Article from 2018 AWS Foundation Grant Winner
Monday, February 4, 2019
I first heard about the AWS Foundation Grant through my good friend and mentor Genevieve Boland, MD, PhD while I was still in training at the Massachusetts General Hospital. She received the grant in 2016 and mentioned to me that it is an excellent opportunity for projects that might be difficult to fund initially through traditional avenues. Oh, and by the way, it provides early visibility and recognition for your work among a large network of prominent women surgeons and beyond. These words of wisdom represent mentorship at its very best, and I have been doing my part in passing it forward to other women surgeons and trainees that are looking to establish a research career.
The thing is that there are not that many of us out there doing this work, and as a result, the odds of winning this grant are far better than many others. It was around that time as a senior surgical resident that I made the decision to become a member of AWS and began participating in advocacy events and attending conferences regularly, given the unique set of issues facing all of us in our respective surgical specialties. After I finished my training in General Surgery and Cardiothoracic Surgery at MGH, I was hired as a Thoracic Surgeon at Memorial Sloan Kettering Cancer Center in 2017 with 40% protected time (a rare occurrence these days in any surgical department) to study molecular signatures associated with treatment response and disease progression in surgically resectable esophageal cancer across various genomic platforms. I am mentored by Dr. Michael Berger, an internationally known computational biologist and Associate Director for the MSK Center for Molecular Oncology.
Since the Dutch CROSS Trial in 2012, which established the current paradigm of chemoradiation followed by surgery in locally advanced esophageal adenocarcinoma, very limited progress has been made in this disease space. The revolution of clinical genomics and precision oncology have disproportionately favored more prevalent and better-funded malignancies, such as melanoma and lung cancer, while novel discoveries in esophageal cancer have lagged behind considerably. What the CROSS Trial showed us, however, is that only approximately 20% of patients actually have an exceptional response to trimodality therapy and benefit from this strategy. Thus, the primary research question that we have posed is: can we predict who will be an exceptional responder vs. non-responder a priori in order to direct treatment in a more precise and personalized fashion? And secondarily, can we use circulating cell-free tumor DNA (ctDNA) markers as a tool to monitor disease burden and treatment response?
After the Cancer Genome Atlas (TCGA) Research Network put forth a novel classification scheme of gastroesophageal cancer in 2017 in terms of varying types of genomic instability (Figure 1), we hypothesized that these subtypes may offer new insight into treatment response. Our approach has relied on collection of both tissue and blood from patients at the time of diagnosis and over the course of treatment for next-generation sequencing using a comprehensive panel of 468 cancer-related genes which comprise our MSK-IMPACT panel. Rather than looking only at individual somatic alterations, we are investigating whether mutational signatures, tumor mutational burden, whole genome doubling, structural variants, and microsatellite instability status correlate with clinical stage, pathologic response, recurrence, and survival. Thus far, we have accrued 75 patients with early and locally advanced esophageal cancer to our IRB protocol, which opened in October 2017, in addition to over 300 patients with metastatic disease that have been previously sequenced at our institution. Preliminary analysis has revealed the following observations:
- Esophagogastric adenocarcinomas are amongst the most hypermutated tumors alongside bladder cancer, melanoma, colorectal cancer, and non-small cell lung cancer (Figure 2a)
- We detected at least one somatic mutation in over 95% of patients using MSK-IMPACT (Figure 2b)
- Only 3% of patients exhibited microsatellite instability in our larger cohort (Janjigian Y et al. Cancer Discovery, 2018), which was far less than observed by the TCGA Research Network
Recent efforts in our laboratory have been focused on development of a similar pan-cancer ctDNA assay, which is a high-sensitivity next generation sequencing test to detect somatic alterations in plasma cell-free DNA in patients with solid tumors. The design of this assay, known as MSK-ACCESS, leverages prior experience and results from our center's mass-sequencing efforts using MSK-IMPACT and includes all known clinically actionable mutations, recurrent hotspot mutations, and highly mutated exons in the MSK-IMPACT dataset. Because tumor DNA concentrations in plasma are typically much lower than in tissue, particularly for patients with early stage disease, duplex molecular barcodes have been incorporated into library construction such that each sample is sequenced to ultra-deep coverage (>20,000x) to maximize the sensitivity for detecting low frequency events. To date, we have successfully extracted circulating cell-free DNA from more than 40 patients in our protocol with sufficient yields (>20ng of DNA). We have further applied the assay above and analyzed ctDNA in a small cohort of patients with stage I-III disease. Mutations from the primary tumor were detected in 60% with locally advanced disease, and 25% of patients with early stage disease thus far. Results from our initial analysis suggest a relationship between ctDNA concentrations and tumor burden/stage, but a larger sample size is needed to validate these data.
I am very grateful to be the 2018 recipient of the AWS Foundation Grant, and I hope more people will apply and take advantage of this opportunity in the future. Establishing any research program is obviously a very resource-intensive proposition (in terms of time, effort, and money), and every single dollar helps. My goal is to apply for an NIH K-level Career Development Award in 2019 to continue to support my work, and I view the AWS Foundation Grant as an important stepping stone in this direction.
Smita Sihag, MD, MPH is an Assistant Attending Surgeon, Thoracic Service at Memorial Sloan Kettering Cancer Center.