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Purpose: Molecular diagnostics including next generation gene sequencing are increasingly used to determine options for individualized therapies in brain tumor patients. We aimed to evaluate the decision-making process of molecular targeted therapies and analyze data on tolerability as well as signals for efficacy.
Methods: Via retrospective analysis, we identified primary brain tumor patients who were treated off-label with a targeted therapy at the University Hospital Frankfurt, Goethe University. We analyzed which types of molecular alterations were utilized to guide molecular off-label therapies and the diagnostic procedures for their assessment during the period from 2008 to 2021. Data on tolerability and outcomes were collected.
Results: 413 off-label therapies were identified with an increasing annual number for the interval after 2016. 37 interventions (9%) were targeted therapies based on molecular markers. Glioma and meningioma were the most frequent entities treated with molecular matched targeted therapies. Rare entities comprised e.g. medulloblastoma and papillary craniopharyngeoma. Molecular targeted approaches included checkpoint inhibitors, inhibitors of mTOR, FGFR, ALK, MET, ROS1, PIK3CA, CDK4/6, BRAF/MEK and PARP. Responses in the first follow-up MRI were partial response (13.5%), stable disease (29.7%) and progressive disease (46.0%). There were no new safety signals. Adverse events with fatal outcome (CTCAE grade 5) were not observed. Only, two patients discontinued treatment due to side effects. Median progression-free and overall survival were 9.1/18 months in patients with at least stable disease, and 1.8/3.6 months in those with progressive disease at the first follow-up MRI.
Conclusion: A broad range of actionable alterations was targeted with available molecular therapeutics.
However, efficacy was largely observed in entities with paradigmatic oncogenic drivers, in particular with BRAF mutations. Further research on biomarker-informed molecular matched therapies is urgently necessary.
Purpose: The WSG-PRIMe Study prospectively evaluated the impact of the 70-gene signature MammaPrint® (MP) and the 80-gene molecular subtyping assay BluePrint® on clinical therapy decisions in luminal early breast cancer.
Methods: 452 hormone receptor (HR)-positive and HER2-negative patients were recruited (N0, N1). Physicians provided initial therapy recommendations based on clinicopathological factors. After prospective risk classification by MammaPrint/BluePrint was revealed, post-test treatment recommendations and actual treatment were recorded. Decisional Conflict and anxiety were measured by questionnaires.
Results: Post-test switch (in chemotherapy (CT) recommendation) occurred in 29.1% of cases. Overall, physician adherence to MP risk assessment was 92.3% for low-risk and 94.3% for high-risk MP scores. Adherence was remarkably high in “discordant” groups: 74.7% of physicians initially recommending CT switched to CT omission following low-risk MP scores; conversely, 88.9% of physicians initially recommending CT omission switched to CT recommendations following high-risk MP scores. Most patients (99.2%) recommended to forgo CT post-test and 21.3% of patients with post-test CT recommendations did not undergo CT; among MP low-risk patients with pre-test and post-test CT recommendations, 40% did not actually undergo CT. Luminal subtype assessment by BluePrint was discordant with IHC assessment in 34% of patients. Patients’ State Anxiety scores improved significantly overall, particularly in MP low-risk patients. Trait Anxiety scores increased slightly in MP high risk and decreased slightly in MP low-risk patients.
Conclusions: MammaPrint and BluePrint test results strongly impacted physicians’ therapy decisions in luminal EBC with up to three involved lymph nodes. The high adherence to genetically determined risk assessment represents a key prerequisite for achieving a personalized cost-effective approach to disease management of early breast cancer.