2020 Therapeutic Resistance Including Serial Biopsy, Rapid Autopsy and Blood-based Biomarkers Platforms

Dejan Juric, MD, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA

Fellow Summary

Authored by Tanya Keenan

Dr. Juric led an inspiring session about discovering therapeutic resistance with serial biopsies, rapid autopsies, and blood-based biomarkers. The key learning points he discussed are outlined below:

  • Make it real by finding the reasons that make you excited and passionate.
  • Don’t make yourself busy – make yourself effective.
  • Precision oncology means having the right treatment for the right patient at the right time.
  • PIK3CA is both a biomarker and a target.
    • It is not an oncogene or a tumor suppressor.
    • Instead, it acts as an amplifier. It is similar to a gas pedal in a car that requires a foot to push it to make a car go.
    • PTEN loss is also needed, and two PIK3CA mutations provide even more gas.
    • The important question to always ask is: what else is going on?
  • Alpelisib alone did not have the same waterfall plot as BRAF inhibitors.
    • PI3K inhibition in ER-positive tumors led to increased ER.
    • Dual inhibition with an estrogen blocker, namely a SERD that inhibits ER and not just estrogen, was required for efficacy.
    • ORR as an endpoint does not matter as much in breast cancer. PFS and OS are much more important.
  • Sequencing of therapies is so poorly studied but very important in drug development.
  • Liquid biopsies are better at detecting acquired resistance and tumor heterogeneity than tissue biopsies.
  • Rapid autopsies allow the combination of multiple tissue and blood biopsies that facilitate scientific discovery.
    • Align stakeholders and get funds by making yourself look bigger than you are.
      • Listing connections on a website will attract more people to work for your program.
      • All you need to start a program is a colleague.
    • Acquired PTEN loss mediates cross-resistance to both CDK4/6 inhibitors and PI3K-alpha inhibitors.
      • PTEN loss is a cross resistance marker indicating that second line therapy with alpelisib will likely not work.
      • Don’t study just resistance. Instead study cross-resistance, specifically why later lines of therapy work less effectively.
      • PTEN loss leads to AKT activation and p27 sequestration, resulting in increased CDK2 activity, which compensates for CKD4/6 inhibition.
        • CDK2 phosphorylates Rb to drive resistance.
        • Lose PTEN protein only without a DNA change, and RNA is still expressed in some.
        • CDK4/6 inhibitor, PI3K inhibitor, and SERD together lead to better responses.
  • Think of yourself as faculty and not junior faculty, as the latter will limit what you think you can do.