New biomarker classifications could improve treatment for high-risk breast cancer patients

Triple negative breast cancer cell in metaphase during cell division. Image courtesy of the National Cancer Institute

Researchers and statisticians at UC San Francisco have developed improved biomarker classifications as part of their research findings in the I-SPY 2 trial for patients with high-risk breast cancer. The new cancer response subtypes reflect responsiveness to drug treatments and aim to help clinicians be more specific in how they target therapies.

Using the full multi-omic molecular characterization of the I-SPY 2 assay (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis) of all tumors and the diverse array of drugs targeting different pathways molecules, the I-SPY 2 researchers were able to access the associated datasets to create breast cancer subtypes corresponding to modern treatments.

The researchers, whose findings were recently published online in cancer cell, show that by combining predictive biomarkers to create predictive breast cancer response subtypes, these subtypes can then be linked to the most effective modern treatments. The best subtyping schemes incorporate Immune, DNA repair, Luminal and HER2 phenotypes. Assigning treatment using these predictive response subtypes can improve treatment efficacy and patient outcomes.

I-SPY 2, sponsored by Quantum Leap Healthcare Collaborative (QLHC) which manages all collaborations between academic and industrial partners, announced that these new subtypes will progress into the next iteration of the I-SPY 2.2 trial.

Using the I-SPY2-990 mRNA/phospho-protein data resource of nearly 1000 patients who participated in 10 arms of the I-SPY 2 trial, researchers assessed 27 predictive biomarkers of I-SPY 2 qualification that led to the development of a response-predictive subtyping scheme to prioritize therapies. First authors Denise Wolfdoctorate and Christina YauPhDs, both from UCSF, used gene expression, protein levels and response data from 10 groups of drugs from the neoadjuvant I-SPY2 trial to create new subtypes of breast cancer that integrate tumor biology beyond clinical hormone receptors (HR) and HER2 status.

“Using these predictive subtypes of response can be used to guide treatment prioritization, will increase response, and revolutionize the way physicians treat their patients,” said Laura van’t VeerPhD, co-director of the UCSF Breast Oncology Program and Principal Scientist for I-SPY 2 Biomarker Studies.

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

The I-SPY 2 trial is considered the archetype of a new approach to clinical trials. Rather than the traditional “one drug, one disease” model for drug development, this is a “platform” trial. I-SPY 2 evaluates multiple drugs (or drug combinations) in parallel with the goal of determining which drugs work best in various types of breast cancer. I-SPY 2 is also designed for efficiency and speed, using an “adaptive” statistical model. Individual patient results are used to refine how investigational drugs are assigned to new patients. Due to its approach, I-SPY 2 can achieve similar results in a fraction of the time with fewer patients than traditional trials. The goal is to get the right drug to the right patient. These new predictive subtypes of response help better characterize a person’s tumor and, from there, determine whether it is likely to respond to specific treatments such as immune checkpoint blockade.

“The past ten years of treating patients through the I-SPY program has taught us that the standard biomarker tests we use today do not allow us to optimize the treatment of our patients,” said Laura EssermanMD, Co-Director of the UCSF Breast Oncology Program and Director of the UCSF Breast Care Center as well as the Principal Investigator of I-SPY 2. “The entire I-SPY team is really excited to see these results and to improve the way we target our therapies. This is an important breakthrough for patients and a clear demonstration that the I-SPY model can not only accelerate the development of new cancer treatments, but also target treatment to the patients who will benefit the most. . This means increasing the chance that a drug will lead to a cure and minimizing the use of other therapies that may not be helpful or add toxicity.

The I-SPY 2 network will prospectively test the response predictive subtyping scheme in I-SPY2.2, an upcoming version of the I-SPY2 trial that incorporates a sequential multiple-assignment randomized trial design (SMART) and tailors treatment within each patient based on biology and response.

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

ASCO presentations using response subtypes from I-SPY2 test data

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

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

Molecular Subtype to Predict Complete Pathologic Response in HER2-Positive Breast Cancer in the I-SPY2 Trial

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

About I-SPY and I-SPY 2 TRIAL

The I-SPY (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis) trial is conducted by a consortium that includes the United States Food and Drug Administration (FDA), leading academic medical centers and patient rights advocates. like Merck and other pharmaceutical and biotechnology companies.

The I-SPY 2 trial is a collaborative effort between academic investigators from 20 leading cancer research centers across the United States and Quantum Leap Healthcare Collaborative, the FDA, and the National Institutes of Cancer Biomarker Consortium. health (FNIH). The main supporters are the Safeway Foundation and the Bill Bowes Foundation.

The adaptive statistical design of the I-SPY 2 trial was developed by the pioneer principal investigators of the I-SPY trial, Laura J. Esserman, MD, MBA, and Donald A. Berry, Ph.D., Professor of biostatistics at the University of Texas MD Anderson Cancer Center and founder of Berry Consultants in conjunction with the FDA, industry, and many top academic collaborators, including the Agent Task Force Chair (Doug Yee, MD, University of Minnesota), Trial Operations Working Group Chair (Angie DeMichele, MD, University of Pennsylvania), and Biomarker Working Group Chair (Laura van ‘t Veer, Ph.D., UC San Francisco). The trial is a unique collaborative effort where more than 100 clinicians are actively engaged in conducting the trial.

The design of the I-SPY 2 TRIAL adaptive trial is based on the Bayesian predictive probability that a biological diet will be statistically superior to standard treatment in an equally randomized confirmatory trial of 300 patients. Diets that have a high Bayesian predictive probability of showing superiority in at least one of the predefined signatures drop out of the trial. Treatment regimens are discarded for futility if they have a low predictive probability of superiority over standard therapy in all signatures. A maximum total of 100 patients can be assigned to each experimental regimen. A plan can be graduated early and at any time after being assigned to 60 patients.

I SPY 2.2 incorporates a more patient-centric design and the ability to test new targeted agents without traditional first-line chemotherapy, followed by the most targeted agents by the new response predictive subtypes in the new improved design. The objective is, within the next 5 years, for 90% of high-risk patients to have a complete response (disappearance of the tumour) with targeted and less toxic combinations before surgery. This will accelerate the ability to personalize care for women with breast cancer.

About Quantum Leap Healthcare Collaborative™

The 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. Bridging the gap between research and clinical care, Quantum Leap works collaboratively with patients, University of California medical researchers, other academic centers nationwide, healthcare innovators and stakeholders – to accelerate medical learning, improve healthcare delivery, create better outcomes and improve quality of life. Our goal is to improve and save lives.

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