 6 in test B (P = 0.007). Among CNA, hemizygous alteration explained majority of the difference (30 in test A and 1 in test B, P = 0.059), followed by amplification (24 in test A and 5 in test B, P = 0.201). The number of drug candidates was 38 in test A and 11 in test B (P = 0.014). Conclusions: Detection of hemizygous deletion and larger panel size resulted in more actionable genes and drug candidates, which might impact clinical practice. Future study of clinical utility of hemizygous deletion and panel size is warranted.

scholarly journals Impact and Diagnostic Gaps of Comprehensive Genomic Profiling in Real-World Clinical Practice

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1156
Author(s):  
Aditi P. Singh ◽  
Elaine Shum ◽  
Lakshmi Rajdev ◽  
Haiying Cheng ◽  
Sanjay Goel ◽  
...  
Keyword(s):  
Academic Community ◽  
Clinical Impact ◽  
Cancer Center ◽  
Genomic Alteration ◽  
Molecular Testing ◽  
Genomic Profiling ◽  
National Guidelines ◽  
Genomic Alterations ◽  
Cancer Management ◽  
Comprehensive Genomic Profiling

Purpose: next-generation sequencing based comprehensive genomic profiling (CGP) is becoming common practice. Although numerous studies have shown its feasibility to identify actionable genomic alterations in most patients, its clinical impact as part of routine management across all cancers in the community remains unknown. Methods: we conducted a retrospective study of all patients that underwent CGP as part of routine cancer management from January 2013 to June 2017 at an academic community-based NCI-designated cancer center. CGP was done in addition to established first tier reflex molecular testing as per national guidelines (e.g., EGFR/ALK for non-small cell lung cancer (NSCLC) and extended-RAS for colorectal cancer). Results: 349 tests were sent for CGP from 333 patients and 95% had at least one actionable genomic alteration reported. According to the reported results, 23.2% had a Food and Drug Administration (FDA) approved therapy available, 61.3% had an off-label therapy available and 77.9% were potentially eligible for a clinical trial. Treatment recommendations were also reviewed within the OncoKB database and 47% of them were not clinically validated therapies. The CGP results led to treatment change in only 35 patients (10%), most commonly in NSCLC. Nineteen of these patients (54% of those treated and 5% of total) had documented clinical benefit with targeted therapy. Conclusion: we demonstrate that routine use of CGP in the community across all cancer types detects potentially actionable genomic alterations in a majority of patients, however has modest clinical impact enriched in the NSCLC subset.

Landscape of cyclin pathway genomic alterations across 7,207 non-prostate genitourinary tumors.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 549-549
Author(s):  
Denis Leonardo Fontes Jardim ◽  
Sherri Z. Millis ◽  
Michele Sue-Ann Woo ◽  
Jeffrey S. Ross ◽  
Siraj Mahamed Ali ◽  
...  
Keyword(s):  
Resistance Genes ◽  
Odds Ratio ◽  
Copy Number ◽  
Resistance Mechanism ◽  
Tumor Type ◽  
Genomic Profiling ◽  
Genomic Alterations ◽  
Lower Likelihood ◽  
Comprehensive Genomic Profiling ◽  
Copy Number Changes

549 Background: Cyclin pathway genomic alterations can be a possible therapeutic target as well as a resistance mechanism for therapy. We describe the landscape of cyclin alterations (alt) in non-prostate genitourinary (GU) cancers. Methods: Consecutive samples were analyzed in a CLIA-certified laboratory using comprehensive genomic profiling (CGP) performed by next-generation tissuesequencing (315 genes, >500X coverage). We describe alterations in activating genes (Table) and co-alterations in resistant genes ( RB1 and CCNE1) (related to cyclin inhibition). Results: Alterations in any cyclin pathway genes were found in 37.9% of bladder/urothelial, 33.8% of testicular, 25.2% of penile and 24.6% of kidney cancers. Most alterations were copy number changes and frequencies varied substantially for each tumor type (Table). The high number of cases permitted identification of interesting patterns of outliers for each histology (examples: testis rhabdomyosarcoma and leydig tumor, 50% and 54.5% CDK4 alt; ureter urothelial, 17% CCND1 amp; bladder squamous, 41% CDKN2A del; kidney malignant rhabdoid, 90% SMARCB1 alt; urethra urothelial, 14.7% CCNE1 alt). Alterations in possible resistance genes RB1 and CCNE1 were more frequent in bladder cancers (especially with a neuroendocrine component). Co-occurrence analysis demonstrated a lower likelihood of concomitant vs. isolated alt in cyclin activating and resistance genes (odds ratio for bladder 0.17, p<0.001; OR testis 0.49, p<0.001 and OR kidney 0.45, p<0.001). Conclusions: Cyclin pathway activating and resistance genomic alt are variable in non-prostate GU tumors. Activating alt often occur without simultaneous resistance alt. Our data may inform opportunities for targeted therapy, especially for rare subtypes.[Table: see text]

GI oncology molecular tumor board: Fostering collaboration and clinical education for personalized therapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 11029-11029
Author(s):  
Joseph Elan Grossman ◽  
Andrea J. Bullock ◽  
Susana Angarita ◽  
Bruno Bockorny ◽  
Farshid Dayyani ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Biological Effects ◽  
Standard Of Care ◽  
Treatment Decisions ◽  
Tumor Board ◽  
Genomic Profiling ◽  
Genomic Alterations ◽  
Therapeutic Implications ◽  
Comprehensive Genomic Profiling ◽  
Molecular Tumor Board

11029 Background: In recent years, genomic profiling has become standard of care for several gastrointestinal (GI) cancers. In addition to standard of care indications, comprehensive genomic profiling has led to novel and expanded applications of targeted therapy, chemotherapy, and immunotherapy and facilitated identification of potential clinical trials. A GI molecular tumor board (MTB) was developed with a goal of improving understanding of the biological effects of genomic alterations and their therapeutic implications to enhance personalized therapy. Methods: Foundation Medicine (FM) collaborated with physicians in the GI oncology group of an academic medical center to develop a GI MTB starting March 2019. As of December 2019, 27 GI oncology cases were presented where FoundationOneCDx testing was performed and a clinical question was posed. Cases were discussed by faculty, fellows, research staff, and a clinical genomic scientist and oncologist from FM. Impacted signaling pathways and biomarkers were discussed for each case alongside clinical content so that physicians could consider therapeutic options and clinical trials. Presenting faculty were asked to complete a questionnaire for each case presented to assess the impact of the MTB discussion on clinician knowledge and patient-level treatment recommendations. Results: Of 27 questionnaires sent to 7 providers, 17 (63%) were completed. Respondents indicated that as a result of the MTB, the treatment plan was changed in 2 cases (12%), reinforced in 9 cases (53%) and in 6 cases (35%) there was no effect. On a Likert scale of 1-4 where 1 is “rare/poorly” and 4 is “great” mean scores were as follows: Did this MTB help you understand the biological effects of the main genomic alteration(s) reported in the case presented? 3.3. Did this MTB help you understand the possible therapeutic implications of the main genomic alterations in the case presented? 3.3. Did this MTB improve your understanding of the role of next generation sequencing and comprehensive genomic profiling in making treatment decisions? 3.4. Conclusions: The results of our questionnaire indicate that treatment decisions were changed in a minority of cases based on the MTB. In most cases, clinical decision making was reinforced and understanding of the biological effects of genomic alterations and their therapeutic implications were improved. Based on this feedback we will continue to refine and integrate the GI MTB into clinical care for patients with GI malignancies, and share our experience locally with other disease groups.

scholarly journals Making the Most of Complexity to Create Opportunities: Comprehensive Genomic Profiling and Molecular Tumor Board for Patients with Non-Small Cell Lung Cancer (NSCLC)

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 609
Author(s):  
Caterina Fumagalli ◽  
Elena Guerini-Rocco ◽  
Massimo Barberis
Keyword(s):  
Lung Cancer ◽  
Small Cell ◽  
Tumor Board ◽  
Genomic Profiling ◽  
Small Cell Lung ◽  
Molecular Alterations ◽  
Comprehensive Genomic Profiling ◽  
Molecular Tumor Board ◽  
Personalized Cancer Therapy ◽  
Personalized Cancer

Personalized cancer therapy matches the plan of treatment with specific molecular alterations [...]

Confirmatory germline testing for presumed germline pathogenic variants using tumor-only testing.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e22524-e22524
Author(s):  
Tomohiro Kondo ◽  
Takahiro Yamada ◽  
Masahiro Yoshioka ◽  
Masakazu Nishigaki ◽  
Yoshihiro Yamamoto ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Regression Analysis ◽  
Logistic Regression Analysis ◽  
Multivariate Logistic Regression Analysis ◽  
Tumor Board ◽  
Genomic Profiling ◽  
Multivariate Logistic Regression ◽  
Pathogenic Variants ◽  
Comprehensive Genomic Profiling ◽  
Germline Testing

e22524 Background: Presumed germline pathogenic variants (PGPVs) can be detected in tumor tissues using comprehensive genomic profiling. Clinicians and patients can decide whether to conduct confirmatory germline testing or not. However, the promoting and obstructive factors for confirmatory germline testing are unclear. Methods: This single institutional retrospective study aimed to identify factors related to confirmatory germline testing in patients with PGPVs. Between April 2015 and April 2019, 270 consecutive patients with cancers of unknown primary site, rare tumors, or solid tumors refractory to standard chemotherapy, who underwent tumor-only comprehensive genomic profiling were reviewed. PGPVs were proposed to be disclosed as variants to the patients by our institutional molecular tumor board. Univariate logistic regression analysis was conducted to investigate the relationship between each patient’s characteristics and confirmatory germline testing. Factors showing a statistical relationship (p < 0.10 in univariate analyses) were included in multivariate logistic regression analysis with a backward selection of variables. Statistical significance was set at p < 0.05. Results: Of the 270 patients who underwent tumor-only comprehensive genomic profiling, 77 possessed PGPVs. The most common PGPVs were TP53 (n = 56), APC (n = 9), PTEN (n = 7), RB1 (n = 6), and BRCA2 (n = 6). Among the 77 patients, only 11 (14.3%) chose to undergo confirmatory germline testing. Multivariate logistic regression analysis revealed that the person disclosing the results (experienced oncologists with knowledge of cancer genome medicine vs. others, odds ratio [OR]: 27.7, 95% confidence interval [CI]: 4.60–167) and study period (OR: 0.110, 95% CI: 0.015–0.787) were independently and significantly associated with confirmatory germline testing. Conclusions: These findings indicate that fostering genomic competency in oncologists and collaborating with genetic experts would facilitate cancer patients and their families to receive genetic medical services in the process of cancer genomic profiling.

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

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.

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