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

SIMPLE SUMMARY: The molecular characterization of tumor tissues has become essential to classify tumors, assess prognoses and optimize treatment. However, there is still no consensus about the use of molecular diagnostics broadly across tumor types due to costs and limited evidence for the actual benefit of tumor-agnostic precision oncology. At our institution, we implemented three complementary NGS assays that are compatible with benchtop sequencing instruments as a diagnostic tool for identifying therapeutic targets and developing tailored treatment recommendations in a Molecular Tumor Board. Specifically, we used a 67-gene panel for the detection of short-sequence variants and copy-number alterations, a 53- or 137-gene panel for the detection of fusion transcripts and ultra-low-coverage whole-genome sequencing for detection of additional copy-number alterations outside the panel’s target regions. The Molecular Tumor Board was able to suggest personalized treatments to 75% of the patients, indicating that a combination of focused genetic diagnostics is highly informative for routine cancer care. 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.