Science at the Interface Between the Lab and the Clinic
Ryan Corcoran, MD, PhD, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA
Authored by Tyler Stewart, MD, Yale New Haven Hospital, New Haven, Connecticut, USA
Understanding the effects of therapy in the tumor
Dr. Corcoran started his lecture discussing the importance of understanding the effect of therapeutics in the disease of interest. He presented data demonstrating the success of BRAF inhibitors in BRAF-mutant melanoma (MM) with response rates > 50%, yet only 5% in BRAF-mutant colorectal cancer (CRC). He further discussed the science behind the difference in response rates, including that in vitro, BRAF inhibitors do not suppress pERK as effectively in CRC as MM. Importantly, even with the addition of a MEK inhibitor, the combination of a BRAF and MEK inhibition does not suppress pERK as well as single agent BRAF inhibition in MM cell lines. The discussion led to the importance of looking at entire pathways, and in this case, the EGFR-BRAF-MAPK pathway. Studies have suggested that BRAF inhibitors are associated with a concurrent upregulation of EGFR which may drive resistance in an adaptive feedback pathway. Preclinical studies with combination BRAF and EGFR inhibitors and BRAF, MEK, and EGFR inhibitors have shown synergy and may overcome this adaptive resistance. And indeed clinically, when the three-agent combination was tested in the clinic, the combination did show a higher response rate (32%) over the single agent BRAF inhibitor (5%) and dual agents BRAF and MEK inhibitors (12%) and BRAF and EGFR inhibitors (15%).
Overcoming therapeutic resistance
The discussion then turned to overcoming resistance. Dr. Corcoran first described the difference between primary and secondary resistance. He then described multiple mechanisms of resistance that have been reported in BRAF-mutant CRC to BRAF inhibitors, including EGFR and MET amplification, KRAS amplification and mutation, NRAS mutation, BRAF amplification, and MEK1 and MEK2 mutations. Importantly, given tumor heterogeneity, multiple mutations are likely to be seen within one individual and even within each specific tumor site. Again, going back to understanding the pathway, he described methods to overcome multiple resistance mechanisms within a single individual. Given that many of the upstream resistance patterns lead to upregulation of the EGFR-BRAF-MAPK pathway, finding a target downstream of all of these may be a method to overcome multiple resistance mechanisms. One potential target would be to directly inhibit ERK with ERK inhibitors, which are now being studied. Further, we discussed mechanisms to identify resistance patterns in individuals such as using circulating tumor DNA (ctDNA). CtDNA may be used at the time of progression to identify multiple resistance patterns (rather than limiting this to a single biopsy), and may provide information to guide further therapy.
Molecular diagnostics to transform therapy
Lastly, Dr. Corcoran dived into discussing ways to use molecular diagnostics to guide therapy. The discussion mainly revolved around using ctDNA in two ways. First, he discussed the use of ctDNA as an early marker for response to therapy. He showed data suggesting that the use of ctDNA at 4 weeks of therapy may predict response to therapy. Thus ctDNA may be used early in treatment to identify patients not likely to respond to the prescribed therapy and to alter treatment earlier, avoiding the toxic effects of the therapy and moving to a more beneficial option. Second, Dr. Corcoran discussed the use of ctDNA to identify individuals who may most benefit from adjuvant therapy. He showed data to suggest that ctDNA is likely a better predictor of risk of relapse than either clinical risk factors or post-operative CEA and discussed a clinical trial which uses ctDNA to identify individuals to receive adjuvant therapy.
Authored by Nirmish Singla, MD, University of Texas Southwestern Medical Center, Dallas, Texas, USA
In this interesting session, Dr. Corcoran discussed the integration of laboratory and clinical research to accelerate advances through three main topics: understanding the effects of therapy in the tumor, overcoming therapeutic resistance, and molecular diagnostics to transform therapy.
First, why do therapies fail? Possible reasons include selecting the wrong target, selecting a target that is important only in a subset of patients, insufficient drug exposure at tolerable levels, or lack of effective target inhibition despite adequate drug exposure. The spectrum of primary versus secondary (acquired) resistance involves a ratio between target alterations and resistance alterations. Selection of the latter in the setting of an initially lower ratio may result in initial response followed by selection of these resistant alterations (secondary resistance).
What are some common mechanisms of resistance? These include target alteration, adaptive, and bypass/escape pathways. Understanding tumor heterogeneity may shed light on further elucidating acquired resistance. In particular, there can be interlesional heterogeneity between distinct metastatic lesions or intralesional heterogeneity within a single metastatic lesion. With these considerations, traditional tissue-based single needle biopsies of tumors carry the risk of undersampling and may vastly underrepresent the overall molecular heterogeneity of a patient’s malignancy. In this context, liquid biopsies may play a growing role, as they provide the ability to detect alterations in circulating tumor DNA (ctDNA) shed by tumor cells throughout the body. As next-generation sequencing technologies continue to evolve and improve on the sensitivity and specificity of ctDNA detection, liquid biopsies may shed light on understanding polyclonal evolution of resistance and heterogeneity during therapy. Emerging applications of ctDNA in guiding therapy may include systematic liquid biopsy collection during targeted therapy or real-time ctDNA monitoring for early prediction of therapeutic response.
Detection of residual disease is a big problem in treated localized tumors, and ctDNA may play a revolutionary role. In theory, the presence of ctDNA following surgery with curative intent may help a clinician determine whether or not a patient has been effectively “cured.” A pragmatic approach may entail sequencing the resected tumor to identify one or more mutations present and subsequently sequencing the plasma by developing a personalized mutation-specific assay for ctDNA detection. As a urologic oncologist, my interest has been primarily in the domain of kidney cancer, and for patients with locally advanced disease (with an historic 30% recurrence rate at 3 years following surgery with curative intent), understanding the optimal sequence of surgery and systemic therapy in a risk-stratified approach has the potential to improve the oncologic outcomes in many of these patients.
In conclusion, 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. And finally, applying emerging technologies to key clinical specimens can accelerate therapeutic development.
Authored by Jonathan Chou, MD, PhD, University of California San Francisco, San Francisco, California, USA
Dr. Corcoran’s talk on science at the interface between the lab and the clinic focused on three important translational oncology themes:
- The need to understand the effects of therapy on tumor;
- The need to understand therapeutic resistance; and
- The need for molecular diagnostics that can potentially transform cancer therapy.
In the first theme, Dr. Corcoran described his work on using BRAF inhibitors in BRAF-mutated colon cancer, where there was a 5% response rate; this rate stood in contrast to BRAF-mutated melanoma, where there was a >50% response rate. He emphasized the importance of taking that observation and understanding the reasons. What was different about the biology of colon cancer versus melanoma? Through a series of studies, Dr. Corcoran and his team showed that vemurafenib treatment in colon cancer cells was not sufficient to inhibit phospho-ERK signaling at longer time points, despite good inhibition at early time points. This work has led to a deeper understanding of parallel pathways that were activated in response to BRAFi in colon cancer (namely through the EGF receptor), which was functional in colon cancer but not in melanomas. In the second part of his talk, Dr. Corcoran focused on studies to identify resistance mechanisms. He related that, in both primary and acquired resistance, there are similar resistance mechanisms that can be learned; there are also some mechanisms that are particular to each scenario. He discussed that, despite finding multiple mutations in different patients (interpatient heterogeneity), his group’s analysis demonstrated that a common theme was the reactivation of MAPK pathways. One of those key pathways led to the hypothesis that incorporating ERK inhibitors would improve responses. While this improved the response rate somewhat, the responses were still suboptimal. Dr. Corcoran discussed that even a sampling of the metastatic lesions was inadequate to understand the entire patient, which led to his third theme of molecular diagnostics. He focused on utilizing circulating tumor DNA (ctDNA) sequencing as a liquid biopsy, which could be used to understand the heterogeneity within colon cancer. In applying this to FGFR inhibitors in FGFR-mutated cholangiocarcinoma, Dr. Corcoran, along with his collaborators, was able to identify multiple point mutations after treatment with the FGFR inhibitor BGJ398. The open question is whether there can be a single therapy that might be able to treat patients with these multiple lesions arising due to therapy. This work on using ctDNA may also have implications for understanding minimal residual disease (MRD) in solid oncology, similar to its current use in hematologic malignancies to develop prognostic tools and inform treatment decisions. This work may also help clinicians decide which patients need adjuvant therapy after resection. Overall, through Dr. Corcoran’s lecture, I gained a better appreciation of the exciting work that could be done by taking clinical observations back to the lab and generating hypotheses from patient samples to formulate key questions in translational oncology.