EGFR Pioneer Keeps Focus on Individualizing Patient Care in Lab and Clinic

Thomas J. Lynch, MD

As director of the Yale Cancer Center and physician-in-chief of the Smilow Cancer Hospital at Yale-New Haven, Thomas J. Lynch Jr, MD, wears many hats. And, having built a career united around two abiding goals of clinical discovery and personalized patient care, that’s just the way he likes it.

“I am actually very lucky; I have two fantastic jobs,” Lynch said. His responsibilities at Smilow, which opened in the fall of 2009, following his own appointment as physician-in-chief in April of that year, have given him the opportunity “to bring a spectacular facility online and deliver the very best care to patients with cancer.”

The hospital consolidated Yale Comprehensive Cancer Center and Yale-New Haven Hospital’s inpatient and outpatient cancer services into one facility. Treatment is organized around 12 cancer program teams, currently treating more patients with cancer than any other hospital in Connecticut.

“My role at Smilow has been very helpful in keeping me focused on patients and why we do what we do,” Lynch continued. “I get to work very closely with patients, with their families, and with providers.”

When Lynch is wearing his other hat at the helm of the Yale Cancer Center, he is involved in organizing and running a large, complex academic institution focused on cancer research, an arena in which he has distinguished himself for his pioneering work in lung cancer for more than three decades.

“What I find so complementary about these two positions is that they really go hand in hand. Without the clinic, the focus of cancer research is lost, and without cancer research, the opportunity to make progress is lost. I’m very fortunate to be able to work in both areas.”

One of Lynch’s many responsibilities at Yale includes developing the Cancer Biology Institute, established in 2010 as the research arm of the Yale Cancer Center. Under the leadership of founding director Joseph Schlessinger, PhD, MSc, chair of Yale University’s Department of Pharmacology, this interdisciplinary institute is dedicated to finding the causes of and potential treatments for cancer through collaborative research. The research is conducted by senior and junior scientists whom Lynch helps to recruit, working in such fields as cell signaling, cancer immunotherapy, and the development of genetically precise treatments geared toward each patient’s molecular profile.

Clinical Research—Front and Center

Research has been a central focus of Lynch’s work since he earned his undergraduate and medical degrees from Yale in the 1980s—and actually, even before that.

The Boston native grew up in a medical family, and he wanted to be a doctor all of his life, he recalled. “My father was one of the first hematologists in the country, so I knew about cancer as a kid. It’s something that I saw as a real problem for patients and families, even when I was a small child.”

“As I began my medical education and training,” he continued, “I was really drawn to the idea that clinical research and the ability to take new drugs and new paradigms and bring them to patients was very exciting and stimulating.”

Lynch carried this ethos with him to Massachusetts General Hospital (MGH), where he completed his internship and residency, joining the medical staff there in 1993 and embarking on a remarkable career dedicated to lung cancer care, research, and teaching.

Breakthrough Discovery of EGFR Mutations in NSCLC

Lynch has conducted dozens of studies focused on personalized cancer therapies and has published more than 100 original scientific papers. He worked with Daniel A. Haber, MD, PhD, director of the MGH Cancer Center, on one of the research teams that delineated the role of EGFR mutations in treatment response among patients with non—small cell lung cancer (NSCLC).

Using the molecular profile of lung tumors, Lynch and his research team have developed methods to predict a tumor’s response to targeted drugs based on confirmed mutations in the EGFR gene. The resulting information enables oncologists to create treatment plans that more effectively target each patient’s specific tumor type. This kind of customized care and personalized medicine is a standard of practice at Yale Cancer Center and Smilow Cancer Hospital.

Lynch describes the discovery that “EGFR mutations were associated with this terrific response to gefitinib” as a major breakthrough in the search for more effective lung cancer treatments. Working with Haber’s laboratory at MGH, along with laboratories at Memorial Sloan Kettering Cancer Center and Dana-Farber Cancer Institute, he added, “We were able to show that EGFR mutations were clearly related to responses to tyrosine kinase inhibitors. When we got the results back from the laboratory and saw that eight of nine patients who we suspected might have the mutation actually did have the mutation—that was a really exciting moment.” This discovery marked the first time in the treatment of lung cancer that a genetic event could be linked to the effectiveness of a drug.

Making Enormous Strides in Treating Cancer

“When I started in lung cancer, we were using step-chemotherapy—drugs which we still use today—platinum-based drugs which have been shown to make patients live longer, but they didn’t have the kind of revolutionary impact that the kinase inhibitors have had in patients who have oncogene-driven disease,” explained Lynch.

“Over the course of my career, we have seen an extraordinary improvement in our understanding of the fundamental biology of lung cancer, appreciating the EGFR mutations and the ALK1 and ROS1 translocations. These are all important drivers of malignancy, and finding drugs that can improve outcomes for these patients is a great accomplishment.”

The Importance of Clinical Trials

The crucial role played by clinical trials in the quest for more effective therapies remains a top priority for Lynch, a focus that goes hand in hand with his desire to offer patients something “that is new, that has the hope of a better outcome than what we’re currently doing,” and is a prime motivator behind his work.

As a doctor, husband, and father, he said that he recognizes that the treatments currently available to treat cancer are not good enough and emphasized that better treatments depend upon more robust participation in clinical trials. Currently only 3% of cancer patients participate in clinical trials in the United States, a rate Lynch deemed “completely unacceptable.”

“What I find is that the vast majority of patients want to participate in clinical trials, they want to advance medicine, so that the next person has a better option than they have. We need to be able to offer these options to every patient with cancer.”

“To miss that opportunity because we were shortsighted in our investment in research would be a tragedy,” he said.

Connecting With Patients

This appreciation for improving patient care by connecting more patients to the right clinical trial stems from Lynch’s overarching concern for enhancing the patient’s experience throughout the course of the disease, a focus he honed early in his career. Lynch was part of the care team at MGH that treated Kenneth Schwartz, a Boston healthcare attorney and nonsmoker who was diagnosed with advanced lung cancer at the age of 40 years. After Schwartz’s 10-month ordeal in battling and ultimately succumbing to the disease, a center in his name was established in 1995 whose primary mission is to optimize and maximize the interaction between patients and caregivers.

Lynch, a founding member and current chair of the Schwartz Center for Compassionate Healthcare’s Board of Directors, said that Schwartz taught him a “tremendous amount about how important it is to remember that the patient is the focus of what we do. Ken taught us to focus on the patient’s experience, on the small things we may sometimes forget about in our busy lives, which mean so much when you are on the other end of the doctor—patient relationship.”

The Schwartz Center’s reach extends well beyond Boston. Its signature program, the Schwartz Center Rounds, for example, has been adopted by hundreds of hospitals and healthcare institutions across the country, including Yale—bringing together caregivers from multiple disciplines to discuss the challenging emotional and social issues that arise in caring for patients.

“As we become more technologically savvy, as we embrace new technologies and new therapies,” said Lynch, “we still need to come back to the fundamentals—that a patient has come to you scared, a patient has come to you with a problem, a patient has come to you needing help.”

“Closer to Free” Through Team Science

Lynch is very optimistic about the future of lung cancer research and the availability of new therapies emanating from all of the players engaged in “team science,” among them the researchers working in the laboratory, physicians in their clinics, and the National Cancer Institute’s collaborative groups.

Currently standing out among these team-driven developments are “the initial responses to the anti-PD-1 therapy that we’ve seen here at Yale,” said Lynch. “My colleague Scott N. Gettinger, MD, was involved with anti-PD-1 early in its development, and seeing these kinds of responses to immune checkpoint inhibition has been incredibly exciting. It tells me that the next 10 years will be a time of terrific advancement in lung cancer and the discovery of new approaches.“

“There are many questions we can answer moving forward with the application of genetics and immunology to cancer and other diseases,” Lynch continued. He forecasts that the next decade in NSCLC research will continue to yield improved outcomes through therapeutic combinations involving chemotherapy, tyrosine kinase inhibitors, and immunotherapies.

“Some of the responses that we’ve seen with the immune-based checkpoint inhibitors have caused us to rethink the paradigms for how we treat lung cancer and when we should incorporate new drugs into the treatment of this disease. It’s really very encouraging.”

At Smilow, where these research accomplishments can translate into changing patients’ lives, the goal of supporting much-needed research through its “Closer to Free” initiative stands as a guiding mantra and mobilizer for the patients, survivors, doctors, and other caregivers working tirelessly to combat the disease.

And that is a philosophy completely in step with that of the cancer hospital’s physician-in-chief.

DR LYNCH’S SELECTED PAPERS

• Lynch TJ, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study [published online April 30, 2012]. J Clin Oncol. 2012;30(17):2046-2054.
• Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363(8):733-742.
• Pao W, Kris MG, Iafrate AJ, et al. Integration of molecular profiling into the lung cancer clinic. Clin Cancer Res. 2009;15(17):5317-5322.
• Lennes IT, Lynch TJ. Quality indicators in cancer care: development and implementation for improved health outcomes in non-small-cell lung cancer. Clin Lung Cancer. 2009;10(5):341-346.
• Maheswaran S, Sequist LV, Nagrath S, et al. Detection of mutations in EGFR in circulating lung-cancer cells [published online July 2, 2008]. N Engl J Med. 2008;359(4):366-377.
• Sequist L, Bell D, Lynch TJ, Haber D. Molecular predictors of response to epidermal growth factor receptor antagonists in non-small cell lung cancer. J Clin Oncol. 2007;25(5):587-595.
• Temel JS, Pirl WF, Lynch TJ. Comprehensive symptom management in patients with advanced-stage non-small-cell lung cancer. Clin Lung Cancer. 2006;7(4):241-249.
• Dias L, Chabner BA, Lynch TJ Jr, Penson RT. Breaking bad news: a patient’s perspective. Oncologist. 2003;8(6):587-596.
• Strauss GM, Kwiatkowski D, Harpole DH, et al. Molecular and pathologic markers in stage I non-small cell carcinoma of the lung. J Clin Oncol. 1995;13(5):1265-1279.
• Lynch TJ Jr, Kalish L, Strauss G, Elias, et al. A phase II study of topotecan in metastatic non-small-cell lung cancer. J Clin Oncol. 1994;12(2):347-352.
• Kim DH, Lynch TJ, Mentzer SJ, et al. Multimodality therapy of stage IIIA, N2 non-small-cell lung cancer: impact of preoperative chemotherapy on resectability and downstaging. J Thorac Cardiovasc Surg. 1993;106(4):696-702.
• Lynch TJ Jr, Clark JR, Kalish LA, et al. Continuous-infusion cisplatin, 5-fluorouracil, and bolus methotrexate in the treatment of advanced non-small cell lung cancer. Cancer. 1992;70(7):1880-1885.