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Functional Precision Medicine Provides Clinical Benefit in Advanced Aggressive Hematologic Cancers and Identifies Exceptional Responders.

ABSTRACT: Personalized medicine aims to match the right drug with the right patient by using specific features of the individual patient's tumor. However, current strategies of personalized therapy matching provide treatment opportunities for less than 10% of patients with cancer. A promising method may be drug profiling of patient biopsy specimens with single-cell resolution to directly quantify drug effects. We prospectively tested an image-based single-cell functional precision medicine (scFPM) approach to guide treatments in 143 patients with advanced aggressive hematologic cancers. Fifty-six patients (39%) were treated according to scFPM results. At a median follow-up of 23.9 months, 30 patients (54%) demonstrated a clinical benefit of more than 1.3-fold enhanced progression-free survival compared with their previous therapy. Twelve patients (40% of responders) experienced exceptional responses lasting three times longer than expected for their respective disease. We conclude that therapy matching by scFPM is clinically feasible and effective in advanced aggressive hematologic cancers. SIGNIFICANCE: This is the first precision medicine trial using a functional assay to instruct n-of-one therapies in oncology. It illustrates that for patients lacking standard therapies, high-content assay-based scFPM can have a significant value in clinical therapy guidance based on functional dependencies of each patient's cancer.See related commentary by Letai, p. 290.This article is highlighted in the In This Issue feature, p. 275.

SUBMITTER: Kornauth C

PROVIDER: S-EPMC9762339 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Functional Precision Medicine Provides Clinical Benefit in Advanced Aggressive Hematologic Cancers and Identifies Exceptional Responders.

Kornauth Christoph C Pemovska Tea T Vladimer Gregory I GI Bayer Günther G Bergmann Michael M Eder Sandra S Eichner Ruth R Erl Martin M Esterbauer Harald H Exner Ruth R Felsleitner-Hauer Verena V Forte Maurizio M Gaiger Alexander A Geissler Klaus K Greinix Hildegard T HT Gstöttner Wolfgang W Hacker Marcus M Hartmann Bernd Lorenz BL Hauswirth Alexander W AW Heinemann Tim T Heintel Daniel D Hoda Mir Alireza MA Hopfinger Georg G Jaeger Ulrich U Kazianka Lukas L Kenner Lukas L Kiesewetter Barbara B Krall Nikolaus N Krajnik Gerhard G Kubicek Stefan S Le Trang T Lubowitzki Simone S Mayerhoefer Marius E ME Menschel Elisabeth E Merkel Olaf O Miura Katsuhiro K Müllauer Leonhard L Neumeister Peter P Noesslinger Thomas T Ocko Katharina K Öhler Leopold L Panny Michael M Pichler Alexander A Porpaczy Edit E Prager Gerald W GW Raderer Markus M Ristl Robin R Ruckser Reinhard R Salamon Julius J Schiefer Ana-Iris AI Schmolke Ann-Sofie AS Schwarzinger Ilse I Selzer Edgar E Sillaber Christian C Skrabs Cathrin C Sperr Wolfgang R WR Srndic Ismet I Thalhammer Renate R Valent Peter P van der Kouwe Emiel E Vanura Katrina K Vogt Stefan S Waldstein Cora C Wolf Dominik D Zielinski Christoph C CC Zojer Niklas N Simonitsch-Klupp Ingrid I Superti-Furga Giulio G Snijder Berend B Staber Philipp B PB

Cancer discovery 20211011 2

Personalized medicine aims to match the right drug with the right patient by using specific features of the individual patient's tumor. However, current strategies of personalized therapy matching provide treatment opportunities for less than 10% of patients with cancer. A promising method may be drug profiling of patient biopsy specimens with single-cell resolution to directly quantify drug effects. We prospectively tested an image-based single-cell functional precision medicine (scFPM) approac ...[more]

PMID: 34635570

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Project description:BackgroundPrecision and matched cancer medicine has the potential to complement the existing biomarker approaches in cancer treatment. However, despite their promising potential, certain negative results have highlighted their limitations in molecular biology-driven treatment strategies. This study aimed to evaluate the clinical benefits of precision therapies.Materials and methodsThree reviewers independently identified and assessed precision and matched cancer treatment studies published between January 2015 and December 2020. Clinical benefits of the treatments included in our cohort were assessed using two established frameworks; the European Society of Medical Oncology-Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS) and the American Society of Clinical Oncology Value Framework.ResultsOf the 290 eligible studies, 130 were for lung cancer, 51 for solid tumors, 24 for melanoma, and 24 for breast cancer. The common targets were: epidermal growth factor receptor (N = 66), serine/threonine-protein kinase B-Raf (N = 40), anaplastic lymphoma kinase (ALK) (N = 34), breast cancer protein (N = 26), phosphatidylinositol-3 kinase/protein kinase B/phosphatase and tensin homolog (PI3K/AKT/PTEN) pathway (N = 19), receptor tyrosine-protein kinase erbB-2 (HER2) (N = 19), mitogen-activated protein kinase (RAS/RAF/MAPK) pathway (N = 18), programmed death-ligand 1 (N = 12), fibroblast growth factor receptor (N = 8), and others (N = 43). The ESMO-MCBS scales ranged from 0 to 4. Based on the clinical benefit values, tumor mutational burden/mismatch repair-deficient/microsatellite instability-high for immunotherapy, anaplastic lymphoma kinase, and neurotrophic receptor tyrosine kinase therapeutic targets were considered high, whereas RAS/RAF/MAPK and PI3K/AKT/PTEN were considered low. Additionally, we found a significant difference between each average score (P < 0.001).ConclusionsThis study showed that precision and matched cancer therapies require further improvement. This is consistent with the views of the tumor board and of clinicians that precision strategies need to be revised to improve their therapeutic effects.

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Functional Precision Medicine Provides Clinical Benefit in Advanced Aggressive Hematologic Cancers and Identifies Exceptional Responders.

Publications

Functional Precision Medicine Provides Clinical Benefit in Advanced Aggressive Hematologic Cancers and Identifies Exceptional Responders.

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