University of Chicago Comprehensive Cancer Center
For nearly 40 years, the University of Chicago (UChicago) Comprehensive Cancer Center (UCCCC) has enjoyed a reputation for excellence and innovation, with more than 200 basic and physician scientists collaborating on research aimed at transforming cancer prevention, screening, and treatment. UCCCC researchers have pioneered studies in a broad range of areas, including the molecular genetics of cancer, cancer immunology, bone marrow transplantation, hormone therapy, and advanced imaging techniques.
As one of only two National Cancer Institute– designated comprehensive cancer centers in Illinois, the UCCCC is committed not only to conducting the highest-quality research and providing the best possible patient care, but also to increasing public awareness, encouraging participation in clinical trials, and eliminating health disparities among ethnic and social groups. Two prime examples of such endeavors are the 1200 Patients Project and the UCCCC breast program.
Initiated at UChicago, and the flagship project of the newly created Center for Personalized Therapeutics directed by Mark J. Ratain, MD, the 1200 Patients Project is examining the feasibility and potential benefits of using a patient’s genetic information to guide pharmacologic treatment decisions and develop personalized therapeutics throughout his or her lifetime. The study was initiated in January 2011 and by April 2012 had enrolled more than 700 of an anticipated 1200 UChicago outpatients.
“We’re hoping that being able to predict up front how a patient will respond to a particular drug will allow physicians to prescribe more precisely and individually, rather than by the usual trial-anderror approach,” said 1200 Patients Project principal investigator and recently named assistant professor of Medicine Peter H. O’Donnell, MD.
Peter H. O’Donnell, MD
Upon enrollment in this first-of-its-kind, 3-year study, each patient submits a single blood sample that is tested for all published genetic markers that might predict response to hundreds of drugs, as well as the likelihood of adverse effects. Patient-specific results will then be made available to study-participating physicians, who will be monitored to determine whether they use the information in decisions about medicine selection or dosing, O’Donnell explained.
O’Donnell collaborated with UChicago’s informatics team to create a prescribing system that integrates patient data with published pharmacogenomic information and generates an easyto- read clinical summary for the 12 UChicago physicians, including three oncologists, participating in the study. One challenge is that new data about genetic markers will need to be incorporated into the system as they’re published, said O’Donnell, noting that stored samples from enrolled patients can be retested when that happens, if necessary.
While the study is not cancer-specific, the database includes chemotherapy agents and other drugs prescribed to cancer patients. To date, a significant amount of research has been performed to examine the interplay between patient DNA and cancer drugs such as irinotecan, tamoxifen, methotrexate, and cisplatin, O’Donnell said.
The potential benefits of such information notwithstanding, consulting genomic prescribing data will necessitate an extra step for treating physicians, which, in turn, could make prescribing decisions more complicated and require an attitudinal adjustment. But O’Donnell doesn’t see that challenge as a downside. Determining how the genomic prescribing system can be integrated into routine care, he said, is one of the most exciting aspects of the study.
The 1200 Patients Project is still in the genetic testing phase, but pharmacogenomic information is expected to be available to the study’s physicians this summer. Already, O’Donnell and his colleagues are looking ahead to additional studies that will help determine how this new model of care could affect patient outcomes, and how well it will be accepted by a larger physician population.
Patient interest has already been robust. “Patients want their physicians to think of them as individuals, not as a disease that’s being treated,” O’Donnell said. “Patients have been exceptionally enthusiastic, and current enrollment has exceeded our expectations.”
UCCCC breast program researchers and clinicians have long been committed to better understanding and addressing health disparities, and to improving care to underserved populations. One example of such endeavors is UChicago’s Center for Interdisciplinary Health Disparities Research (CIHDR), which has coordinated its research with the infrastructure of the university’s Specialized Program of Research Excellence (SPORE) in Breast Cancer.
In their efforts to uncover the reasons behind cancer health disparities, CIHDR and SPORE investigators are advancing research into prevention, early detection, and treatment—all while fostering trust between UChicago and its neighbors through a wide range of outreach activities. Research efforts are focused on the interplay of genes and the environment in the development of triple-negative breast cancer, with a multidisciplinary team of scientists working to identify genes relevant to the cancer’s development, determine their role in inherited susceptibility, and perform genetic epidemiologic analyses that can be used in the clinic.
The interplay between environment and genetics is of particular interest to professor of Medicine Suzanne Conzen, MD, who, along with her colleagues in the laboratory, is examining the ways in which environmental factors might affect the development and growth of malignancies— and, ultimately, response to treatment and likelihood of recurrence. Using a mouse model, Conzen and David Lee Shillinglaw Distinguished Service Professor in Psychology Martha McClintock, PhD, have shown that social isolation is associated with altered gene expression in the animals’ mammary glands; in isolated animals, systemic glucocorticoid levels were higher and triplenegative tumors grew larger. Specifically, three enzymes critical to glycolysis have been found to be significantly elevated in the isolated female animals’ mammary adipose tissue. The next step is to determine whether such changes favor breast cancer cell proliferation and increased resistance to chemotherapy effectiveness.
Suzanne Conzen, MD
“In this setting, social isolation is a model for exposure to unrelenting stressors over which the individual has no control,” Conzen said. “And while we can’t say that these findings can be extrapolated to humans, there certainly is a growing understanding of the physiologic impact of chronic stress in a wide range of disease states.”
Conzen, who is also the co-leader of the UCCCC’s Molecular Mechanisms of Cancer (MMC) Program, notes that larger translational studies have demonstrated a link between tumor glucocorticoid receptor overexpression and poor outcomes in women with early-stage breast cancer, a relationship that appears specific to estrogennegative tumors.
In a phase I trial, UCCCC and Evanston Hospital- NorthShore University Health System investigators are examining the use of a glucocorticoid receptor antagonist in conjunction with chemotherapy. Once safety is established, the goal will be to evaluate the protocol to determine if blocking glucocorticoid receptor activity might enhance the effectiveness of chemotherapy in women with non-estrogen-sensitive tumors whose disease is resistant to treatment.
Conzen is quick to point out that it’s the physiologic response to stress, rather than the stress itself, that produces the altered hormonal milieu leading to changes in gene expression. “As clinicians, we need to adopt a proactive approach with regard to assessing our patients’ levels of stress, and determining what, if any, mechanisms are in place (or will be needed) to help them to deal with that stress effectively,” she said. Conzen went on to note that social stressors may be especially prevalent in underserved populations, since feelings of isolation and societal discrimination are reported with greater frequency by women in such populations.
She cited a small but excellent randomized trial, in which supportive therapy involving stress reduction and mood improvement was shown to lower recurrence rates in women with early-stage breast cancer.1
“This is also a trust issue,” Conzen said, “that becomes highly relevant to treatment and recurrence once a woman is diagnosed with cancer.” She said that investigators, including Cathy P. Hall, MSN, RN, OCN®, et al, suggest that training healthcare workers in cultural sensitivity and, therefore, more effective communication with patients, could increase participation in breast cancer screening.2
At a center committed to research such as UCCCC, it’s vital to have nurses on hand who are equipped to serve as patient educators and advocates. “Cancer patients who enroll in clinical trials are generally looking for life-saving treatment, and are essentially doing so in uncharted waters. The ability to establish trust is critical,” says research nurse associate for UChicago’s hematology/oncology program Elizabeth Manchen, MS, RN, OCN®.
Typically, Manchen waits for the physician to explain the treatment protocol and any potential adverse effects, and then “translates” to ensure that all explanations have been understood. “This is when I usually field a barrage of questions about logistics and the ‘what ifs’ of embarking on a new treatment protocol,” she said.
It’s also during this initial meeting that Manchen establishes herself as the patient’s primary advocate. “While trial participants are assured that we’re all acting in their best interest, it helps them to know they’ll also have one go-to person who will always be in their corner,” she said. “I reassure them that they’ll always be able to reach me, that we know what to do in the event of adverse effects, and that, if desired, they can withdraw their consent to participate at any time.”
Manchen also stresses the positives, explaining to patients that they’ll likely be seen more frequently and followed even more closely than if they were on standard therapy.
To be the most helpful to patients, Manchen said, nurses must be knowledgeable about clinical trials.
Because Manchen typically works with phase II protocols, doses have been established and many potential adverse effects have already been identified. “I rely heavily on the established protocols and also share information with nurses across the country,” she said. “I also get useful feedback about unanticipated adverse effects—and, at times, how best to manage them—from our trial participants.”
Manchen, who stressed the importance of staying up to date on novel treatments, added that it’s especially important for nurses to familiarize themselves with the various drug pathways, which provide vital information about mechanisms of action and adverse reactions.