Dataset Information

Combined Focused Next-Generation Sequencing Assays to Guide Precision Oncology in Solid Tumors: A Retrospective Analysis from an Institutional Molecular Tumor Board.

ABSTRACT:

Background

Increasing knowledge of cancer biology and an expanding spectrum of molecularly targeted therapies provide the basis for precision oncology. Despite extensive gene diagnostics, previous reports indicate that less than 10% of patients benefit from this concept.

Methods

We retrospectively analyzed all patients referred to our center's Molecular Tumor Board (MTB) from 2018 to 2021. Molecular testing by next-generation sequencing (NGS) included a 67-gene panel for the detection of short-sequence variants and copy-number alterations, a 53- or 137-gene fusion panel and an ultra-low-coverage whole-genome sequencing for the detection of additional copy-number alterations outside the panel's target regions. Immunohistochemistry for microsatellite instability and PD-L1 expression complemented NGS.

Results

A total of 109 patients were referred to the MTB. In all, 78 patients received therapeutic proposals (70 based on NGS) and 33 were treated accordingly. Evaluable patients treated with MTB-recommended therapy (n = 30) had significantly longer progression-free survival than patients treated with other therapies (n = 17) (4.3 vs. 1.9 months, p = 0.0094). Seven patients treated with off-label regimens experienced major clinical benefits.

Conclusion

The combined focused sequencing assays detected targetable alterations in the majority of patients. Patient benefits appeared to lie in the same range as with large-scale sequencing approaches.

SUBMITTER: Tarawneh TS

PROVIDER: S-EPMC9496918 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Publications

Combined Focused Next-Generation Sequencing Assays to Guide Precision Oncology in Solid Tumors: A Retrospective Analysis from an Institutional Molecular Tumor Board.

Tarawneh Thomas S TS Rodepeter Fiona R FR Teply-Szymanski Julia J Ross Petra P Koch Vera V Thölken Clemens C Schäfer Jonas A JA Gremke Niklas N Mack Hildegard I D HID Gold Judith J Riera-Knorrenschild Jorge J Wilhelm Christian C Rinke Anja A Middeke Martin M Klemmer Andreas A Romey Marcel M Hattesohl Akira A Jesinghaus Moritz M Görg Christian C Figiel Jens J Chung Ho-Ryun HR Wündisch Thomas T Neubauer Andreas A Denkert Carsten C Mack Elisabeth K M EKM

Cancers 20220912 18

<h4>Background</h4>Increasing knowledge of cancer biology and an expanding spectrum of molecularly targeted therapies provide the basis for precision oncology. Despite extensive gene diagnostics, previous reports indicate that less than 10% of patients benefit from this concept.<h4>Methods</h4>We retrospectively analyzed all patients referred to our center's Molecular Tumor Board (MTB) from 2018 to 2021. Molecular testing by next-generation sequencing (NGS) included a 67-gene panel for the detec ...[more]

PMID: 36139590

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Project description:BackgroundWith rapid advances in genomic medicine, the complexity of delivering precision medicine to oncology patients across a university health system demanded the creation of a Molecular Tumor Board (MTB) for patient selection and assessment of treatment options. The objective of this report is to analyze our progress to date and discuss the importance of the MTB in the implementation of personalized medicine.Materials and methodsPatients were reviewed in the MTB for appropriateness for comprehensive next generation sequencing (NGS) cancer gene set testing based on set criteria that were in place. Because profiling of stage IV lung cancer, colon cancer, and melanoma cancers were standard of care, these cancer types were excluded from this process. We subsequently analyzed the types of cases referred for testing and approved with regards to their results.Results191 cases were discussed at the MTB and 132 cases were approved for testing. Forty-six cases (34.8%) had driver mutations that were associated with an active targeted therapeutic agent, including BRAF, PIK3CA, IDH1, KRAS, and BRCA1. An additional 56 cases (42.4%) had driver mutations previously reported in some type of cancer. Twenty-two cases (16.7%) did not have any clinically significant mutations. Eight cases did not yield adequate DNA. 15 cases were considered for targeted therapy, 13 of which received targeted therapy. One patient experienced a near complete response. Seven of 13 had stable disease or a partial response.ConclusionsMTB at University of Alabama-Birmingham is unique because it reviews the appropriateness of NGS testing for patients with recurrent cancer and serves as a forum to educate our physicians about the pathways of precision medicine. Our results suggest that our detection of actionable mutations may be higher due to our careful selection. The application of precision medicine and molecular genetic testing for cancer patients remains a continuous educational process for physicians.

Project description:The incidence of new cancer cases is expected to increase significantly in the future, posing a worldwide problem. In this regard, precision oncology and its diagnostic tools are essential for developing personalized cancer treatments. Nowadays, it is almost impossible to separate technology and digitization from medicine and health sciences, and digital pathology (DP) is emerging as one of the most influential technologies in the transition towards the 4P of new medicine (preventive, participatory, personalized and predictive). DP is a particularly key strategy to study the interactions of tumor cells and the tumor microenvironment (TME), which play a crucial role in tumor initiation, progression and metastasis. The purpose of this study was to integrate data on the digital patterns of reticulin fiber scaffolding and the immune cell infiltrate, transcriptomic and epigenetic profiles in aggressive uterine adenocarcinoma (uADC), uterine leiomyosarcoma (uLMS) and their respective lung metastases, with the aim of obtaining key TME biomarkers that can help improve metastatic prediction and shed light on potential therapeutic targets. Automatized algorithms were used to analyze reticulin fiber architecture and immune infiltration in colocalized regions of interest (ROIs) of 133 invasive tumor front (ITF), 89 tumor niches and 70 target tissues in a total of six paired samples of uADC and nine of uLMS. Microdissected tissue from the ITF was employed for transcriptomic and epigenetic studies in primary and metastatic tumors. Reticulin fiber scaffolding was characterized by a large and loose reticular fiber network in uADC, while dense bundles were found in uLMS. Notably, more similarities between reticulin fibers were observed in paired uLMS then paired uADCs. Transcriptomic and multiplex immunofluorescence-based immune profiling showed a higher abundance of T and B cells in primary tumor and in metastatic uADC than uLMS. Moreover, the epigenetic signature of paired samples in uADCs showed more differences than paired samples in uLMS. Some epigenetic variation was also found between the ITF of metastatic uADC and uLMS. Altogether, our data suggest a correlation between morphological and molecular changes at the ITF and the degree of aggressiveness. The use of DP tools for characterizing reticulin scaffolding and immune cell infiltration at the ITF in paired samples together with information provided by omics analyses in a large cohort will hopefully help validate novel biomarkers of tumor aggressiveness, develop new drugs and improve patient quality of life in a much more efficient way.

Dataset Information

Combined Focused Next-Generation Sequencing Assays to Guide Precision Oncology in Solid Tumors: A Retrospective Analysis from an Institutional Molecular Tumor Board.

Background

Methods

Results

Conclusion

Publications

Combined Focused Next-Generation Sequencing Assays to Guide Precision Oncology in Solid Tumors: A Retrospective Analysis from an Institutional Molecular Tumor Board.

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