Molecular characterization and clinical impact of co-occurring mutations in patients with NSCLC harboring genomic alterations of MET.

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.

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Clinical impact of molecular tumor profiling in pediatric, adolescent, and young adult patients with extra-cranial solid malignancies: An interim report from the GAIN/iCat2 study.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.10005 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 10005-10005

Author(s):

Alanna J. Church ◽

Laura Corson ◽

Pei-Chi Kao ◽

Alma Imamovic-Tuco ◽

Wenjun Kang ◽

...

Keyword(s):

Targeted Therapy ◽

Solid Tumors ◽

Clinical Care ◽

Young Patients ◽

Clinical Impact ◽

Adolescent And Young Adult ◽

Genomic Alterations ◽

Molecular Alteration ◽

Tumor Profiling

10005 Background: Next generation sequencing (NGS) assays are now a standard part of clinical care for many adult solid cancers. The significance of molecular tumor profiling for the care of children with cancer is not well understood.We aimed to determine the clinical impact of identifying genomic alterations by NGS for young patients with relapsed, refractory, or high-risk extracranial solid tumors. Methods: We report on the first 389 participants in a prospective cohort study enrolling patients at 12 institutions with extracranial solid tumors diagnosed at age 30 years or less. Targeted DNA NGS was performed on one or more tumor samples from each patient. Selected patients also had tumors subjected to RNA sequencing. Test results were returned to the treating oncologist and follow-up treatment and response data were collected.Identified genomic alterations were classified according to evidence of impact on diagnosis, prognosis or response to targeted therapy matched to an identified alteration (matched targeted therapy, MTT) using established guidelines. Response to MTT was determined and reported as a response if either there was radiographic response according to RECIST or the duration of therapy was > 4 months. Results: Molecular tumor profiling (MTP) was successful in 345 (89%) patients (mean age 11 years at diagnosis; 65% with sarcoma). Two hundred and ninety-nine patients with MTP results (87%) had one or more alterations of clinical significance. Genomic alterations with diagnostic, prognostic or therapeutic significance were present in 208 (60%), 51 (15%) and 240 (70%) patients, respectively. Of the 240 patients with tumors harboring genomic alterations designated as having therapeutic impact, 23 (11%) had Tier 1 molecular findings. 205 patients were eligible to receive MTT based on having a molecular alteration with therapeutic significance and sufficient follow-up; 31 of these patients (15%) received MTT. Seven patients (23%) receiving MTT responded, 6 of these were kinase fusions. All of the responders received targeted therapy matched to a fusion and 78% of diagnostically significant alterations were fusions. Conclusions: Molecular tumor profiling has a significant impact on diagnosis and treatment recommendations for young patients with extracranial solid tumors. These results emphasize the importance of fusion detection for patients with sarcomas and rare tumors. Clinical trial information: NCT02520713.

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Molecular characterization and clinical impact of t(11;15)(q23;q14-15) MLL-CASC5 rearrangement

Haematologica ◽

10.3324/haematol.2013.095638 ◽

2014 ◽

Vol 99 (1) ◽

pp. e11-e13 ◽

Cited By ~ 4

Author(s):

J. J. Yang ◽

T. S. Park ◽

S.-T. Lee ◽

J.-Y. Seo ◽

S. H. Oh ◽

...

Keyword(s):

Molecular Characterization ◽

Clinical Impact

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

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15671 ◽

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.

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