A message from Dr. F. Marc Stewart
As medical director of Seattle Cancer Care Alliance, I would like to welcome you to The Leading Edge, the SCCA’s community physician update. Each quarter a new topic will be highlighted to give you the latest news on leading-edge therapies that SCCA physicians are offering.
In this issue, we’ve highlighted gastrointestinal cancers, including the latest treatments and information about early detection and prevention. Each article includes contact numbers if you would like more information. Additionally, each issue will include a resource section describing how you can refer your patient to SCCA should you decide to do so. We will occasionally include patient educational tools and other helpful information.
Please feel free to let us know how we may provide you with information to help you educate your patients.
- F. Marc Stewart, MD Medical Director, SCCA; Professor of Medicine, University of Washington; Member, Fred Hutchinson Cancer Research Center
In this issue
- Early detection and treatment optimization for colon cancer - Dr. William M. Grady
- The future of cancer therapy – targeting tumor stem cells - Dr. Edward Lin
- Gastrointestinal Cancer Prevention Program
- Neuro-oncology comes to SCCA
- How to refer a patient
- How to consult with a specialist
- Survivorship Program
- Lung Cancer Early Detection and Prevention Clinic
by Dr. William M. Grady email@example.com
Stem cells and cancers bear strikingly similar biologic characteristics, notably limitless self-renewal potential. Indeed, literature suggests that only 1 to 2 percent of cancer cells are cancer stem cells, now found in gliomas, melanomas, Dr. William M. Grady, gastroenterologist at Seattle Cancer Care Alliance, is studying diagnostic assays for the early detection of colon cancer and the optimization of treatment for this cancer. He is also creating mouse models of colon cancer that genetically recapitulate colon cancer in order to use them as preclinical models for biomarker and treatment studies.
“These models are providing insight into the relevant signaling pathways that are deregulated in colon cancer cells and are pointing the way for early studies in people,” says Dr. Grady. “For instance, we have used the models to show that a cytokine called transforming growth factor beta (TGF-ß) acts as a barrier to prevent the transformation of colon polyps into colon cancer. So these results suggest that if we can determine how TGF-ß signaling blocks the progression of a polyp to cancer, we can design therapies directed at preventing the polyps from turning into cancer. The identification of TGF-ß having a role in this process takes us one step closer to figuring out how polyps turn into cancer. We are doing similar work with liver cancer, but those studies are in earlier stages of progress than are the colon cancer models.” These studies are relevant to colon cancer in people because one-third of colon cancers have mutations in a gene for the TGF-ß receptor, called TGF-ß receptor type II, and three-quarters of colon cancers acquire resistance to TGF-ß. With his mouse model studies of colon cancer, Dr. Grady is finding that transforming growth factor ß receptor type II (TGFBR2), the cellular receptor for TGF-ß through which TGF-ß affects the behavior of cells, plays an important role in colon carcinogenesis. “TGFBR2 is an essential component of the TGF-ß receptor complex, which mediates the effects of the multi-functional cytokine, TGF-ß,” he says.
TGF-ß through TGFBR2 and its partner TGFBR1 regulate a variety of cell functions including cell growth, senescence, differentiation, extracellular matrix remodeling, and genomic stability. Thus, TGFBR2 inactivation likely affects tumor formation through a variety of mechanisms, including excess cell proliferation, increased cell invasiveness, regulation of genomic stability, etc.
“Interestingly,” Grady says, “unlike classical hormones whose actions are few and specific, TGF-ß can cause these myriad effects on a cell because TGF-ß’s effects depend on the type and state of the cell, termed the ‘cellular context.’ Our preliminary data demonstrates that the cellular context dependence of TGF-ß’s effects dictates the consequences of the loss of TGF-ß signaling in colon cancer and that those consequences are a result of cooperation of TGFBR2 inactivation with other genes commonly mutated in colon cancer.”
Dr. Grady has now proposed, and is beginning to carryout, a series of studies to determine the effects of TGFBR2 inactivation in the context of known genetic events that occur commonly in colon cancer (e.g. APC, KRAS2, and TRP53 mutations). These studies will use novel model systems to determine how TGFBR2 inactivation affects tumor cell behavior, especially in the context of mutant APC, KRAS2, and TP53. These studies have yielded novel genetic models for the classic adenoma-cancer pathway and an unprecedented model for the hyperplastic polyp-to-cancer path, which is a newly discovered way for colon cancers to form.
In addition, mutations in APC activate an important signaling pathway called the Wnt pathway and mutations in KRAS2 activate a signaling pathway called the MAPK signaling pathway. Dr. Grady’s studies will allow an investigation of how deregulation of these different pathways cooperate to cause cancer to form.
In light of the development of new therapies directed at these signaling pathways (i.e. the TGF-ß, Wnt, and MAPK pathways), there is substantial promise that these models will be useful in the pre-clinical analysis of the effectiveness of these compounds.
Specific aims of this study are:
- To determine the effect of TGF-ß signaling pathway inactivation in the setting of Apc mutation and Wnt signaling activation on intestinal cancer formation.
- To determine if TGF-ß signaling pathway inactivation cooperates with Kras2 mutation and Ras-Raf pathway activation in intestinal cancer formation.
- To determine the in vivo consequences of TGFBR2 inactivation on colon cancer initiation and progression using novel mouse models of intestinal cancer that genetically recapitulate human colon cancer, Apc1638N; LSL-KrasG12D; Tgfbr2IEKO, and Apc1638N; LSLTrp53R172H; Tgfbr2IEKO mice.
by Dr. Edward Lin
Stem cells and cancers bear strikingly similar biologic characteristics, notably limitless self-renewal potential. Indeed, literature suggests that only 1 to 2 percent of cancer cells are cancer stem cells, now found in gliomas, melanomas, and cancers of the colon, liver, kidney, and prostate. CD133, a stem cell marker, identifies these cancer stem cells but also enriches the endothelial progenitors mobilized from the bone marrow that are found in cancer patients. More importantly, elevated circulating endothelial progenitor levels are a proven favorable cardiovascular risk factor.
The hypothesis that Dr. Edward Lin, associate professor at University of Washington and Fred Hutchinson Cancer Research Center, tested is that whether elevated stem cell levels measured by CD133 mRNA in the peripheral blood predict bad cancer outcomes.
At the 2007 American Society of Clinical Oncology conference, Dr. Lin presented initial evidence at an oral session on molecular genetics that elevated stem cell marker CD133 mRNA predicts colon cancer recurrence. Dr. Lin used real-time RTPCR to quantify CD133 mRNA levels from peripheral blood mononuclear cells (PBMC) of 66 colorectal cancer patients. Data showed that risk of colorectal cancer recurrence was 22 times higher among patients with CD133 levels > 4.79 compared with those with levels of ≤4.79 (P=0.02) and patients with advanced staging (III/IV) have a 17 times higher risk of recurrence compared with patients with stage I-II disease. Additionally, CD133 levels >4.79 were also associated with a poor survival probability (P = 0.035).
With cancer stem cells or normal stem cells in the peripheral blood being rare and difficult to characterize, Dr. Lin believes, “large prospective studies with serial time points, uniform stage I-III colon cancer, and standardized commercial-grade assays are warranted.” The full manuscript is now published in the August 2007 issue of Cancer.
In another manuscript (partly presented at ASCO 2007) entitled “Paradoxical relapse-free survival advantage in metastatic colorectal cancer,” Lin shows that maintenance therapy of capecitabine and oral 5FU with celecoxib (an arthritis medication), leads to prolonged complete remission in a selected group treated with combined modality therapy. It is widely understood that the median survival for patients with metastatic colorectal cancer is 20 months after chemotherapy treatment and 40 months after surgery. When Lin treated patients with this combination maintenance therapy combined with multimodality therapy, the median survival went up to 51 months from start of maintenance therapy and to 70 months from onset of metastasis. “Those with confirmed complete response had enjoyed a three-year relapse-free survival of 100 percent, despite the fact that they did not have surgical resection or had positive margin resection,” says Lin. “That is the paradox since 86 percent of the patients are expected to recur within the first year.”
Lin’s sample size is small, but all 19 patients had unresectable metastatic colorectal cancer and were from the previous retrospective study of 66 patients treated before 2003. But he has waited several years, watching his patients for relapses and had studied additional patients since 2003. Nine of the 19 patients experienced a relapse after a median follow-up of 31 months. The two-year relapse-free survival (RFS) was 71 percent (95 percent CI, 0.59-1.00) for the 14 unresected and R1-2 resected patients and 20 percent (95 percent CI, 0.10-0.38) for the 5 R0 resected patients (p = 0.07). “The paradoxical RFS advantage was due to maintenance XCEL (p = 0.002), but not any other prognostic or treatment factors in a univariate analysis,” writes Lin in his paper. “All relapses were in situ following discontinuation of XCEL except for the resected cases. Maintenance XCEL also conferred an OS benefit (p= 0.04). The median OS from XCE Land from onset of metastasis was 51.9 months (95 percent CI, 45 months – not reached [NR] and 73.3 months (95 percent CI, NR-NR months), respectively.”
The institutional review board approved Lin’s retrospective study. Nineteen out of 66 patients with unresectable metastatic colorectal cancer achieved complete response with XCEL. But how does this work? “Maintenance XCEL paradoxically improves survival outcomes likely through targeting colorectal cancer micrometastasis,” Lin states.
Eight patients had surgery (three being positive margin resections) and approximately half had chemoradiation with XCEL. “Therefore, most of the durable CR would be due to dormant micrometastasis rather than pathological CR,” he postulates. One patient with synchronous rectal cancer with liver (5 percent) experienced pathological CR at both sites even though only the rectum received chemoradiation.
Macroscopic tumors regress into metastasis, potentially rich in cancer stem cells, that are resistant to conventional chemotherapy or radiation. Lin says that “XCEL appears to inhibit endothelial progenitors required for the earliest step of tumor angiogenesis.” In contrast, tumor angiogenesis might be awakened with conventional chemotherapy administered at maximal tolerated dose, which stimulates endothelial progenitor mobilization.
Celecoxib, a specific COX-2 inhibitor, reduces 50 percent of malignant polyps originating from aberrant crypt cells. But, “celecoxib may attenuate capecitabine-induced handfoot syndrome and improve clinical outcomes,” Lin reported previously. COX-2 is linked to Wnt, a key signaling pathway in stem cell renewal.
In a first step, Lin and others initiated a National Cancer Institute-sponsored phase III clinical trial to look at handfoot syndrome in breast and colorectal cancer patients. “After this study concludes, we’ll try the maintenance therapy on these patients as well,” Lin says. With results as good as he has seen, Lin believes study participants will still be willing to take part in a shortterm, 16-week study randomized to placebo versus celecoxib. Continuation of therapy will be made at the clinicians’ discretion. Lin says that the CD133 mRNA assay, that he and others developed, will be used to gauge the peripheral blood stem cell (endothelial progenitors) levels that have implications in cancer and in heart disease, a topic that is also linked to COX-2 inhibitor use.
Dr. Lin joined Seattle Cancer Care Alliance in 2006 from MD Anderson Cancer Center in Houston, where he researched and led two patent fillings by MD Anderson. Capecitabine is manufactured by Roche Laboratory and Celecoxib is a trademark of Pfizer, Inc.
For your patients that have an increased risk of developing gastrointestinal cancers due to family history or personal risk factors, you may want to explore the services of the GI Cancer Prevention Program at Seattle Cancer Care Alliance. The program is tailored to each patient’s needs. At the appointment, the patient receives a personal risk assessment and develops a cancer prevention and screening plan with consultation from the providers. The program includes three gastroenterologists specializing in a variety of hereditary colorectal cancer syndromes, a certified genetic counselor specializing in hereditary gastrointestinal cancers, a nutritionist specializing in cancer prevention, and a gynecologic oncologist who meets with women who have hereditary syndromes that increase their risk to developing gynecological cancers, as well as gastrointestinal cancers. Patients will receive information about hereditary and non-hereditary GI cancer risk factors and strategies for lowering risk. Components of the plan may include chemoprevention, cancer screening, risk-reducing surgery, changes in diet and vitamin supplements, and new technologies or developments.
Signs of a hereditary gastrointestinal syndrome include:
- A strong family history (two or more close relatives on the same side of the family with cancer, at
least one of which is a GI cancer, especially if cancer was diagnosed before age 50)
- Diagnosis of GI cancer before the age of 50
- Any colon polyps before the age of 40
- More than 10 colon polyps at any age
- Diagnosis of two or more types of cancer (one of which is a GI cancer)
- An abnormal result on a genetic test that is consistent with a diagnosis of a hereditary GI cancer syndrome, such as Lynch syndrome (also known as hereditary non-polyposis colorectal cancer syndrome) or familial adenomatous polyposis (FAP)
Referrals may be made by calling (206) 288-1024.
The relationship between tobacco usage and lung cancer is the best established in all of medicine. In Western Washington, 44 percent of all cases of lung cancer are diagnosed in people who actually quit smoking 10 years prior to diagnosis. It was believed that once a smoker quit the habit their risk for lung cancer significantly dropped. Research has shown that this is not the case; Lung cancer risk is fixed at the time the first cigarette is smoked.
With this in mind, physicians at Seattle Cancer Care Alliance and Fred Hutchinson Cancer Research Center would like to build a cohort study of former smokers to study this phenomenon. The Lung Cancer Early Detection and Prevention Clinic will help smokers and former smokers determine their overall health risks due to smoking and may include screening CT scans for nodules, as well as other lung health tests. It will also help to recruit participants in this study for the future.
The mission of the Lung Cancer Early Detection and Prevention Clinic is to improve the length and quality of life among patients at risk for lung cancer and other disorders caused by tobacco by delivering and integrating state-of-the-art clinical care and research targeted at enhancing prevention, early detection, and treatment.
In summer 2007, Dr. Marc Chamberlain became chief of Seattle Cancer Care Alliance’s Neuro-Oncology Program, part of the University of Washington’s Department of Neurology and new Division of Neuro-Oncology, where he is also a professor.
The focus of this program will be to treat patients with brain or spinal cancers as well as concentrating research efforts to understanding and treating these diseases. New staff joining the program includes a research nurse, program coordinator, information data manager, nurse practitioners, and clinic nurses at University of Washington Medical Center.
Dr. Chamberlain received his medical degree in 1977 from Columbia University, College of Physicians and Surgeons. He holds a degree in Zoology and Biochemistry from the University of California Berkeley. He has published over 170 papers and developed many of the methods used today in evaluating and managing neoplastic meningitis. Since 1995, Dr. Chamberlain has focused increasingly on clinical trials for primary brain tumors.
To refer your patient to the Neuro-Oncology program at Seattle Cancer Care Alliance, call 206-598-1934.
Lung Cancer Early Detection and Prevention Clinic: (206) 288-SCCA (7222). More information is available on the Web at www.sccaearlydetection.org.
How do I refer a patient?
Call our Intake Office at (206) 288-1024.
General Oncology patient case discussions will be transferred to the appropriate Patient Care Coordinator. Marrow or Stem Cell Transplant patient referral cases will be transferred to the Clinical Coordinator. We will review the case with you to determine if it would be beneficial for the patient to come to SCCA for treatment.
What happens after referral?
SCCA is committed to ongoing communications with referring physicians to maintain seamless patient care. UW Medicine offers a secure electronic connection through U-Link to give you instant access to your patient’s information and updated records while at SCCA. Contact the Physician Liaison Program at (206)598-4972 to sign up. Current users may access U-Link at: http://mindscape.mcis.washington.edu/
Use the MEDCON Consultation Service to consult with UW physicians who practice at SCCA. Call (206) 543-5300 in the Seattle area or toll-free (800) 326-5300. The consultation is free.
Fred Hutchinson Cancer Research Center’s Survivorship Program provides clinical care, patient education, and research opportunities to patients who have survived cancer and are not in active cancer treatment or are in long-term therapy to prevent recurrence. Services are provided through the
Hutchinson Center and SCCA, and are supported by the Lance Armstrong Foundation. Survivorship program patients receive thorough screenings and health evaluations by our health-care team, a Survivorship Care Plan that lists therapy and medical information related to the patient’s diagnosis and any possible long-term problems, and recommendations for patients and their health-care providers to ensure that patients stay as healthy and informed as possible.
Click here for more information or contact The Survivorship Program at (866) 543-4272.
A PDF version of the Winter 2008 issue of The Leading Edge
Print out this color PDF of the 12th issue of The Leading Edge.
The SCCA Adult Bone Marrow Transplant News is a publication presenting the latest information on bone marrow transplant research at SCCA, providing up-to-date information for all health care professionals caring for transplant patients.
Read about important outcomes research at the Fred Hutch that may benefit your patients.
Each issue of Clinical Trials Monthly highlights several of the more than 200 clinical trials that are currently recruiting patients at SCCA.
Each quarterly Leading Edge newsletter will highlight a new topic to give you the latest news on leading-edge therapies that SCCA physicians are offering.