Science at the Interface Between the Laboratory and the Clinic
Ryan Corcoran, MD, PhD, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA
Fellow Summary
Authored by Brian Grieb
Dr. Corcoran explored two themes to improve patient care during his presentation. First, we were encouraged to identify mechanisms of resistance. Dr. Corcoran compared the targeting of BRAF mutations in melanoma and colorectal cancer (CRC). In this pathway, mutant BRAF activates MEK, which in turn phosphorylates ERK, leading to proliferation and cell survival signaling. While patients with BRAF mutant melanoma demonstrate a 50% response rate (RR) to BRAF inhibitors, CRC patients display a RR of only 5%. However, upon analysis of pre- and post-treatment patient biopsies, CRC samples had increased downstream pERK expression post-treatment compared to melanoma. This stems from the observation that in CRC, pERK provides negative feedback signaling to EGFR, which can activate BRAF through activation of RAS. As such, loss of physiologic EGFR inhibition by pERK drives BRAF inhibitor resistance in CRC. Targeting of both BRAF and EGFR in mutant BRAF CRC xenografts demonstrated synergy. When a similar strategy was implemented in human trials, the RR improved from 5% with BRAF inhibition to 15% with dual inhibition. Addition of a MEK inhibitor for triple inhibition of the pathway further improved the RR to 32%. As such, persevering to understand resistance to a viable drug target can produce clinical benefit.
The second theme of Dr. Corcoran’s talk focused on the clinical applications of circulating tumor DNA (ctDNA) analysis. Simply knowing a mechanism of resistance in theory is not enough. Genetic mutations that enable resistance must be detected; however, both intralesional and interlesional heterogeneity decrease the sensitivity of single needle biopsy. Analysis of ctDNA, or “liquid biopsy”, can be employed to overcome geographic heterogeneity and increase sensitivity. As an example, 18 of 23 patients with a single post-progression needle biopsy had additional resistance-enabling mutations identified by analysis of ctDNA.
Merely detecting the presence or absence of ctDNA reliably may also prove to be clinically important. In stage II CRC, 10-15% of patients will recur following curative-intent surgery, but adjuvant chemotherapy is not standard of care. If a personalized ctDNA mutational assay crafted from genetic aberrations found within the resected primary CRC possessed a high enough sensitivity and specificity, could this test be used to identify post-surgical stage II patients who would benefit from adjuvant chemotherapy? The NRG-GI005 clinical trial seeks to answer this important question. In the trial, patients with stage IIA CRC are randomized to current standard of care with active surveillance or ctDNA assay-directed therapy. Furthermore, the Stand Up to Cancer CRC Dream Team is deploying a clinical trial in stage III CRC patients post-adjuvant mFOLFOX to determine if those with persistent ctDNA would benefit from continued adjuvant therapy.
Whether as a method to detect mechanism of resistance in genetically heterogeneous cancers or as a means to refine the delivery of adjuvant therapy in stage II/III CRC, analysis of ctDNA will surely be a driving force in translational oncology in the years to come.
Fellow Summary
Authored by Everett Moding
Novel approaches to analyze human samples have accelerated the transition between bench and bedside, enabling new insights into the mechanisms of therapeutic efficacy and resistance. Dr. Corcoran focused on colorectal cancer to describe how preclinical discoveries can be translated to the clinic and how we can learn from therapies that ultimately fail in clinical trials.
Innate resistance remains a common issue that limits the efficacy of targeted treatments. However, it is important to tease apart the reason for lack of efficacy when therapies fail, because these insights can inspire the next generation of treatments. For example, the success of MAPK pathway inhibitors in BRAF mutant melanoma led to significant excitement about this target in BRAF mutant colorectal cancer. However, BRAF inhibitor monotherapy led to an overall response rate of only 5% in colorectal cancer. By analyzing pre-treatment and on-treatment tumor biopsies, it became clear that monotherapy or even dual BRAF/MEK blockade failed to fully inhibit MAPK signaling. However, combining BRAF, MEK, and EGFR inhibition helped to overcome innate resistance and achieve response rates of 30%.
In patients who initially respond to targeted therapies, acquired resistance can ultimately lead to cancer relapse. As a result, understanding the mechanisms of acquired resistance could enable more durable therapeutic strategies. One important underlying mechanism of resistance is tumor heterogeneity, which can lead to clonal evolution and the emergence of resistant tumor subclones during targeted therapy. Liquid biopsies offer a unique insight into the heterogenous resistance mechanisms that tumors can develop during therapy. Because circulating tumor DNA, tumor cells, and exosomes can be shed from all of the tumors within a patient, liquid biopsies better characterize tumor heterogeneity than traditional tissue biopsies. For example, circulating tumor DNA identified additional resistance mechanisms in 78% of patients with colorectal cancer over traditional tissue biopsy alone. Importantly, circulating tumor DNA may enable the identification of emerging resistance mechanisms real-time to guide adaptation of therapy during treatment.
Beyond identifying mechanisms of resistance, liquid biopsies are novel tools to assess minimal residual disease in localized cancer. Detection of circulating tumor DNA requires highly sensitive and specific techniques, but several studies have demonstrated that circulating tumor DNA can predict relapse after curative treatment for solid tumors such as colorectal cancer. Most clinical trials assign all patients to adjuvant therapy or placebo despite the fact that the majority of patients with localized disease are often cured by surgery or radiation therapy. Because circulating tumor DNA can identify patients with minimal residual disease that cannot be seen on imaging, liquid biopsies have the potential to revolutionize the treatment of localized cancer by selecting patients who could benefit from adjuvant therapy. Clinical trials are currently underway testing the viability of this approach in stage II and III colon cancer.
Fellow Summary
Authored by Yonina Murciano-Goroff
Dr. Corcoran’s fascinating talk on “Science at the Interface between the Laboratory and the Clinic” was divided into three sections.
In the first section, he discussed the challenges of understanding how therapies alter tumor biology. He posited that therapies tend to fail for one of several reasons: either the target is inappropriately credentialed or perhaps is only important for a subset of patients; the drug achieves insufficient concentrations or was otherwise ineffective at inhibiting the target; or the therapeutic index was not wide enough to allow tolerability. Dr. Corcoran emphasized that in the event of a negative trial, it is critical to keep an open mind about which of these biologic explanations have yielded the unexpected clinical results. He highlighted his experiences in elucidating the biology of the MAPK pathway in colorectal cancers. As he explained, dual BRAF/MEK blockade is now a standard of care for BRAF V600E mutant melanoma, but it is unfortunately much less effective in BRAF V600E mutant colorectal cancer. While initial hypotheses focused on whether colorectal cancer was less MAPK pathway addicted than melanoma, biopsies from patients on trial at day 15 showed inadequate suppression of the pathway in response to BRAF/MEK inhibition. This led to the hypothesis that perhaps colorectal cancers are highly addicted to the MAPK pathway, but reactivation of the pathway through RTKs needs to be blocked to effectively suppress growth. Triple therapy with the addition of an EGFR inhibitor has increased response rates, though more work is still needed.
The second section of Dr. Corcoran’s talk focused on therapeutic resistance. He discussed one of the challenges faced by precision oncology, the diversity of mechanisms of primary and acquired resistance that can develop. He discussed strategies, such as “convergent” inhibition downstream of several resistance mechanisms, to try to overcome resistance. Dr. Corcoran then emphasized that not only can there be multiple resistance mechanisms in different patients, but there can be inter- and even intra-lesional heterogeneity. Liquid biopsy constitutes a valuable means of circumventing the challenges of such heterogeneity and can be more useful than invasive biopsies in this regard.
In the final section of his thought-provoking talk, Dr. Corcoran transitioned to discussing “molecular diagnostics to transform therapy.” In addition to using liquid biopsies to detect mechanisms of resistance and guide treatment options, Dr. Corcoran highlighted his and Dr. Chabner’s work on using cfDNA to guide assessment of minimal residual disease in solid tumors. He explained that with sensitive and specific assays, it is possible that we will be able to detect patients in need of additional therapeutic intervention at an earlier, potentially curable stage and spare other patients from unnecessary therapies.
Dr. Corcoran’s talk concluded with a vision for translational oncology, uniting bench and bedside to alter how trials are conducted and how specimens from them are analyzed to maximize progress in the field.
Fellow Summary
Authored by Kenji Tsuchihashi
In Dr. Corcoran’s talk, he focused on three important topics regarding science at the interface between the laboratory and the clinic.
1. The importance of understanding the effects of therapy in the tumor
2. The need to overcome therapeutic resistance
3. The role of molecular diagnostics in transforming therapy
Firstly, he described the following four reasons for failure of targeted therapies: 1. wrong target, 2. target important only in a subset of patients, 3. drug does not achieve sufficient exposure at tolerable levels, and 4. drug does not effectively inhibit target despite adequate exposure. He presented BRAF mutant colorectal cancer (BRAF mt CRC) as the example of “drug does not effectively inhibit target despite adequate exposure” and also showed its overcoming strategy. The response rate of BRAF inhibitor for BRAF mt CRC is low, with a rate of 5%. pERK is activated after the exposure to BRAF inhibitor. Combined BRAF and MEK inhibition increases response rate to 12%. Further, the addition of inhibition of EGFR, which is the upstream of RAS-RAF-MEK, effectively suppresses reactivation of pERK and increases response rate to > 30%.
Second, he presented an overview of resistance mechanisms regarding targeted therapy. Acquired resistance means the disease progression after response. He showed the example of BRAF mu CRC treated with combination of BRAF and MEK inhibition. Diversity of resistance were detected by the comparison of pre-treatment and post-treatment tumor tissue. He next described the importance of considering interlesional and intralesional tumor heterogeneity when tackling acquired resistance. Liquid biopsy is effective for identifying the heterogeneous resistance mechanism. He finally proposed the treatment strategy based on real-time assessment of resistance mechanism by liquid biopsy.
Third, he showed the utility of liquid biopsy for detecting residual disease after surgery or surgery plus adjuvant chemotherapy by sequencing tumor DNA and plasma ctDNA. He showed the data of predicting relapse in stage II CRC. The existence of post-operative ctDNA predicted the recurrence better than clinical risk factors or post-operative CEA level. Based on these findings, he introduced the following two clinical trials: Phase II/III study of ctDNA as a predictive marker for response to adjuvant chemotherapy in patients with stage II colon cancer, and Identification and treatment of micrometastatic disease in Stage III colon cancer.
In summary, understanding resistance mechanisms may guide strategies to overcome resistance. Assessing the actual impact of therapies on target tissues can provide insight into efficacy. Serial clinical specimens to monitor the effects of therapy are critical to fuel discovery. Applying emerging technologies to key clinical specimens can accelerate therapeutic development.
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