Canadian Research Leader Makes Worldwide Impact on Lung Cancer

Frances Shepherd, MD

When Frances A. Shepherd, MD, FRCPC, first took an interest in lung cancer, the standard treatment for localized disease was to cut out the tumor and hope for the best, while the standard treatment for metastatic disease was to prescribe pain medication and send the patients home to die.

Shepherd has spent more than 3 decades demonstrating that medical oncology can help patients with lung cancer during all stages of their journey. She worked on some of the earliest clinical trials to prove the value of chemotherapy in metastasized disease and then led studies that demonstrated the curative potential of chemotherapy after complete resection and the efficacy of molecularly targeted agents such as erlotinib (Tarceva).

Her commitment to clinical trials research led Shepherd to become the chair of the Lung Cancer Committee of the National Cancer Institute of Canada Clinical Trials Group (now the Canadian Clinical Trials Group), a post that gave her a voice in every lung cancer trial for 19 years and helped make the country into a center of lung cancer research.

“I had no real ambition to do clinical trials during medical school or immediately thereafter, but then I took part in my first Lung Cancer Study Group trials and all my plans changed,” Shepherd said. “Once you are bitten by that trial bug—once you realize that you can do work that improves treatment for everyone—you never want to do anything else.”

Shepherd received her medical degree from the University of Toronto in 1970, went to Montreal for her internal medicine residency at Royal Victoria Hospital, and soon decided she wanted to specialize in cancer treatment. This was an unusual decision for a promising young doctor in the 1970s because oncology was only a fledgling specialty at the time. It still lacked both the recognition of the medical establishment and a formal training program in Canada.

Designing Influential Trials

Cancer treatment was improving rapidly, though, and Shepherd sensed an opportunity to do interesting and important work. When the University of Toronto launched its program to train medical oncologists, she was one of the first to sign up.The decision to specialize in lung cancer was, at that time, less calculated. Toronto General (now University Health Network, a large universityaffiliated hospital complex that includes Princess Margaret Cancer Centre and has been Shepherd’s base since 1975) had one of the premier thoracic surgery units in North America. Surgeons at the hospital, along with medical and radiation oncologists and lung cancer pathologists, were among the founding members of the North American Lung Cancer Study Group. It was through this Clinical Cooperative Research Group that Shepherd was introduced to clinical trials. In the nearly 4 decades that have followed, Shepherd has participated in more than 100 clinical trials, and she has led many of the most influential among them.

The JBR.10 North American Intergroup trial, for example, made chemotherapy after complete surgical resection a new global standard of care for patients with stage IB or II non—small cell lung cancer (NSCLC). Shepherd and her colleagues randomized 482 patients who had undergone surgery to either observation or treatment with vinorelbine plus cisplatin. On average, patients who received the chemotherapy lived significantly longer (94 vs 73 months; HR for death during the study period, 0.69; P = .04). They also had a higher 5-year survival rate (69% vs 54%; P = .03).

“That was a critical trial for several reasons,” Shepherd said. “We did not simply find that chemotherapy extends life for a few months or years—although it certainly did that for many patients—we also found that it increased the cure rate. The chemotherapy was effective enough in a significant percentage of patients to destroy undetected microscopic cancer cells. Those are people who otherwise would have suffered recurrence and death, but instead had the chance to live healthy lives. That is a rare victory, indeed, in the world of lung cancer, and it was very gratifying.”

Another important aspect of the JBR.10 trial was the unprecedented decision to collect and save tissue samples from patients who took part; in fact, the trial was the first lung cancer trial ever to stratify by an oncogene driver. Shepherd and her colleagues established a trial-associated tissue bank.

Time has borne out Shepherd’s intuition; sample collection has become increasingly common over the past 2 decades, and now almost all large trials set up tumor banks. Furthermore, samples from this bank established more than 20 years ago are still being evaluated in collaboration with researchers in Canada, the United States, and Europe.

Most cancer trials now utilize tumor genetic information in various ways, but that is a recent development. Among the first big cancer studies to show that individual tumor genes affect response rates to specific cancer treatments was another Shepherd-led trial: the BR.21 trial of erlotinib. Shepherd and her colleagues randomized 731 patients with NSCLC who had already failed 1 or 2 prior treatments to erlotinib or placebo. Although only 8.9% of patients who received erlotinib responded compared with less than 1% of those in the placebo group (P <.001), those in the erlotinib cohort had significantly longer overall survival (6.7 vs 4.7 months). It certainly was not a cure; it was, however, the trial that led to the approval of the first molecularly targeted lung therapy treatment. Once again, the tumor bank associated with this trial proved invaluable to the work.

Emphasizing Collaboration

This research has also provided much information about the 15% to 20% of patients (often young women) who develop lung cancer with no history of smoking or tobacco exposure. These cancers frequently are driven by mutations in key oncogene pathways.Shepherd emphasized that such triumphs take years to accomplish, however, and no investigator can expect many in an entire career. “Trials require collaboration, patience, and perseverance. Even when everything goes smoothly, the whole process takes years, and in the postoperative setting, as many as 7 to 10 years. No single person ever has anything approaching control over a large trial. It is a hugely collaborative process and rightly so,” said Shepherd, who is now a full professor of medicine at the University of Toronto and the Scott Taylor Chair in Lung Cancer Research at Princess Margaret Cancer Centre. “All that said, if you have the right temperament, the rewards more than justify the effort.”

Just getting into a position to propose a large trial takes years of work. Shepherd spent more than a decade working as a junior collaborator on large trials and showing her ability to run small trials before reaching the front rank of researchers. She worked one day at a time to build a reputation for doing good work, keeping to schedules, contributing to meetings, and doing everything else she could to be a valuable teammate. She emphasizes that the secret for building a successful career is collaboration. Start locally, then build up to national and international collaboration. Cancer knows no geographic boundaries, she says, nor should cancer researchers.

Shepherd also attributes some of her success to having outstanding mentors, particularly her surgical colleagues, and perhaps timing and good luck with many of her projects, but her colleagues say luck has little to do with her success.

“Part of her success is just pure output. Even by the standards of people who are extremely bright and motivated, she uses some combination of organization and efficiency to accomplish a phenomenal amount each day,” said Penelope “Penny” Bradbury, MB BCh, FRACP, MD, a medical oncologist at Princess Margaret Cancer Centre and an associate professor at the University of Toronto’s Department of Medicine. “But what’s probably even more important is the way she works with other people. She makes everyone around her better.

She has this way, when she’s discussing ideas with you, of cutting right to the heart of something and helping you see things more clearly. She is also incredibly generous with her own ideas. She will come up with something no one else saw and just let others take the lead on it.”

Those same skills helped Shepherd rise to the top of organizations such as the American Society of Clinical Oncology and the European Organisation for Research and Treatment of Cancer—despite being neither American nor European. They also allowed her to spend nearly 2 decades atop the Lung Cancer Committee for the National Cancer Institute of Canada Clinical Trials Group.

Colleagues say this last position was probably the most important because it enabled Shepherd to expand and improve lung cancer research around the world, as well as to build Canada’s standing in the world of cancer research. Shepherd used her position not only to steer Canada’s limited research dollars into high-impact studies that proved the value of lung cancer treatment and research, but also to use multinational alliances and fundraising to increase the total number of research dollars available. Shepherd has also excelled at fundraising closer to home, a skill that helps her institution maintain output when others are tightening their belts.

“She is one of the most successful fundraisers here, having single-handedly raised funds for at least 6 endowed chairs—which cost $2 million each&mdash; dedicated to lung cancer research. These chairs established by Dr Shepherd now support lung cancer research in all disciplines as well as the lung cancer early detection program at Princess Margaret,” said Ming-Sound Tsao, MD, FRCPC, who runs the translational research lab at Princess Margaret Cancer Centre and collaborates closely with Shepherd in translational research projects.

“Most of this money comes from relatives of Dr Shepherd’s lung cancer patients whom she has cared for and also from industries whose drugs that she has helped to bring to successful clinical trials. This speaks to the respect for her integrity and accomplishments that her patients (and their relatives) have for her and also others she has worked with,” Tsao said.

Shepherd has reached the point in her career where she is helping junior colleagues get trials up and running rather than launching new trials of her own, but she is still excited about research. Shepherd believes that each new discovery will help doctors deploy existing treatment options more effectively and maximize the benefit they can provide for patients with the next generation of targeted therapies.

She also, like nearly everyone else in cancer research, is excited about immunotherapy, but her excitement is tempered with considerable concern about the economics. “The promise is tremendous, but the costs truly are frightening,” she said. “It is one thing to spend the sort of money these drugs cost on a less common cancer like melanoma. It is entirely different to spend it on 1 of the big 3 cancers. If they work as well as we hope, we will have to find the money somewhere, but we are talking about the sort of money that will noticeably affect total annual healthcare spending for all nations.”

As much as immunotherapy and molecularly targeted medications promise to extend the lives of patients with lung cancer, Shepherd feels that the key to saving lives is prevention—clearly, smoking cessation is crucial&mdash;along with early detection. “For all the advances we are making, I doubt that we will see a cure for advanced lung cancer in my lifetime,” she said.

“There is a real opportunity, however, for researchers to save lives through early detection right now. We know that CT screening can find the disease early enough to cure it. The key to making the idea cost effective is identifying the correct high-risk population to scan and when and how often to scan them. Screening is directed at smokers, and so smokingcessation programs must go hand-in-hand with the scans. We cannot miss this teachable moment.”