Sunday, September 25, 2022

New biomarker classification may improve treatment of high-risk breast cancer patients

A triple-negative breast cancer cell in metaphase during cell division. Image by National Cancer Institute

UC San Francisco research scientists and statisticians have developed improved biomarker classifications as part of their research results in the I-SPY 2 trial for high-risk breast cancer patients. The new cancer response subtypes reflect response to drug treatment and are intended to help clinicians be more precise in how to target therapies.

Comprehensive multi-omic molecular characterization of all tumors tested and drugs targeting different molecular pathways, using I-SPY 2 (Screening Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis) A diverse array of I-SPY 2 researchers were able to access related datasets to create breast cancer subtypes to match modern treatments.

The researchers, whose findings were recently published online in Cancer Cell, show that by combining predictive biomarkers to predict breast cancer subtypes, these subtypes can be matched to the most effective modern therapies. As the best subtyping schema includes immune, DNA repair, luminal and HER2 phenotypes, treatment assignment using these response predictive subtypes can improve efficacy of treatment and patient outcomes.

I-SPY 2, sponsored by the Quantum Leap Healthcare Collaborative (QLHC), which manages all collaborations between academia and industry partners, announced that these new subtest tests will move into the next iteration of I-SPY 2.2.

Using I-SPY2-990 mRNA/phospho-protein data processing from approximately 1000 patients who participated in the 10 arms of the I-SPY 2 TRIAL, researchers evaluated 27 predictive I-SPY 2 qualifying biomarkers, leading to A response-predictive subtest schema was developed for prioritizing treatments. First authors Denise Wolf, PhD, and Christina Yau, PhD, both UCSF, used gene expression, protein levels, and response data from 10 drug-arms of the I-SPY2 neoadjuvant trial to create a new breast cancer subtype, which is clinically relevant. Beyond tumor biology. Hormone-receptor (HR) and HER2 status.

Co-director of the UCSF Breast Oncology Program, Laura van te Weer, PhD, said, “These responses to predictive subtypes can be used to guide treatment priority, increased response, and the way in which physicians can use these responses.” It will revolutionize the way we treat our patients.” and lead scientist for the I-SPY 2 Biomarker Study.

The triple negative, as well as HER2 negative hormone receptor positive high-risk groups are divided into 3 different response predictive subtypes; HER2 positive groups are divided into 2 response predictive subtypes. The researchers demonstrate that the use of subtype schemas representing multiple drug targetable pathways allows more appropriate classification of tumors and is an improvement over current standard methods.

The I-SPY 2 trial is considered the epitome of a new approach to clinical trials. Instead of the traditional ‘one drug, one disease’ model of drug development, it is a ‘platform’ trial. I-SPY 2 evaluates multiple drugs (or combinations of drugs) in parallel with the goal of determining which drugs work best in different types of breast cancer. I-SPY 2 is also designed for efficiency and speed by employing an ‘adaptive’ statistical model. The results for each patient are used to refine how investigational drugs are administered to new patients. Because of its approach, I-SPY 2 can achieve similar results in a fraction of the time with fewer patients than conventional tests. Its purpose is to deliver the right medicine to the right patient. These new response predictive subtypes help to better characterize an individual’s tumor and thereby determine whether they are likely to respond to specific therapies such as immune checkpoint blockade.

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UCSF Brest co-director, Laura Esserman, said, “The past ten years of treating patients within the i-SPY program has taught us that the standard biomarker tests we use today allow us to guide the course of treatment for our patients. Do not allow customization. Director of the Oncology Program and UCSF Breast Care Center as well as I-SPY 2 principal investigator. “The entire I-SPY team is really excited to see these results and to improve the way we target our treatments. This is a significant advance for patients, and a clear demonstration that the I-SPY model is not only new Not only could it accelerate the development of cancer treatments, it could also target treatments to patients who would benefit most. This means that one drug increases the chances of a cure and reduces the use of other treatments. that may not be useful or may add toxicity.”

The I-SPY 2 network will potentially test the response-predictive subtyping schema in I-SPY2.2, an upcoming version of the I-SPY2 trial that includes a sequential multiple assignment randomized trial (SMART) scheme and treatment based on individual patients. Customizes. On biology and reaction.

The I-SPY2-990 mRNA/RPPA data resource is now publicly available. “This dataset will be an invaluable resource to the breast cancer research and drug development community, and ultimately to patients,” Esserman said.

ASCO submissions using response subtypes from I-SPY2 test data

In addition to the findings presented in this study, three abstracts to be presented this week at ASCO 2022 include the use of I-SPY data and improved response prediction by new subtype schemas within traditional breast cancer receptor subtypes. These studies include:

Pathologic Complete Response (pCR) Rates for HR+/HER2- Breast Cancer by Molecular Subtype in the I-SPY2 Trial

Molecular subtypes for predicting pathological complete response in HER2-positive breast cancer to the I-SPY2 test.

Improved pathological complete response rate for triple-negative breast cancer in the I-SPY2 trial

About I-SPY and I-SPY 2 Testing

The I-SPY (Investigation of Serial Studies to Predict Your Medical Response with Imaging and Molecular Analysis) trial is conducted by a consortium that coordinates the U.S. Food and Drug Administration (FDA), major academic medical centers, and patient advocates as a single brings together. as Merck and other pharmaceutical and biotech companies.

I-SPY 2 TRIAL is a collaborative effort between 20 major cancer research centers across the US and academic investigators from the Quantum Leap Healthcare Collaborative, FDA, and the Foundation for the National Institutes of Health (FNIH) Cancer Biomarker Consortium. Prominent supporters include The Safeway Foundation and the Bill Bowes Foundation.

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The adaptive statistical design of the I-SPY 2 TRIAL was developed by the lead investigators for the I-SPY trial, Laura J. Esserman, MD, MBA, and Donald A. Berry, PhD, professor of biostatistics at the University. Several key academic collaborators, including Texas MD Anderson Cancer Center and FDA, founder of Berry Consultants in collaboration with industry, and Agents Working Group Chair (Doug Yee, MD, University of Minnesota), Trial Operations Working Group Chair (Angie DeMichel). MD, University of Pennsylvania), and Biomarkers Working Group Chair (Laura van t Weer, PhD, UC San Francisco). The trial is a unique collaborative effort where more than 100 clinicians are actively engaged in conducting the trial.

The I-SPY 2 TRIAL adaptive-trial design is based on the Bayesian predictive probability that an organic regimen will be shown to be statistically superior to standard therapy in an equally randomized 300-patient confirmatory trial. Regiments with a high Bayesian predictive probability of showing superiority in at least one of the predefined signatures graduated from the test. Regimens are discarded to futility if they show a low predictive probability of showing superiority over standard therapy across all signatures. A maximum total of 100 patients can be assigned to each experimental regimen. A regimen can be graduated quickly and at any time after 60 patients are assigned.

I SPY 2.2 includes a more patient-centered design and the ability to test new targeted agents without conventional chemotherapy as a first line, followed by new and improved design to rank the most targeted agents by new response predictive subtypes. The goal, over the next 5 years, is to have 90% of high-risk patients experience a complete response (disappearance of the tumor) with targeted and less toxic combinations prior to surgery. This will accelerate the ability to personalize care for women with breast cancer.

Quantum Leap Healthcare Collaborative™ . about

I-SPY 2 TRIAL is sponsored by Quantum Leap Healthcare Collaborative™, a 501c(3) charitable organization. Quantum Leap is dedicated to integrating high-impact clinical research with patient care to improve and save lives. By bridging the gap between research and clinical care, Quantum Leap works in collaboration with patients, medical researchers from the University of California, other academic centers nationwide, healthcare innovators and stakeholders – to accelerate learning in medicine. To improve the delivery of healthcare. Better outcomes, and increased quality of life. Our goal is to improve and save lives.

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