Biomarkers: Breast Cancer – Daniel Rotroff SABCS 2022 GENIE Trial
What will help identify (biomarkers) genetics and inflammatory markers that predict chemotherapy-induced peripheral neuropathy? So the GENIE Study aims to develop biomarkers for peripheral neuropathy in patients treated with taxane chemotherapy for breast cancer patients. Peripheral neuropathy occurs in about 70% of patients with breast cancer.
They’re treated with taxanes. Most of those patients will have relatively mild symptoms that resolve shortly after their infusion. But in a subset of patients, those symptoms can be pretty severe. And in some patients, that can also persist for months or even years after they complete their chemotherapy.
And so these patients have symptoms ranging from numbness or tingling in their fingers and their feet to what is sometimes described as a burning sensation, and it can be pretty severe and debilitating for some patients. And it is one of the primary dose-limiting toxicities for taxane chemotherapy.
And what we wanna do is develop biomarkers that can predict which patients are at risk of developing peripheral neuropathy with taxanes so that we can predict those patients risk assessment and clinical decisions can be made around whether that’s the most appropriate therapy for them, or maybe they need a different dose to start out with to try to make sure that they can stay on their treatment that’s going to be the most effective for them (treatment response).
Our study is unique in the aspect that we’re doing multi-omic analysis. So we’re actually collecting blood samples from patients prior to the initiation of their chemotherapy. During and after their chemotherapy, we’re using 6 different omics technologies and using machine learning to identify the best combination of markers that can most accurately identify which patients are at a higher risk.
What are the most common questions you are asked by your colleagues about this study?
I think the most common question that we get asked is, “Why are we collecting blood samples, like during and after the chemotherapy is initiated?” Since ideally, we want to look at blood samples prior to the initiation of the air chemotherapy. And that’s one of the really interesting aspects of this study.
So not only are we collecting data prior to the initiation of treatment. So we can predict which patients are at risk that haven’t been treated yet. But we’re also looking to develop treatment biomarkers because we believe that there might be molecular signatures that only become present once the induction of chemotherapy has been initiated.
And so there could be patients that we can’t identify prior to their treatment starting but there might be other patients where once they receive their chemotherapy, it kicks off a molecular cascade that then might be indicative as a leading indicator of then developing neuropathy in the near future.
And so we’re looking to develop, both pre-treatment and on-treatment biomarkers. And then our post-treatment biomarker, or the post-treatment measurements we’re doing is to monitor the changes in (many) biomarkers as those symptoms resolve in patients. because we think that biomarkers that are changing both with increasing and decreasing symptoms are probably more likely to be causally related to the underlying disorder. And so we’re hoping that’s going to help us develop even more robust, biomarkers.
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6 Key Takeaways on the GENIE Clinical trial in Biomarkers
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Taxanes are a type of chemotherapeutics commonly used to treat breast and ovarian malignancies, among others. Taxane-induced peripheral neuropathy (TIPN) affects the quality of life during and after therapy for up to 70% of patients.
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Although certain patients may have a genetic propensity for chemotherapy-induced peripheral neuropathy, genetic indicators have proven inconsistent in their ability to predict this condition (CIPN). In addition, various molecular markers (e.g., metabolites, mRNA, miRNA, and proteins) may be informative for predicting CIPN, although they have not been thoroughly investigated.
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We began the Genetics and Inflammatory Markers for CIPN (GENIE) research to explore this clinical gap in identifying patients at risk for TIPN. This longitudinal, multicenter observational study evaluates genetic variation, metabolites, DNA methylation, gene expression, and circulating cytokines/chemokines in 400 breast cancer patients prior to, during, and after taxane treatment.
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Prior research efforts concentrated on specific substances, pathways, or cells of interest; however, modern -omics methods, such as metabolomics, proteomics, and epigenetics, provide a broader analysis of complex biological system.
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This project aims to enable early detection of individuals at risk for developing TIPN, give a tool to adapt taxane treatment to reduce morbidity from TIPN, and enhance patient quality of life.
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Model Development Overview To find the appropriate set of biomarkers to include in the multimodal TIPN biomarker signature, different ways to analyse data from a repeated measures research will be implemented. We anticipate a massive, high-dimensional data set containing multiple genetic, epigenetic, transcriptomic, and metabolic parameters from hundreds of patients across time using this methodology.
Will this data affect clinicians today?
So this clinical research is still pretty early. We’re about halfway through our enrollment. We have some really promising preliminary data that shows that we’re about 84% accurate at predicting which patients will develop moderate to severe neuropathy. But we still have a lot of work to do to fine tune our models.
We have plans for doing an independent validation so we’ll be able to really rigorously vet the accuracy and the performance of our biomarker signature. And then we have plans to commercialize this, where we will work with a company to develop point of care testing so that this can be actually implemented in the clinic and be made widely available to the many breast cancer patients that are receiving this type of chemotherapy.
Unfortunately, it’s not ready yet, but we are hoping that in the near future we’ll have something that’ll help translate into the clinic.
What is the next step for this research?
So the next step is that we’re going to be continuing our enrollment. And we are adding some additional omics platforms to it. So we’re going to be doing some additional molecular (biomarkers) characterization. We’re going to continue to fine tune our models, and we have plans for an independent validation. And that’s really the next step, which is to validate our initial findings to make sure that they’re rigorous and will actually work with the accuracy we expect when they’re applied to new patients coming in.
What are the key takeaways from this research and data?
I think the key takeaways are that this multi-omics approach can be really effective at developing a more comprehensive picture of the patient’s current disease state and that identifying, through multiple different technologies, converging ideas that sort of converge on single pathways can be really powerful.
And we’ve seen that with our initial data so far. Multiple omics that sort of converge on a single pathway. We can tend to find more robust signatures and even in fewer, smaller subsets of patients than we would otherwise need to enroll if we were only looking at a single technology.
So I think one of the big takeaways is, to really think about using these more comprehensive approaches to characterize patients because there’s a lot more information that can be gleaned.
Final Thoughts
I think that there’s a lot of promise in oncology for using precision medicine and targeted therapies. And a lot of the new technologies for sequencing are really changing the landscape for how cancer is treated. However, there are a lot of barriers along the way, not just the sequencing and the interpretation, but also just access to those tests and breaking down barriers in the clinic to make sure those tests are available and properly interpreted for patients.
And so there’s We need not only the research aspects in discovering these, but we also need innovation all the way down the line to making sure that those results are interpreted and made available. Clinical decisions can be made based on those results.
Daniel Rotroff, PhD, MSPH – About The Author, Credentials, and Affiliations
Daniel Rotroff, a PhD and MSPH holder, is an Assistant Professor/Staff in the Department of Quantitative Health Sciences at the Lerner Research Institute at the Cleveland Clinic. He also is involved with clinical trails, with a focus on biomarker research clinical trials.
Reference
NIH – A Multimodal Approach to Discover Biomarkers for Taxane-Induced Peripheral Neuropathy (TIPN): A Study Protocol. NIH, September 29, 2022