Cancer and Collaboration

Levy_MiaOne of the bedrocks of our organization is encouraging collaboration between scientists and institutions. We feel strongly that we will find a cure faster when great minds work together. That is why we are so excited about this news from our partners at Vanderbilt-Ingram Cancer Center, who have joined an international consortium of leading cancer centers to share genomic data from patients in an effort to accelerate the pace of cancer research and improve precision medicine.

The American Association for Cancer Research (AACR) launched the AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE) to facilitate data sharing among major cancer centers and researchers.

VICC’s participation in AACR Project GENIE has been spearheaded by Mia Levy, M.D., Ph.D., Ingram Assistant Professor of Cancer Research and director of Cancer Health Informatics and Strategy, pictured here.

“As physicians we are all generating massive amounts of data about patients and the genetic mutations in their tumors, along with patient response to medications and other treatments. But much of that data is kept in silos and has not been shared. AACR Project GENIE is one of the first efforts to make some of this data available for cancer researchers so that we can accelerate the pace of discovery,” Levy said.

Click here to read more.

Gene Mutations May Predict Melanoma Response to Immunotherapies

Douglas Johnson, M.D.

Christine Lovly, M.D., Ph.D.

Melanoma patients whose tumors test positive for mutations in the NRAS gene were more likely to benefit from new immunotherapy drugs, according to a new study led by Vanderbilt-Ingram Cancer Center (VICC) investigators.

Douglas Johnson, M.D., assistant professor of Medicine, and Christine Lovly, M.D., Ph.D., assistant professor of Medicine and Cancer Biology, are co-first authors of the study, conducted in conjunction with colleagues from Memorial Sloan Kettering Cancer Center (MSKCC), New York, and Massachusetts General Hospital (MGH), Boston. The study was funded in part by the T.J. Martell Foundation and published in Cancer Immunology Research.

“We studied a small group of patients but the results were quite suggestive,” Johnson said. “This study highlights the need to find predictive markers that can help us understand which patients will respond to therapy.”

To read more, please click here.

Guest Blog Post: Important Advice if You’re Considering Mastectomy

Ingrid Meszoely, M.D. is Associate Professor of Surgical Oncology and Clinical Director, Vanderbilt Breast Center at Vanderbilt-Ingram Cancer Center.

Following the completion of several large studies in the late 1980s and early 1990s involving thousands of women, it was clearly determined that the number of years a woman lived following breast cancer surgery was exactly the same whether she underwent mastectomy (removing the whole breast) or lumpectomy (just removing the part  of the breast with the cancer). This was a big breakthrough for breast cancer treatment with the realization that more surgery doesn’t result in better outcomes.  Initially this resulted in a trend of women choosing lumpectomy over mastectomy in order to preserve their breasts.

However in recent years, as Dr. Kummerow and many other researchers have found, there is a nationwide trend in choosing mastectomy over lumpectomy despite there being no clear survival advantage.  In addition, many women choose to undergo mastectomy of the non -affected breast despite the fact that the risk of developing cancer in this breast is very low and that it does not have any effect on survival from their current breast cancer.

As a breast cancer surgeon, I see this same phenomenon in my own practice.  The choice of mastectomy on one or both sides is often driven by multiple factors including the fear of cancer coming back or a new cancer on the other side and the wish to do everything one can to prevent this.  This often provides some sense of control and peace of mind in the setting of an overwhelming diagnosis.

When a woman is diagnosed with early breast cancer and given the choice of mastectomy or lumpectomy because she is a candidate for either procedure, the options should be considered carefully.

It should be clearly recognized that mastectomy does not provide 100 percent protection from cancers coming back. Cancers often come back at other sites outside of the breast before they return in the area of the removed breast tissue.  Because mammograms or other imaging studies are not routinely used after mastectomy, the finding of recurrences along the chest depends on continued routine self -exam and clinical exam by their doctor when the tumor is large enough to feel as opposed to being detected on mammogram when it is very small.

Mastectomy is also associated with increased complications compared to lumpectomy and these are often related to the reconstruction, which can be discouraging.  It is even more devastating when there are complications related to the unaffected breast when women choose mastectomies on both sides.

Lymph node surgery often is performed in the setting of mastectomy.  If just a single lymph node is found to be involved with breast cancer, removal of additional lymph nodes is recommended which can result in added complications. However if a lumpectomy is chosen, generally 3 or more lymph nodes need to be involved with cancer before more lymph nodes are removed.

When a woman presents with newly diagnosed early breast cancer and is put in the position of making a decision between lumpectomy and mastectomy, a thoughtful discussion should be initiated with her treating physicians.  Ultimately, the decision is very personal and she should choose the procedure that suits her lifestyle and provides her with the greatest sense of wellbeing.

 

PALB2 Gene Mutation Affects Breast Cancer Risk

Having a family history of breast cancer nearly doubles a woman’s risk of developing the disease and genetic factors are known to play a major role in the origin of breast cancer.

The BRCA1 and BRCA2 genes were identified as major breast cancer susceptibility genes nearly 30 years ago and it is estimated that these gene mutations explain about 50 percent of familial breast cancer cases.  BRCA1 and BRCA2 mutation tests have been widely used in high risk women (e.g., women with a strong family history of breast cancer) for risk assessment and management which may include prophylactic surgical and drug therapy intervention.

However, a significant fraction of familial breast cancer cases remain unexplained. A recent study identified the PALB2 gene as another major breast cancer predisposition gene. The PALB2 (Partner and localizer of BRCA2) gene produces a protein that is crucial for key BRCA2 functions. Mutation carriers of this gene were found to have a 35 percent risk of developing breast cancer by the age of 70, triple the risk seen in the general population.  For breast cancer diagnosed before age 40, having PALB2 mutations was related to an 8 to 9-fold increased risk.  It is estimated the PALB2 mutations explain about 2 to 3 percent of familial breast cancer risk. This study expanded our knowledge of genetic contributions to the familial profile of breast cancer.

Currently, the benefit and risk of deploying preemptive measures like surgery or drug therapy based on PALB2 mutation status is unknown. While the utility of applying PALB2 mutation information for risk management of high risk populations needs to be further investigated, individuals with known mutations of this gene are encouraged to seek genetic counseling because PALB2 mutations are also known to increase the risk of pancreatic cancer and may increase the risk of ovarian cancers. Mutations in PALB2 are very rare in the general population. Thus, screening for PALB2 in the general population appears to be unnecessary.

Xiao Ou Shu, M.D., Ph.D., MPH
Ingram Professor of Cancer Research
Vanderbilt-Ingram Cancer Center

HPV-Positive Head and Neck Cancer Patients May be Safely Treated with Lower Radiation Dose

A new study suggests that lowering the dose of radiation therapy for some head and neck cancer patients may improve outcomes and cause fewer long-term side effects.

The research was presented by lead author Anthony Cmelak, M.D., professor of Radiation Oncology at Vanderbilt-Ingram Cancer Center (VICC), during the 50th annual meeting of the American Society of Clinical Oncology (ASCO), held recently in Chicago.

The study focused on patients with newly-diagnosed oropharyngeal cancers related to the human papilloma virus (HPV). More than two-thirds of new head and neck cancer patients have HPV-positive tumors and the number of these patients is on the rise. Cmelak’s prior cooperative group study found that patients with HPV-positive oropharyngeal cancer have significantly longer survival rates than patients whose tumors are HPV negative.

For the new study, 80 HPV-positive patients with stage III, or IVa,b squamous cell cancer of the oropharynx received induction chemotherapy, including paclitaxel, cisplatin and cetuximab.

After chemotherapy, 62 of the patients showed no sign of cancer and were assigned to receive a 25 percent lower dose of intensity-modulated radiation therapy – an advanced technology that targets the radiation beam more accurately to treat the tumor without harming surrounding tissue. The rest of the patients received a standard IMRT dose. The drug cetuximab was also given to both groups of patients along with the IMRT treatment.

Two years after treatment, the survival for the low-dose IMRT patients was 93 percent.  Those who did not have complete resolution of cancer following induction and went on to get full-dose radiation had an 87 percent two-year survival. Eighty percent of the low-dose patients and 65 percent of standard IMRT patients also showed no evidence of tumor recurrence.  Ninety-six percent of those who had minimal or no smoking history had no evidence of tumor recurrence after two years following treatment, and long-term side effects were minimal.

The investigators concluded that patients with HPV-positive cancer who had excellent responses to induction chemotherapy followed by a reduced dose IMRT and cetuximab experienced high rates of tumor control and very low side effects particularly for those with a minimal smoking history.

Treating tumors in the delicate head and neck region often causes side effects that can be troublesome and long-lasting, including difficulty swallowing, speech impairment, dry mouth, problems with taste and thyroid issues, so any therapy option that reduces these side effects can have an impact on patient quality of life.

“Treatment for head and neck cancer can be quite grueling, so it’s very encouraging to see we can safely dial back treatment for patients with less aggressive disease and an overall good prognosis, particularly for young patients who have many years to deal with long-term side effects,” said Cmelak.

He noted that lower-dose IMRT is not recommended for patients with HPV-negative cancer or larger tumors.

The authors note that further studies of reduced-dose IMRT in HPV-positive patients are warranted.

Other investigators include Jill Gilbert, M.D., VICC; Shuli Li, Ph.D., Dana Farber Cancer Institute, Boston, Massachusetts; Shanthi Marur, M.D., William Westra, M.D., Christine Chung, M.D., The Johns Hopkins University School of Medicine, Baltimore, Maryland;  Weiqiang Zhao, M.D., Ph.D., Maura Gillison, M.D., Ph.D., The Ohio State University, Columbus, Ohio; Julie Bauman, M.D., Robert Ferris, M.D., University of Pittsburgh Cancer Institute; Lynne Wagner, Ph.D., Feinberg School of Medicine, Northwestern University, Chicago, Illinois; David Trevarthen, M.D., Colorado Cancer Research Program, Denver;  A. Demetrios Colevas, M.D., Stanford University, California; Balkrishna Jahagirdar, M.D., HealthPartners and Regions Cancer Care Center, St. Paul, Minnesota;  Barbara Burtness, M.D., Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Funding was provided by The National Cancer Institute, a division of the National Institutes of Health (CDR0000665170).

 

Guest Blog Post: Breast Cancer Research is Saving Lives

Dr. Jennifer Pietenpol, Director of the Vanderbilt-Ingram Cancer Center, B.F. Byrd Jr. Professor of Oncology and Professor of Biochemistry and Otolaryngology (with notebook), meets with breast cancer advocates.

Dr. Jennifer Pietenpol is Director of the Vanderbilt-Ingram Cancer Center, B.F. Byrd Jr. Professor of Oncology and Professor of Biochemistry and Otolaryngology.

During October, the nation seems to be awash in the color pink as individuals, sports figures and even businesses recognize Breast Cancer Awareness Month. This colorful display is a visual reminder that more than 230,000 women will be diagnosed with breast cancer this year and nearly 40,000 will die from the disease. We all have a stake in trying to save the lives of these family members, friends and neighbors.

The encouraging news is that breast cancer death rates in the U.S. are actually falling, thanks to better diagnostic tools and improved cancer therapies. Vanderbilt-Ingram Cancer Center in Nashville has been one of the leaders in the effort to understand what is happening at the molecular level in breast cancer and to test new therapies to address those molecular markers.

In the past two years, investigators in my laboratory have discovered at least six subtypes of triple negative breast cancer – a particularly aggressive form of the disease for which there are few treatments. We are now initiating clinical trials to target these subtypes with specific therapies. A clinical trial for the luminal androgen receptor subtype will combine anti-androgen therapy with a drug targeting the PI3K pathway, which is often altered in this subtype. Another clinical trial will use chemotherapy with a PI3K inhibitor to target the other subtypes of triple negative breast cancer.

Using tumor biopsies that are embedded into the trials, we will also gain information about why certain tumors respond to these treatments while others don’t. In other breast cancer studies, we have tested new therapies that can shrink breast tumors before surgery, giving some women the option for less aggressive surgery and a better chance for a cure.

Many of these research initiatives at Vanderbilt-Ingram are made possible through the support of the T.J. Martell Foundation, which has been a longtime partner of the Cancer Center. In 1993, the Martell Foundation helped launch the Frances Williams Preston Laboratories in support of cancer research at Vanderbilt. Today, under the leadership of Harold (Hal) Moses, M.D., director emeritus of Vanderbilt-Ingram, dozens of scientists in the Preston Laboratories are exploring the mysteries behind breast cancer and working to uncover clues that will lead to better treatments.

In an era of dwindling federal funding for research, financial support from organizations like the T.J. Martell Foundation is crucial for the future of our research mission. We are grateful for the grassroots efforts of Martell-supported initiatives like Team Martina, an organization of singer Martina McBride’s fans who raise funds in support of breast cancer awareness and research. Martina McBride and Team Martina recently donated more than $40,000 to Vanderbilt-Ingram to help us expand our leading-edge cancer research efforts.

Genetic Evaluation and Testing for Cancer – Guest Post

Many thanks to Georgia L. Wiesner, M.D., Director, Vanderbilt Hereditary Cancer Program, for this informative guest blog post.

Recent headlines about Angelina Jolie, a well-known actress and movie producer, and her decision to have a prophylactic bilateral mastectomy to reduce risk for breast cancer have taken the world by surprise. In a recent article, Ms. Jolie outlined her genetic evaluation in which she was found to be the carrier of a mutation in a gene called BRCA1. Because of her gene status, she decided to reduce risk for breast cancer by removing her normal breast tissue.

Why would someone choose to have such a “radical” response to cancer risk? In order to understand the dilemma that many people face, it is important to know that Ms. Jolie’s situation is relatively unusual. In fact, mutations in BRCA1 and BRCA2 only account for 5 percent to 10 percent of breast cancers and 10 percent to 15 percent of all ovarian cancers every year. If a person is found to have a high-risk mutation, then prophylactic surgeries are one of several high-risk management options.  In addition to surgery, there are certain medications as well as enhanced screening and surveillance available for these patients. An important point is that anyone considering this option should be evaluated by a specialist prior to making such an important decision.

The next question might be “how does someone know whether they are at high-risk for cancer?” Fortunately, there are genetic specialists and other health professionals who can help patients understand whether they are at high risk for cancer and then guide patients through the process of genetic testing. The process of genetic evaluation risk assessment and counseling is a new area of medicine called cancer genetics. Genetic professionals will use details from the family history to determine whether testing is a reasonable option.

The Vanderbilt-Ingram Cancer Center, a recognized leader in genetic medicine for cancer, has recently established the Clinical and Translational Hereditary Cancer Program with the primary mission to care for patients and families at high risk for cancer. Importantly, after patients are seen in the Hereditary Cancer Clinic, they can be referred to other caregivers, such as surgeons or high-risk nurse practitioners for further care.

Main Points

  • A small number of people will have an inherited risk for cancer
  • It is important to know your family history of cancer
  • Genetic evaluation and counseling is the first step in understanding cancer risk
  • The VICC Hereditary Cancer Clinic at Vanderbilt University Medical Center is open to all patients for full evaluation and counseling
  • Appointments can be made by calling (615) 343-7400

Georgia L. Wiesner, M.D.
Director, Vanderbilt Hereditary Cancer Program
Ingram Professor of Cancer Research and Professor of Medicine

Vanderbilt Researchers Find Potent Genetic Risk Factor for Breast Cancer

Researchers at Vanderbilt University have found a powerful new genetic risk factor for breast cancer.

Using data from population-based studies of women in Shanghai, China, Jirong Long, Ph.D., assistant professor of Medicine, and colleagues discovered a deletion in a cluster of genes, called APOBEC3 genes, that are known to trigger DNA mutation and which have previously been implicated in cancer.

If a woman has a deletion in one of the two sets of genes she inherits from her parents, her risk of breast cancer increases by 31 percent. If the deletion is present in both sets of genes, her risk increases by 76 percent.

“This is the first copy number variation or CNV identified for breast cancer and is one of the strongest common genetic risk variants identified so far for breast cancer,” the researchers reported in the Journal of the National Cancer Institute.

For the full article, please click here.

Guest Blog Post – The Biologic Picture of Melanoma

Jeffrey A. Sosman, M.D., Director, Melanoma and Tumor Immunotherapy Program
Vanderbilt-Ingram Cancer Center

In the past 10 years, mutations found in melanoma (the most deadly form of skin cancer) have led directly to the development of effective therapies. One example is the BRAF mutation and its inhibitor drug vemurafenib.

The New York Times reported on a new finding uncovered in the DNA of a large number of melanomas tested with extensive DNA sequencing of the whole genome.  This new mutation found by two independent groups is actually not present in a gene that produces a functional protein or enzyme.  Instead, it is a mutation in the portion of the DNA that regulates the expression of an enzyme, telomerase. Telomerase protects the chromosomes from breakdown and the cell from death. High levels of telomerase are seen in many cancer cells, including melanoma, and it protects the cancer cells from a normal dying process.

In a mechanism previously never reported, the newly discovered mutation changes the regulatory portion of DNA so it may be very vulnerable towards activation. In this way, the mutation indirectly allows the telomerase level to increase.

This mutation is found in these exact locations in about 70 percent of melanomas. The mutation provides a link between the BRAF mutations and the regulatory portion of another gene.

The new discovery adds one more piece to the biologic puzzle of melanoma. With each additional piece we are closer to completing the biologic picture of melanoma, which will further our ability to define treatment approaches to kill this deadly cancer.