Cleveland Clinic researcher discovers genetic cause of thyroid cancer

Genetic analysis revises treatment recommendations related to thyroid cancer

Friday, December 23, 2011, Cleveland: Cleveland Clinic researchers have discovered three genes that increase the risk of thyroid cancer, which is has the largest incidence increase in cancers among both men and women.

Research led by Charis Eng, M.D., Ph.D., Chair and founding Director of the Genomic Medicine Institute of Cleveland Clinic's Lerner Research Institute, included nearly 3,000 patients with Cowden syndrome (CS) or CS-like disease, which is related to an increased risk of breast and thyroid cancer.

Mutations in the PTEN gene are the foundation of Cowden syndrome. PTEN is a tumor suppressor gene, helping to direct the growth and division of cells. Inherited mutations in the PTEN gene have been found in approximately 80 percent of Cowden syndrome patients. These mutations prevent the PTEN protein from effectively regulating cell survival and division, which can lead to the formation of tumors.

"Our investigation into the genetics behind thyroid disease raises important details relevant to diagnosis and treatment," said Dr. Eng. "We hope to promote the earliest diagnosis and most targeted treatment possible."

The conclusions of this research, published in the Journal of Clinical Endocrinology & Metabolism, found that all six patients under age 18 had pathogenic PTEN mutations. The researchers recommend that the thyroids of children with PTEN mutation-causing CS-related disease receive increased surveillance.

Children with thyroid cancer are recommended to have testing for PTEN mutations, which could warrant surveillance for additional cancers or maladies. In contrast, alterations in the SDH and KLLN genes did not associate with thyroid cancer in children.

PTEN gene testing in the setting of genetic counseling is already routinely practiced, and has been a powerful gene-enabled diagnostic test which then personalizes clinical screening and treatment. Once SDH and KLLN findings are independently validated, the tests could be implemented as a clinical routine test as well. Importantly, these three genes belong to different cell pathways so that specific molecular-targeted treatments can be utilized depending on which gene is involved.

CureToday.com: Winter 2011 Article - "Patients on Angiogenesis Inhibitors Should Be Monitored for Heart Issues"

Patients on Angiogenesis Inhibitors (Including Sutent - jhh) Should Be Monitored for Heart Issues

BY KATHY LATOUR
PUBLISHED DECEMBER 21, 2011

Researchers studying the side effects of new cancer treatments have determined that patients taking a class of drugs that target the VEGF pathway should be monitored for cardiac issues that include high blood pressure, heart attack and congestive heart failure.

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The issue is not to stop the drugs’ use but to make oncologists aware that patients taking these drugs need monitoring, says Javid Moslehi, MD, co-director of the Cardio-Oncology Program at the Brigham and Women’s Hospital and Dana-Farber Cancer Institute in Boston.

VEGF, or vascular endothelial growth factor, is a protein released more abundantly by tumors, which signals the growth of blood vessels to feed the tumor, a process called angiogenesis. The increasing numbers of angiogenesis inhibitors in development have made this an important area of research, Moslehi says. During the past seven years, four drugs that target the VEGF pathway have been approved by the Food and Drug Administration for use in a number of cancers, including brain, colon, lung, kidney, liver and gastrointestinal tumors. In addition to Avastin (bevacizumab), the FDA has approved Nexavar (sorafenib), Sutent (sunitinib) and Votrient (pazopanib).

“It has been recognized that these drugs cause hypertension,” Moslehi says, “but it was often ignored because they were treating the patient for cancer. But hypertension can be a long-term issue and lead to a number of cardiovascular diseases, including heart failure and stroke.”

A study reported earlier this year in the Journal of Clinical Oncology examined five randomized trials, which compared 3,784 women with metastatic breast cancer who received chemotherapy regimens containing Avastin with women given regimens that did not include the drug.

“This analysis showed a significant increase in [risk for] high-grade congestive heart failure in women taking Avastin—almost five times higher,” says Toni Choueiri, MD, assistant professor of medicine at Harvard Medical School and lead researcher. “This is clinically significant.” Only 1.6 percent of women taking Avastin actually had high-grade congestive heart failure, so while it’s important to note there is a significantly increased risk, there is still a low incidence overall.

In the study, Choueiri points to research on mice indicating that those lacking the VEGF gene have thinned myocardial walls. “What we know is that VEGF may have cardioprotective effects, and when you block it you may get a certain cardiac toxicity,” Choueiri says, adding that physicians may not have attributed symptoms associated with heart failure to Avastin since symptoms could be attributed to other causes, particularly in the breast cancer population where women may have received other treatments recognized as having cardiac toxicity. For this reason, he says, incidents may not have been cited in the studies.

Moslehi and Choueiri point to the trial process for the newer drugs as a time to identify potential cardiac side effects, learn how they can be managed and determine whether they are reversible.

In October, Moslehi and colleagues published a letter in The New England Journal of Medicine that indicated in certain cases that the heart failure seen with Nexavar and Sutent is reversible. “But more studies are needed that prospectively examine these unwarranted side effects.”

Moslehi and Choueiri have joined forces and combined their expertise—cardiology and oncology—to examine the effects of VEGF inhibitors on the cardiovascular system.

“Ultimately, treating the cardiovascular effects of novel chemotherapies requires a team effort between various physicians working together for the benefit of the patient,” Moslehi says.

Health News - Removal of lymph nodes during surgery for thyroid cancer may be beneficial

Procedure may reduce recurrence rates, lower tumor marker levels

By Rachel Champeau

Papillary thyroid cancer accounts for the majority of all thyroid malignancies, which primarily impact women. A new study indicates that routinely removing lymph nodes in the neck in these cancer patients may help prevent the disease from coming back.

When thyroid cancer metastasizes, lymph nodes in the neck may be affected, but these lymph-node tumors can be tiny and may not be detected by ultrasounds done before surgery to remove the diseased thyroid — or even during the procedure itself.

In an international academic study published in the December issue of the journal Surgery, UCLA researchers and colleagues demonstrate that routine removal of neck lymph nodes during initial thyroid surgery for papillary cancer may lead to lower disease recurrence rates and lower levels of thyroglobulin, a thyroid tumor marker that can be an indicator of disease when elevated.

Although it is standard procedure in some cancer centers, there has been debate in the worldwide surgical community about the benefits of routinely removing neck lymph nodes, a procedure known as prophylactic central neck lymph-node dissection, or CLND.

"We found that re-operation rates due to cancer were lower in patients who had routine removal of these lymph nodes, which suggests a more thorough surgical clearance of disease," said the study's senior author, Dr. Michael Yeh, an associate professor of surgery at the David Geffen School of Medicine at UCLA. "Our findings may help add to growing evidence that this additional procedure, performed during initial thyroid surgery, may be helpful in management of papillary thyroid cancer."

For the study, researchers examined data on 606 patients who received care in one of three endocrine surgical units in the U.S., England and Australia. Patients were divided into two groups: Group A patients had undergone total thyroid removal alone; Group B patients had undergone both thyroid removal and dissection of central neck lymph nodes. Patients were followed for an average of three-and-a-half years following surgery.

The standard pre-operative evaluation of all patients included a fine-needle biopsy of the primary thyroid tumor and determination of neck lymph-node disease status through physical examination and ultrasound of the neck.

The rate of disease recurrence in the entire study population was 6.9 percent. The researchers found that the need for central neck re-operation was significantly lower among patients who had undergone the routine initial central neck lymph-node dissection, compared with those who had undergone only thyroid removal (1.5 percent vs. 6.1 percent).

Stimulated thyroglobulin levels were also lower among patients in Group B, which may demonstrate a more thorough clearing of disease in the patients who had both thyroid and neck lymph-node removal procedures, the researchers said.

"This significant reduction in the need for further surgery in the critical central area of the neck is important, since it reduces risk to the many vital structures housed here, such as the nerves supplying the voice," said study co-author Dr. Mark Sywak of the University of Sydney in Australia.

UCLA's Yeh noted that blood thyroglobulin levels are a useful and sensitive measure in tracking disease recurrence, especially when many tumors in this area are too tiny to be detected using a physical exam or ultrasound.

Rates of temporarily low calcium levels, a common side effect, were significantly higher in Group B patients (9.7 percent), who had neck lymph nodes removed, than in Group A patients (4.1 percent) who had thyroid-removal surgery alone. The rate of long-term complications was low for both groups — about 1 percent.

The researchers said the next step may be to conduct a prospective, randomized clinical trial to further assess the impact of routinely removing central neck lymph nodes during initial surgery for papillary thyroid cancer.

The study took place at UCLA Medical Center; the University of Sydney, Australia; and Hammersmith Hospital at Imperial College London.

Other study authors included Aleksandra Popadich, James C. Lee, Stan Sidhu, Leigh Delbridge and Mark Sywak from the University of Sydney endocrine surgical unit; Olga Levin and Kevin Ro, both students at the David Geffen School of Medicine at UCLA; Stephanie Smooke-Praw from the department of medicine at the Geffen School of Medicine; Maisam Fazel, Asit Arora, Neil S. Tolley and F. Fausto Palazzo from the department of thyroid and endocrine surgery at Hammersmith Hospital in London; and Diana L. Learoyd from the department of endocrinology at Royal North Shore Hospital in New South Wales, Australia.

Clinical Trial Update following Cycles 39 and 40

Hi, Everyone - I made my 12-weekly visit to St. Louis on December 14 for my quarterly poking and prodding.  I got good news again - no new tumors and no growth in the existing ones.  Yea!  There was no shrinkage, but the point of the study is to try for no growth. They are now calling me a Progression Free Survivor (PFS).  Rather an impressive-sounding label, isn't it?  I got no new details about how the study is going from St. Louis, not even hints, but my Lincoln oncologist told me that I'm the longest surviving person with this type of cancer that he's ever heard of.  I hope they say that at my funeral in about 40 years! The side effects, etc., have been about the same but I'm getting used to them after 4-and-a-half years on Sutent.  (That doesn't mean I still don't look for ways to minimize them!) Christopher flew down with me this trip, which was nice.  He's a senior and Washington University in St. Louis is a school he's interested in.  They seem to be interested in him as well.  He came down to be interviewed by their admissions department.  He left feeling pretty good about how things went.  It would be nice if it went so well that they offered him lots and lots of financial aid to attend, but we'll have to wait and see. While Christopher was interviewed in one room, a few other admission people came out and talked to me about him.  They were all familiar with his activities and academics, oddly enough.   They wanted to talk to me mainly about Show Choir and Band and how he managed to do both while taking as many AP classes as he did.  They were really impressed that he chose to take summer classes to free up time during the school year for those other activities.  (And here I thought it was just to avoid mowing the lawn!) He's been admitted to the U of Nebraska and Nebraska Wesleyan here in Lincoln as well as Iowa State (which should make his mother's side of the family happy).  There are a few other schools he's applied to but hasn't heard back from.  I'm not sure to what college he's leaning at the moment, but he has plenty of time to make a decision. Sara and Matthew are both fine.  Matthew's been singing a lot this month with the Lincoln Boys Choir, among other things.  He's about ready for everything to be over though.  His final concert is Sunday, December 18, at 5:00 at St. Paul Church, for all you Lincoln people. My next trip will be March 7.  I bet the daffodils will be up down there by then. Thanks again for all your continuing prayers and support.  Hope you all have a very Merry Christmas and a Great 2012! John