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

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


Fellow summary authored by Jamie Schneider, MD, PhD

Dr. Dejan Juric gave a compelling presentation on therapeutic resistance, rapid autopsy, and blood-based biomarker platforms. He focused on the interplay between preclinical scientific studies and the early clinical testing space, highlighting the importance of thinking critically about the target, biomarker, and disease selection. Thought-provoking concepts were also raised around whether early-phase clinical testing should be carried out in disease-specific or disease-agnostic contexts and how to think about restricting patient populations by biomarker selection in early-phase clinical testing.

Dr. Juric emphasized that precision oncology means developing the right treatment for the right patient at the right time. In particular, he gave an update on the precision oncology efforts carried out in the space of targeting PIK3CA mutations in advanced breast cancer. PI3K signaling regulates a broad range of cellular functions and its aberrant activation is among the most common oncogenic events across cancer types.

PIK3CA mutations mimic and enhance dynamic events during natural activation of PI3K. The level of activation depends on the specific type of mutation, underscoring the need for meticulous consideration of mutation type identified by molecular genotyping panels performed on patients. For instance, certain PIK3CA mutations such as H1047R have a greater effect in changing basal activity of the target while other mutations impact different aspects of catalytic activity. He reviewed that double mutations in cis activate PIK3CA through a combination of protein disrupter membrane binder mechanisms. Preclinical data showed mammary gland-specific expression of PIK3CA H1047R mutations induce tumors in vivo, thus spurring further interest in clinical development of isoform-specific PIK3CA inhibitors for early phase clinical testing.

Dr. Juric also discussed the differential effects of PI3K inhibitors in solid tumors, highlighting the need for iterative development of increasingly select inhibitors that are isoform- or mutation-specific. He reviewed the data from pre-clinical and early clinical studies on the FDA-approved PIK3CA inhibitor alpelisib. Other PI3K small molecule inhibitors are also in development, some of which are isoform-specific against alpha or beta isoforms, and some of which are mutant-specific (e.g. H1047R). The first-in-human trial of alpelisib in PIK3CA-altered solid tumors was a basket trial with model response rates.

Dr. Juric stressed that follow-up on this initial trial was critical to understand the biology underlying why some patients did respond while others did not. He emphasized that starting with clinical annotations and moving to comparative molecular analyses was critical in identifying etiologies of why certain patients respond. His team identified that PI3K mutant tumors have complex genomic landscapes with frequent co-occurrences of multiple oncogenic drivers and that dual inhibition with an estrogen blocker was required for efficacy. Combination regimens of ER + PI3Ka inhibition with alpelisib + fulvestrant significantly enhanced response rates, prompting moving from phase 1 directly to randomized phase 3 testing in the SOLAR-1 trial. As anticipated, the SOLAR-1 trial met its primary endpoint of PFS with the combination regimen (compared to placebo + fulvestrant). Interestingly, results from this study were published around the same time that CDK4/6 inhibitors were shown to have a marked OS benefit, clouding the optimal incorporation of PI3K inhibitors in either the first-line or later. He emphasized the importance of considering how new treatments fold into the current therapeutic landscape and how the landscape changes quickly, necessitating the reworking of sequencing of treatments. More work is underway in elucidating sequencing and combinations of CDK4/6, PI3K, and mTOR inhibitors in conjunction with endocrine therapy.


STOFF 2024 Button


Privacy Policy | Terms of Use | Contact Us

Society for Translational Oncology (STO) is a 501(c)(3) not-for-profit organization.