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Leyland-Jones, MB BS, PhD, a renowned oncologist and translational scientist, has helped develop several mainstay oncologic treatments and the targeted breast cancer therapy trastuzumab.
Brian Leyland-Jones, MB BS, PhD
Brian Leyland-Jones is committed to eradicating cancer—and he’s willing to go anywhere to do it.
During a career spanning more than 30 years, that philosophy hasn’t been easy on the doctor’s personal life. But it has given the renowned oncologist and translational scientist the opportunity to conduct groundbreaking laboratory and clinical research, and to treat patients, at a half-dozen of the world’s top cancer institutions— not to mention becoming a citizen of two countries besides his native England.
In April 2012, Leyland-Jones, MB BS, PhD, made his latest move into the directorship of Edith Sanford Breast Cancer Research in Sioux Falls, South Dakota, a new genomic research program and treatment center. In that role, he is overseeing the use of a $100 million gift from Denny Sanford, a credit and banking industry entrepreneur whose mother died of breast cancer when he was 4 years old. The center will explore the application of genomics in matching targeted treatments to patients.
At the same time, Leyland-Jones is serving as a senior scientist at the related Sanford Research, an integrated health system headquartered in Sioux Falls and in Fargo, North Dakota. In his lab there, the doctor uses model systems to discover pathways that drive cancer and find therapies that suppress them.
Although accepting the position at Edith Sanford meant leaving a tenured professorship at Emory University, in balmy Atlanta, Georgia, to move to snowy South Dakota, the 63-year-old doctor didn’t hesitate.
“When the CEO of Edith Sanford asked me how I’d feel about living here, I said that I would go anywhere I felt the mission could be achieved,” he recalled. “I want to leave this world in a better state than how I found it, and this is the greatest opportunity I have of making a significant difference. I truly feel that breast cancer is going to transform, in the next four to seven years, into an extremely chronic disease, and that we will come as close to the word ‘cure’ as we possibly can. It’s an absolutely transformative time.”An expert in pharmacodynamics, pharmacokinetics, and pharmacogenetics, Leyland- Jones has contributed to that change by designing and running an array of clinical trials, most of them in patients with breast cancer. Along the way, he helped develop the anthracycline, antimetabolite, and platin families of drugs that are now mainstays of oncologic treatment, as well as the targeted therapies trastuzumab and bevacizumab.
Leyland-Jones has also helped to disprove some theories about how best to treat breast cancer patients. He was a major contributor to the design of the phase III HERA trial (ESMO 2012: Abstract LBA6), which demonstrated that two years of adjuvant trastuzumab was no better than the standard one year of treatment for women with HER2-positive, early-stage breast cancer.
In the ATAC (Lancet. 2010;11:1135- 1141) and BIG 1-98 (J Natl Cancer Inst. 2012;104:441-451) trials, Leyland-Jones and colleagues cast doubt on the use of the cytochrome CYP2D6 as a biomarker for the benefits of tamoxifen in patients with hormone receptor-positive breast cancer.
“When I first joined the cancer world, something like 70% of the treatments we administered to patients did not benefit them,” Leyland-Jones said. “Over the years, there have been a number of markers postulated to guide therapies much better; two of these were serum HER2 testing and CYP2D6. In doing larger trials and overviews, we’re showing that some of these postulates don’t work, and trying to come up with really genuine biomarkers to direct which patients should get which drugs.”
The doctor also left his mark on the cancer community by running the Developmental Chemotherapy Section of the National Cancer Institute (NCI), in Bethesda, Maryland, which at the time was testing between 70 and 80 potential anticancer drugs in settings from the laboratory to phase III clinical trials. In addition, he built oncology programs into comprehensive cancer centers at McGill University in Montreal, Canada, where he served as the Minda de Gunzburg Chair in Oncology, and at Emory University, where he was executive director of the Winship Cancer Institute.
As Leyland-Jones moved through those experiences, he became increasingly convinced that he needed to focus his attention on exploring genomics in cancer treatment.
At Sanford, he’ll start that quest with a small trial that will select treatment for patients with metastatic breast cancer based on an analysis of the full genomic sequence of their tumors. Ideally, future trials at Sanford will add to the evidence that genomically guided medicine is superior for treating breast cancer patients compared with nongenomically guided medicine, the doctor said.
“I’d not be here at Sanford, preparing with our partners to run full genomic trials over the next two, three, or four years, if I did not think the proudest accomplishments are yet to come,” he said.As excited as Leyland-Jones is about the project, it represents only part of what he does as director of Edith Sanford Breast Cancer Research.
Since he began there, the doctor has divided his working hours about equally between tumor boards or clinically related activities, time in his own lab—whose staff moved with him from Emory—and other national or international biomarker research efforts in large cooperative groups, including the Eastern Cooperative Oncology Group (ECOG), the International Breast Cancer Study Group (IBCSG), and Breast International Group (BIG). Having recently secured his South Dakota license, he has also started seeing breast cancer patients twice a week.
In addition, the doctor teaches residents and fellows. “If there’s one simple message that I always try to get across to them,” he said, “it’s that every decision that is made about any patient outcome is a completely shared experience. You have to respect what the patient wants to do.”
At the same time, oncologists must guide their patients, he said.
An example of what can happen when the culture of an area has a strong effect on patient attitudes, Leyland-Jones said, is the high rate of mastectomy among patients with breast cancer in South Dakota, as compared with that in other states.
“Patients in this area of the country often come in and say, ‘I’ve got this cancer, and I don’t care—I’ll have a mastectomy,’ ” he said. “But there are so much kinder and more precise methods, like lumpectomy or radiation, so the continued education of our patients is really important. It allows you and the patient to make the absolute best decision together.”
Another of Leyland-Jones’ goals at Sanford is helping to shape it as a model of sophisticated cancer-care delivery to a rural community.
Sanford’s network reaches into such areas, in part, by sending out mammography vans, the doctor said. In all, the network provides nearly 65,700 mammography screenings each year.
Including 35 hospitals, 36 long-term care facilities, and 140 clinic locations, Sanford has more than 1200 physicians who care for patients in 126 communities within eight states, and also conducts national and international collaborations through the Sanford World Clinic, according to a spokesman.
“Our health network covers more, in terms of land mass, than any other,” Leyland-Jones said.
Sanford also boasts a growing patient biobank, the doctor added. “The idea is that, as we accumulate more and more knowledge on genomic medicine, one can go to the biobank and use DNA, RNA, and protein aberration patterns to individualize both risk assessment, and also what interventions are needed in patients,” he said. “We’re making this a key part of the total health experience.”Leyland-Jones didn’t start out aspiring to be a doctor or a scientist.
“Until I was 14 or 15, I was aiming at either being a concert pianist or a university mathematician,” he said. “But I began to realize, at around 15 or 16, that while I was extremely good at both, I was not in that critical top 1% capable of making it in either field. So I moved to something where I could make a huge difference—medicine.”
In his hometown of 110 people, Shrewsbury— within Shropshire, England—Leyland- Jones was easily able to find the inspiration to follow that dream. The village of “old timbered buildings” had been home to Charles Darwin, who wrote part of On the Origin of Species there. Leyland-Jones also was impressed by his town’s general practitioner, and eventually followed in the doctor’s footsteps by attending medical school at the University of London.
Leyland-Jones got a promising start when he earned a BSc in biochemistry there in 1970, with first class honors. But while completing his bachelor of medicine and medical degrees at St. Mary’s Hospital Medical School at the university, he considered changing his career path.
“Much of the education was rote learning; the anatomy was incredibly tedious, just poring over every single muscle and remembering names and distributions,” Leyland-Jones said. “Having come from the math world, I missed the higher-level thought. Then a very senior student, Arthur Hibble, took me and some others to the bedside of some patients, and really showed us the complete link between biochemistry, pharmacology, physiology, and medicine, and how you could integrate all the other disciplines to impact therapy and the outcome on the patient. It was transformative, and it brought me back into medicine.”
Leyland-Jones interned at several London hospitals before being invited by renowned pharmacologist Marcus M. Reidenberg, MD, to serve a clinical fellowship at the New York Hospital, associated with Cornell University, in 1977.
Simultaneously, Leyland-Jones completed a fellowship in medical oncology at Memorial Sloan-Kettering Cancer Center/Memorial Hospital in Manhattan, eventually serving as an assistant professor in oncology (developmental chemotherapy) and pharmacology.
“My life then was largely running phase I trials,” including one exploring the mechanisms of renal toxicity caused by chemotherapeutic agents, the doctor said. “We were at the cutting edge of bringing completely new drugs into the clinic, and I also ran a mechanistic pharmacology lab.”
Years later, in 2004, Leyland-Jones returned to St. Mary’s to earn his PhD in pharmacology.
Under the Microscope:
As director of Edith Sanford Breast Cancer Research in Sioux Falls, South Dakota, Brian Leyland-Jones, MB BS, PhD, is overseeing the use of a $100 million gift from entrepreneur Denny Sanford to explore the application of genomics in matching targeted treatments to patients with breast cancer.
In an interview with OncologyLive, Leyland-Jones explained the design and goals of the first studies that will be funded with the gift, and how the research program is expected to develop from there.
Q: You have an initial grant-funded genomics trial set to begin. Who will participate in the trial?
A: The trial will include 25 patients with metastatic breast cancer—second-line and thereafter—and we’ll conduct it with several key partners. The Scripps Research Institute will do exome and RNA sequencing, and our colleagues at George Mason University, in Virginia, will do laser capture of microdissection: It is critical, when one takes the biopsies, that the tumor is microdissected away from the stroma to obtain a pure tumor signal. While George Mason will measure, in particular, phosphorylated proteins, we will perform immunohistochemistry in our own Sanford Research network. In summary, we are looking at the tumor at multiple levels (DNA, RNA, and protein), so as to make the most educated decision—using this compilation of information— on the best targeted therapy to treat the patient.
Q: What is the design of the trial?
A: Each patient will have a biopsy pretherapy. That biopsy will be microdissected, and we will extract DNA, RNA, and protein, which will be distributed to five centers to be profiled. We will sequence both the patients’ normal germline and tumoral DNA. After analysis, all the information will be collated and presented to a sequencing tumor board.
The composition of the tumor board will be the same as a typical tumor board, but with greater enrichment by genomic and bioethics personnel. This group of physicians, radiologists, pathologists, scientists, and bioethicists will look at the complete history, clinical exam, pathology, imaging, and genomics of each patient, and put that all together to make a decision on how best to treat.
We plan to present all the information on each patient to the tumor board within 14 days after pretreatment biopsy.
Once treatment has been initiated, we will offer each patient the opportunity to have another biopsy conducted after eight days, in order to identify tumoral feedback loops/parallel pathways to which the tumor reverts as a survival mechanism.
Q: What is the study’s endpoint?
A: We see this as part of the rite of passage away from 60 years of crudely directed chemotherapy, with its difficult side effects, into the administration of tailored, targeted therapy. It is a feasibility trial from the viewpoint of whether we can perform the entire process of tumor microdissection and nucleic acid and protein extraction, and execute and compile all the information from all the different labs, within 14 days. We are also trying to discern which platforms are the most useful in terms of deciding therapy, how feasible it is to perform the day 8 biopsy and, finally, how the various physicians, patients, and bioethicists manage this large amount of information in choosing therapies.
Q: How do you expect this research program to develop once the first trial has been completed?
A: The first trial will lead to a subsequent, larger, single-arm trial including 150 to 200 patients, which will benefit operationally from what we learn in this one. We will conduct that trial, hopefully, in concert with Wayne State University [in Michigan], Scripps Health, and Stanford University.
The subsequent trial will ask the definitive randomized question of genomically targeted therapy versus nontargeted state-of-the art treatment. This should provide definitive proof that genomically guided medicine has a significant impact on the outcome of patients with metastatic breast cancer, as compared with state-of-the-art, nongenomically guided medicine.
“I trained originally in biochemistry, oncology, and clinical pharmacology,” he said. “This was to retrain me in modernday molecular pharmacology.”Leyland-Jones left New York in 1983, when he was asked to consider a position with the NCI by one of his bosses at Sloan-Kettering, who was also taking a job with the government agency. In addition to heading the Developmental Chemotherapy Section there, Leyland- Jones conducted breast cancer research in the lab of Ken Cowan, MD, PhD, now director of the Eppley Cancer Center at the University of Nebraska Medical Center in Omaha.
Six years later, Leyland-Jones felt ready to take on a chairmanship, and secured a position as founding chair of the Department of Oncology at McGill.
“They had a fractured clinical trials program in several of their five hospitals, and wanted someone to bring the effort together,” Leyland-Jones recalled. “We had to build several of the divisions from scratch (including epidemiology and clinical pharmacology), and unify cancer research and clinical trials across the McGill network. When I moved there in 1990, most of the well-to-do patients would go elsewhere to look for state-of-the-art treatment, but after four or five years—in sarcoma, for instance—we had as many trials running as other leading US cancer centers, and we knew we had succeeded.”
After about 17 years at McGill and a cluster of three deaths in his family, Leyland- Jones recalled, “I asked myself whether I wanted to stay there for the rest of my life or look for one more opportunity.” The reassessment ended with his move to Emory in 2006.
“Georgia was the largest state in the country that did not have an NCI-designated cancer center,” he said, “so I worked very aggressively for two years and got them designation for the first time in 30 years. It was backbreaking, but it was an invaluable experience.”
With that task completed, Leyland- Jones followed his interest in genomic research to Stanford University, in California, for a sabbatical in the summer of 2011. He worked with the breast and genomics teams there to focus his thoughts, expand his knowledge of genomic medicine, and build collaborations between himself, the university, and ECOG.
“I realized I wanted to run large trials in genomic medicine, and that it would cost a lot of money, and that’s where Sanford and I came together,” Leyland-Jones said. “Denny Sanford had the vision and the generosity to put in the $100 million gift, and even before that, a very strong commitment to genomic medicine had been established by H. Eugene Hoyme, MD, chief academic officer at Sanford Health. It was a perfect setting that included money, direction in genomic medicine, and a large population of patients in whom one could execute the trials.”After chipping away at cancer’s defenses for more than three decades, Leyland-Jones remains convinced that he’s doing the right thing by dedicating his life to his work. But he knows that determination has come at a cost.
“Looking back, I deeply regret not getting married and having a family,” he said. “I’ve come close to getting married a couple of times, but in the end, I am truly married to my career.”
Instead, Leyland-Jones hopes to leave a legacy of knowledge that will lead to different and better treatments for cancer.
“I can well see, God willing, before I die, that all the routine toxic chemotherapy we’ve used over the years is going to be essentially forgotten, and that we will end up matching well-tolerated targeted treatments and combinations based on the exact, individual genomic profile of the patient,” he said. “We’re right at the cusp of that transformational change.”