Fellow Focus in Four will introduce you to fellows from each section in the Department of Internal Medicine. This month's fellow is Jennifer M. Kwan, MD, PhD.
Jennifer M. Kwan, MD, PhD, knows about firsts. She’s the first cardio-oncology fellow at the Yale School of Medicine (YSM), spearheading a growing community of physicians in this rapidly evolving field. Cardio-oncology lies at the intersection of cardiology and oncology, aiming to understand and address the potential cardiovascular side effects associated with cancer treatment but also how cancer and heart disease can affect each other in a recent review she co-authored. With greater numbers of novel therapies, from targeted treatment like tyrosine-kinase inhibitors to immunotherapies like checkpoint inhibitors or CART therapy, and their associated cardiotoxicities, the demand for this interdisciplinary field has been rising steadily over the last two decades.
Kwan Chosen as Inaugural Cardio-Oncology Fellow
Regarding the rise of cardio-oncology fellowships and one being developed at YSM, Kwan remarked, “It was just the natural and increasing demand, not only at Yale, but around the country, around the world, because these new therapies that allow cancer patients to live longer and have more fulfilling lives can also have significant cardiovascular complications. Those trained before the advent of these novel therapies have less experience with dealing with the adverse CV outcomes of these agents” Kwan focuses on the molecular biology and genetics side of cardio-oncology, working on understanding the interface and adverse cardiovascular outcomes associated with cancer patients.
Her interest in research began in her undergraduate years at the University of California-Berkeley. She became involved in projects analyzing the de novo synthesis of lipids and glucose in HIV patients on antiretroviral treatment therapies given the increased risk of insulin resistance and lipid derangements in these patients. Later, in a genetics lab for her honors thesis, she identified novel enhancer sequences that regulated the fruit fly immune response - findings that were later published in a Molecular Cell paper. In addition to her research, Kwan became involved in free clinics, “I appreciated how gratifying patient care could be. You’re helping to address their health issues, improve their quality of life. At the same time, there were some conditions that we didn’t have good treatments for. I could see the role of research in helping to improve patient care and treatment and having clinical care inform the right research questions to ask.”
That idea of constant innovation to improve patient care pushed her to pursue an MD/PhD in the Medical Scientist Training Program, a National Institutes of Health (NIH)-funded program, where she received her PhD in Biochemistry and Molecular Genetics in Chicago using genetic mouse models to evaluate the role of the insulin-Akt pathway in tumorigenesis and fat formation. Her bench research continued during her residency, where she performed NextGen sequencing and examined RNA transcriptomics of human inflammatory cells and exosomes (tiny lipid particles that carry bioactive cargo like proteins and antibodies), trying to discern differences between lean and obese individuals in terms of their inflammatory expression profiles and outcomes after she found that obesity could increase risk of cardio-renal syndrome and worsen outcomes for obese renal transplant patients in a large registry of more than 191k patients. During residency, she also cared for young patients who developed heart failure while getting chemotherapy for their breast cancer as well as patients who suffered heart attacks while on checkpoint inhibitor therapy and that inspired her to pursue cardio-oncology research. She did postdoctoral work as a visiting scholar at UCSF to mine the UCSF and entire University of California database of 16 million patients to assess cardiotoxicities associated with oncologic therapies with ongoing work in this area.
Following her graduation, she chose YSM’s cardiovascular medicine fellowship because of its strong research track record and opportunities. She remembered, “I thought it would be a great place to do my cardiology training, but also be able to get involved and keep involved with cardio-onc research as well. It was the drive for finding a place that had a good fit for cardio-oncology research and strong clinical mentors that led me to Yale.”
With one of her mentors, Dr. Lauren Baldassarre, Kwan worked on a project to evaluate breast cancer patient outcomes and correlated that with cardiac MRI findings as well as evaluate the cardiovascular outcomes of patients on a novel immunotherapy agent, mogumulizumab, after reporting the first case of mogamulizumab related myocarditis.
When COVID-19 hit, Kwan contributed to research to investigate whether certain molecular signatures in the blood correlated with worse clinical outcomes in COVID-19 infection in a multi-disciplinary team that included cardiologists, hematologists and pulmonologists. Working with Drs. Stephanie Halene and John Hwa, Kwan also spearheaded a project to evaluate the impact of clonal hematopoiesis of indeterminate potential (CHIP) (a condition that increases with age, increases the risk of heart disease, heart failure, blood borne malignancies and increases mortality by 1.5 fold) in breast cancer and heart failure patients at Yale. CHIP involves somatic mutations in hematopoietic stem cells that can accrue as humans age. She found that CHIP was highly prevalent in the cancer cohort (>40) and heart failure cohort (192) with up to 38% and 43% having CHIP, respectively. Kwan is now looking at an even larger heart failure cohort of ~ 500 patients working with Dr. Jeffrey Testani with ongoing enrollment of oncology patients with plans to include Yale Generations patients.
What they’ve seen is that our oncology and heart failure patients have a much higher prevalence of CHIP at younger ages than previously reported, raising questions of how these patients should be screened and monitored. Kwan has characterized over 80 different serum cytokines/chemokines/angiogenic factors and adipokines in these patients and is correlating these with outcomes. Kwan said, “We don’t have any guidelines for patients with CHIP right now, unfortunately, so it’s really a case-to-case basis because this is such a new entity. We’re planning to establish a CHIP clinic to enable Yale to provide cutting edge clinical and preventative care and to be able to perform research to inform us on how to best care for these patients.” At this clinic, they could monitor these patients over time, building a cohort where they could potentially identify certain culprit pathways that would serve as good therapeutic targets for these patients that would reduce their risk of heart disease and heart failure. With other places already starting CHIP clinics, Yale has an opportunity to stay ahead of the curve with research as a driver.
Clearly, for Kwan, research and her education as a physician-scientist is a critical part of her identity as a cardiologist. She was driven to physician-scientist training when she realized the extent that therapies could be improved for various conditions. Kwan cited amyloid as an example, “At that time there were no good therapies for TTR amyloid, there was not much people could do. But now there are novel therapies for this condition from small molecule inhibitors, RNAi to gene editing thanks to research in this area. Having a better understanding of how research can improve patient care and therapies that would improve their quality of life got me interested in doing both at that time.” However, her appreciation for physician-scientist training and contributions extends beyond her own training.
In 2020, she conducted studies surrounding the effects of the pandemic on physician-scientists. One of her COVID-19 studies detailed that stress levels shot up and productivity dropped for physician-scientists, whose research took a backseat for clinical work; these effects are particularly worrying for early career physician-scientists, as a massive hit to research productivity could mean they’re at risk for not being able to turn out manuscripts or get renewal for grant funding. Kwan said, “If that happens, you’re likely to leave research careers altogether.” After additional analysis of NIH-funded research, she also found that early career development awards (crucial for enabling physician-scientists to stay in research careers) success rates have dropped from ~50% two decades ago to now, between 25% to 30%. If the funding isn’t there, physician-scientists in general will be forced to abandon research and go back to clinical duties. You lose that person’s talent and all the skill sets that they’ve acquired over their years to do research and their unique role in bridging the basic science, translational research worlds with the clinical worlds.”
It was the drive for finding a place that had a good fit for cardio-oncology research and strong clinical mentors that led me to Yale.
Jennifer M. Kwan, MD, PhD
In response, as the resident, fellow, junior faculty section co-chair for the American Physician Scientists Association, Kwan and her collaborators became champions for physician-scientists in the U.S., proposing a policy letter that included support of the RISE Act, which was omitted from the recent pandemic relief package, thus preventing support to be given to scientists and physician-scientists following COVID-19 productivity setbacks. However, it is supposed to come back to the House of Representatives for re-deliberation. “So that, I think we need to support. The other items we are proposing in that letter includes increased dedicated funding for physician-scientists via K awards and the R01 funding mechanism and 2) bridge-funding for early-career physician-scientists.”
Bridge-funding entails buying 50% of their research time, providing them with $100k per year to cover their research salary for three years. “During that time, they’re encouraged to apply for career development awards, other grants, but it also protects their time to do research.” She recently co-authored an op-ed on the topic in the Hill to highlight the importance of this support. Kwan is having ongoing discussions with national policy leaders and has garnered the support of several specialty societies for this proposal.
Kwan is highly motivated, and looking forward, five, ten, years in the future. “I want to identify and develop novel therapies, leverage imaging findings in cardiac MRI that may be predictive of outcomes and contribute to evidence based guidelines to improve the cardiovascular outcomes and health spans for cardio-oncology and CHIP patients. I’ll also continue to be an advocate for physician-scientists. I want to influence policies that would increase the success for physician-scientists who come after me, because this cohort plays a crucial role in understanding disease, prevention of disease and developing therapies for conditions that we currently have no treatment for or suboptimal treatment for.”