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AACR 2023: Taming the Wilderness Beyond the Frontiers of Oncology

As the first big U.S. pan-cancer congress of the year, the American Association for Cancer Research (AACR) annual meeting often sets the tone for the year ahead and gives a good insight into the hot research topics for that year. This year’s theme, ‘Advancing the Frontiers of Cancer Medicine’, places an important focus on progress, and how much more of it we still have to make for patients.

With that in mind, I’d like to highlight one of the studies Foundation Medicine and our collaborators are bringing to AACR this year, that has the potential to advance the current frontier.

The growing blind spot in monitoring due to advances in treatment

Current monitoring approaches and technologies can come with limitations due to cancer’s ability to make some radiologic scans ambiguous. This is particularly apparent in diseases known to metastasize to the bone, such as hormone receptor (HR) positive breast and prostate cancer. Checkpoint inhibitors as a therapeutic modality are also known to result in “pseudo-progression” in radiologic scans, that can make a cancer look like it is stable or has grown, when in reality, the inflammation is signaling the success of the therapy resulting in tumor shrinkage.

Accurate disease monitoring is a particular area ripe for disruption for the growing number of patients living with chronic cancer, due to advances in treatment extending the lifespan of some patients for decades from their original diagnosis. Monitoring can provide complementary insights to help track tumor development in real time and alter the treatment approach in line with the evolving mutations that drive tumor progression.

Survival for patients with metastatic castrate resistant prostate cancer (mCRPC) often extends into multiple decades, resulting in a situation where the archival tumor biopsy from their original diagnosis no longer represents the genomic landscape that is driving their tumor in the present day.

Prostate specific antigen (PSA) is perhaps the most widely used biomarker in prostate cancer and has been the gold standard throughout the course of the disease for over 30 years. The arrival of androgen receptor signaling inhibitors (ARSi) such as abiraterone and enzalutamide have transformed outcomes in the mCRPC and are being used at increasingly earlier stages of disease. Over time however, tumors can evolve to no longer respond to long-term ARSi therapy, resulting in treatment failure and tumor progression. PSA is a poor predictor of survival in the advanced setting, particularly in less AR-dependent disease, and there is a growing need for new tools that will enable disease progression to be identified much earlier in the patient journey, to better inform clinical response.

As part of our long-standing partnership with Genentech, we conducted a retrospective analysis of the IMbassador250 clinical trial, a prospective phase III international multicenter trial enrolling 759 men with mCRPC who had prior progression on abiraterone, with or without prior taxane, randomizing to enzalutamide +/- atezolizumab.

The aim of the retrospective analysis, which used our research whole genome methylation assay, was to determine if decreases in tumor fraction (TF), a way to measure the level of circulating tumor DNA in each blood sample, after 6 weeks of therapy would reliably predict overall survival (and thereby confirm treatment response), independent of PSA or radiographic progression.

The results confirmed this hypothesis; changes to TF provided numerically superior of overall survival compared to PSA in mCRPC patients receiving enzalutamide +/- atezolizumab in the post-abiraterone setting.

Furthermore, TF demonstrated the ability to independently predict overall survival at an earlier time point compared to radiographic progression, suggesting its potential as a new monitoring tool that could allow clinicians to detect tumor progression and alter treatment strategies earlier than through current methods.

Forging the path ahead to the next frontier

Through the introduction, development, and integration of comprehensive genomic profiling (CGP) into the clinical and research landscapes, and the growth of our world-leading genomic databases, we have remained at the leading edge of progress in oncology for more than a decade.

Key to our progress was, and still is, the ability to look past the frontier. Even as we bring new, potentially practice-changing data to AACR, we continue looking forward – pushing the boundaries of science with the goal of delivering breakthroughs that help more patients in the future.

April 11, 2023 Priti Hegde, PhD Chief Scientific Officer, Foundation Medicine

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