Glitches in DNA repair genes predict prognosis in pancreatic cancer

January 14, 2009

SAN FRANCISCO - Variations in mismatch repair genes can help predict treatment response and prognosis in patients with pancreatic cancer, according to research from The University of Texas M. D. Anderson Cancer Center presented today in advance of the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium.

In the study, single nucleotide polymorphisms (SNPs) in genes involved in DNA mismatch repair were associated with response to gemcitabine (Gemzar)-based preoperative chemoradiation, tumor resectability (the likelihood of removing the entire tumor), and overall survival.

"Gemcitabine is a major chemotherapeutic agent used to treat pancreatic cancer, but we don't understand why some patients respond and most patients do not," said Donghui Li, Ph.D., the study's lead author and professor in M. D. Anderson's Department of Gastrointestinal Medical Oncology. "There has been no biomarker for pancreatic cancer used in the clinic to predict response. Our research interest has been to determine whether genetic variation in DNA repair can be a predictor of treatment response or a prognosis factor for patient survival."

DNA repair is a complicated process, Li noted, with various mechanisms responsible for identifying and correcting different types of DNA damage. Mismatch repair genes correct mistakes in DNA replication or trigger cell death (apoptosis) if repair is not possible. Ensuring cell death is critical to preventing the runaway cell division that occurs in malignant tumors.

In the study, Li's group obtained DNA samples from 154 patients with potentially resectable pancreatic adenocarcinomas who were participating in phase II clinical trials of preoperative gemcitabine-based chemoradiation. The researchers evaluated 15 SNPs (also called genotypes) among eight mismatch repair genes (EXO1, MLH1, MSH2, MSH3, MSH6, PMS1, TREX1, and TP73) and correlated them with tumor response to gemcitabine, the likelihood of achieving complete tumor resection, and overall survival.

Individually, five genotypes were associated with tumor response to preoperative gemcitabine-based chemoradiation; six were associated with tumor resectability, and ten were associated with overall survival. However, the combined effects of several genotypes on patient survival were dramatic. For example, 20 of 25 patients with 0 to 1 abnormal genotype were alive at the completion of the study (after a median follow-up time of 49.9 months). In contrast, median survival times were 36.2 months for patients with 2 adverse genotypes; 23.9 months for those with 3; 16.3 months for those with 4; 13 months for those with 5; and 8.3 months for those with 6 - 7.

If confirmed by other researchers, these findings could have a profound effect on how pancreatic cancer is treated. Having established biomarkers like abnormal mismatch repair genes, for example, would make choosing which patients might benefit from surgery much easier, Li explained.

"The doctor always faces a tough choice," Li said. "Among the pancreatic tumors that are technically respectable, 25-30 percent might have very small tumors that have already metastasized to the liver or other organs. For these patients, the tumors recur very shortly after surgery, so these patients actually do not benefit from the traumatic and difficult surgery."

The study results also suggest that variations in mismatch repair genes could be useful in determining which patients will respond best to gemcitabine-based chemoradiation. Having this information would allow physicians to move more quickly to give alternative drugs to a patient unlikely to respond to gemcitabine, Li explained.

"We hope that in the future we will be able to run a genetic test that will help doctors predict a patient's outcome and help them select the best therapy for each patient," Li concluded.

University of Texas M. D. Anderson Cancer Center

---

---

	Pancreatic Cancer: A Patient and His Doctor Balance Hope and Truth (A Johns Hopkins Press Health Book) by Michael J. Lippe (Author), Dung T. Le (Author) Michael J. Lippe was diagnosed with pancreatic cancer in 2007. This is his story, and the story of pancreatic cancer, narrated by Lippe and Dr. Dung T. Le, the physician who is treating him.In telling these stories, Lippe and Le alternate chapters. Lippe writes about the early signs that something was wrong; Le continues with a description of pancreatic cancer, its symptoms, and its treatments. Lippe talks about his prognosis, contemplates the prospect of death, and describes how he began to cope; Le explains the importance, for both doctor and patient, of balancing hope and truth. Lippe speaks frankly about the toll the disease takes on his marriage and family; Le offers a general picture of what most patients can expect with their illness. The book concludes with Lippe and Le’s...
	Pancreatic Cancer: It's a Family Affair by Lisa M Strahs-Lorenc (Author) This is not another book about cancer. The 22 contributors from 20 families who have contributed their stories, their feelings and their advice have done so in order to help others feel that they are not alone. They represent spouses, siblings, adult children and patients themselves. There are 4 survivors as of the writing of this book. In addition, all proceeds from the sale of this book will be going to the Lustgarten Foundation and the Pancreatic Cancer Action Network that offer support and research for an eventual cure of this deadly disease.
	Johns Hopkins Patients' Guide to Pancreatic Cancer (Johns Hopkins Medicine) by Nita Ahuja (Author), JoAnn Coleman (Author) The Johns Hopkins Patients Guide to Pancreatic Cancer is a concise, easy-to-follow how to guide that puts you on a path to wellness by explaining pancreatic cancer treatments from start to finish. It guides you through the overwhelming maze of treatment decisions, simplifies the complicated schedule that lies ahead, and provides valuable tools to help you to put together your plan of care. Empower yourself with accurate, understandable information that will give you the ability to confidently participate in the decision making about your care and treatment.
	100 Questions & Answers About Pancreatic Cancer, Second Edition by Eileen O'Reilly (Author), Joanne Frankel Kelvin (Author) Whether you re a newly diagnosed pancreatic cancer patient, a survivor, or a friend or relative of someone with pancreatic cancer, this book offers help. The only text to provide a doctor s and patient s view, 100 Questions & Answers About Pancreatic Cancer, Second Edition gives you authoritative, practical answers to your questions about treatment options, post-treatment quality of life, sources of support, and much more. The authors, a medical oncologist and a nurse with 25 years of experience with cancer patients, provide a comprehensive, step-by-step discussion of what you can expect in the diagnosis and treatment of pancreatic cancer, while patient commentaries provide a real-life understanding of what these steps might mean for your day-to-day life. This book is an invaluable...
	The Ride Of My Life: A Fight To Survive Pancreatic Cancer by Bob Brown (Author) Insightful, humorous, and inspiring memoir of self-described "regular guy" Bob Brown's courageous battle with pancreatic cancer and his journey through the medical community to save his life. In a conversational tone that feels like you're chatting with a lifelong friend, Bob shares the play-by-play of his fight to stay alive and make the right treatment decisions, affirms the difference a positive attitude can make, and celebrates the unexpected gift of a new perspective on life. What would you do upon hearing your doctor utter the words "inoperable pancreatic cancer"? If you or someone you love has been diagnosed, this amazing story of survival will move you, amuse you, and instill hope in your heart.
	Surviving: How We Loved Through Pancreatic Cancer by K. Blake Cash (Author) "Emma was still channeling Rocky Balboa, talking about how she was going to beat cancer. She defined survival as completely defeating the disease. I defined survival as weathering the storm with grace. She was so strong, surviving on the force of her will. But her body wasn't cooperating, no matter how hard her spirit fought" "Surviving" is the story of one couple's journey with cancer, from diagnosis to death, written by the surviving member of that couple, K. Blake Cash "Beautifully told . . . honest as an arrow" -author and humorist Barry Parham "a beautiful piece of work . . . I know in my heart that she is "out and about" watching over us even now" -Dr. Harish Lavu, Assistant Professor of Surgery, Thomas Jefferson University
	Pancreatic Cancer (M.D. Anderson Solid Tumor Oncology Series) by Andrew M. Lowy (Editor), Steven D. Leach (Editor), Philip Philip (Editor) Since the previous M.D. Anderson Solid Tumor Oncology Series publication on pancreatic cancer, there have been major advances in our understanding of molecular events which underlie pancreatic cancer development, both in the sporadic and inherited forms. This book provides information on the recent progress and improvements. It brings to the forefront the most current advances that have been made in understanding pancreatic cancer development and successfully treating this disease.
	Defeat Cancer: 15 Doctors of Integrative & Naturopathic Medicine Tell You How by Connie Strasheim (Author), 13 Cancer Doctors (Author), Richard Linchitz MD (Introduction), Robert Rowen MD (Introduction) ONE-ON-ONE WITH 15 CANCER DOCTORS: If you traveled the world for appointments with fifteen cancer doctors, you would discover many of the cutting-edge treatments used to heal the body from cancer. You would also spend thousands of dollars on hotels, plane tickets, and medical appointment fees-not to mention the time that it would take to embark on such a journey. Even if you had the time and money to travel, would the physicians have enough time to answer all of your questions? Would you even know which questions to ask? In this long-awaited book, health care journalist Connie Strasheim has done all the work for you. She conducted intensive interviews with fifteen highly regarded doctors who specialize in cancer treatment, asking them thoughtful, important...
	What to Eat if You Have Cancer (revised): Healing Foods that Boost Your Immune System by Maureen Keane (Author), Daniella Chace (Author) Fuel your body to fight cancer Cancer and cancer treatment take a toll on your body, but you can help make cancer treatment more effective and reduce its unpleasant side effects with good nutrition. What to Eat if You Have Cancer presents the best foods to fight cancer and suggests ways to keep your body strong--knowledge you need to take control of your health. A vital resource for cancer patients, this revised edition contains new recipes, new menus, and the latest research on cancer and nutrition. With the help of What to Eat if You Have Cancer, you will learn The foods to eat and the foods to avoid in your fight with cancer The proper use of supplements in nutrition therapy How to create personalized meal plans to complement different types and phases...
	Pancreatic Cancer : A Simple Guide to Pancreatic cancer (Simple Solutions Presents) Pancreatic cancer is one of the ten fastest growing cancer in America and it is important to learn about because it is a silent killer. This is because at times it is difficult to ascertain if you have this type of cancer until it may be too late. This report contains an introduction to pancreatic cancer, risks involved, signs to look out for, and some natural preventative and corrective measures that you can take. This is a simple and straightforward guide that will give you a better understanding of this deadly disease.