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Researchers from UC San Francisco have defined new biomarker-specific breast cancer subtypes for high-risk patients, as part of the I-SPY 2 trial. The subtypes reflect responsiveness to drug treatments and should help guide targeted therapy. The team also determined that the best subtyping schemas incorporate immune, DNA repair, luminal, and HER2 phenotypes.

Their findings were recently published in Cancer Cell.  The senior authors are Laura Esserman, MD, Co-Director of the UCSF Breast Oncology Program and Director of the UCSF Breast Care Center, and Laura van’t Veer, PhD, Co-Director of the UCSF Breast Oncology.

“The past ten years of treating patients within the I-SPY program has taught us that the standard biomarker tests that we use today do not allow us to optimize treatment for our patients,” said Esserman, I-SPY 2 principal investigator.

The I-SPY 2 (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis) does comprehensive multi-omic molecular characterization of all tumors and the diverse array of drugs targeting different molecular pathways. Using this approach, the researchers were able to create breast cancer subtypes to match current treatments. They found they could improve treatment efficacy and patient outcomes, particularly by using immune, DNA repair, luminal, and HER2 phenotypes.

The I-SPY2-990 mRNA/phospho-protein Data Resource contains data from nearly 1000 patients who participated in 10 arms of the I-SPY 2 TRIAL. Researchers evaluated 27 predictive I-SPY 2 qualifying biomarkers which led to the development of a response-predictive subtyping schema for prioritizing therapies. They used gene expression, protein levels and response data from 10 drug-arms of the I-SPY2 neoadjuvant trial to create new breast cancer subtypes that incorporate tumor biology beyond clinical hormone-receptor (HR) and HER2 status.

“Use of these response predictive subtypes can be used to guide treatment prioritization, will increase response, and will revolutionize the way in which physicians treat their patients” said van’t Veer, lead scientist for the I-SPY 2 biomarker studies.

The triple negative, as well as the HER2 negative hormone receptor positive high-risk groups, are divided into three different response predictive subtypes while the HER2 positive groups are divided into two response predictive subtypes. The researchers demonstrated that using the subtype schema, which represents several drug targetable pathways, allows more appropriate classification of tumors and is an improvement over current standard methods.

A Novel Trial Model

Rather than the traditional ‘one drug, one disease’ model for drug development, I-SPY 2 is a ‘platform’ trial. It evaluates multiple drugs (or combination of drugs) in parallel with the goal of determining which drugs work best in various types of breast cancer. The trial is sponsored by Quantum Leap Healthcare Collaborative (QLHC).

The I-SPY 2 network will prospectively test the response-predictive subtyping schema in I-SPY2.2, an upcoming version of the I-SPY2 trial that incorporates a sequential multiple assignment randomize trial (SMART) scheme and adapts treatment within individual patients based on biology and response.

The team also announced that the I-SPY2-990 mRNA/RPPA Data Resource will be publicly available. This database contains gene expression, protein/phosphoprotein, and clinical data, including HR, HER2, and MP status, for the patients included in the analysis.

“This dataset will be an invaluable resource to the breast cancer research and drug development community, and ultimately to patients,” said Esserman.


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