Certain genetic alterations may explain head and neck cancer survival disparities

Author: staff

Certain genetic alterations to the PAX gene family may be responsible for survival disparities seen between African-American and non-Latino white men with head and neck cancer, according to results presented here at the Sixth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved, held Dec. 6-9.

“During the last 30 years, the overall five-year relative survival rates for head and neck squamous cell carcinoma (HNSCC) have increased, but despite that, the gap in overall survival rates between non-Latino white patients and African-American patients has remained unchanged,” said Rafael Guerrero-Preston, Dr.P.H., assistant professor at Johns Hopkins University in Baltimore, Md. “This disparity may be due to differences in genetic and epigenetic alterations among African-American patients.”

To test this theory, Guerrero-Preston and colleagues performed a two-stage epigenomic study. In the stage-one discovery phase, the researchers used next-generation sequencing and array-based technologies to evaluate 107 HNSCC samples. In the stage-two validation phase, they validated the findings of the discovery phase and evaluated their effect on survival rates in 279 patient samples from The Cancer Genome Atlas project.

“Our results highlight the differential genomic and epigenomic alterations in PAX, NOTCH, and TP53 pathways between African-American and non-Latino white HNSCC patients, which underlie the complex biology of morphologically similar tumors and explain HNSCC survival disparities,” Guerrero-Preston said. “If further validated in larger cohorts, these discoveries could be used to develop genomic and epigenomic panels that will enable more treatment options, a reduction in treatment cost, and improvement in survival rates for patients with HNSCC.”

The researchers found that African-American HNSCC patients had higher frequencies of p53, FBXW7, and NOTCH1 mutations and no differences in PAX1 or PAX5 methylation across all tumor sites combined. However, when they looked at data based on each tumor site, some differences were discovered.

African-American patients with HNSCC had higher ZIC4, PLCB1, and PAX5 promoter methylation and p53 mutations compared with non-Latino white patients. African-American patients also had no NOTCH1 mutations in nonoropharynx HNSCC. However, in the oropharynx, African-American patients had a higher frequency of combined NOTCH1 mutations and PAX1 methylation.

In contrast, non-Latino white patients with HNSCC had a higher frequency of PAX5 promoter methylation and combined p53 mutation or PAX5 methylation in the oropharynx compared with African-American patients.

All patients with greater PAX5 methylation and p53 mutations had worse overall survival, the researchers found.

Source: American Association for Cancer Research

December, 2013|Oral Cancer News|

Study reveals genetic diversity within tumors predicts outcome in head and neck cancer


Researchers at the Massachusetts General Hospital (MGH) and Massachusetts Eye and Ear Infirmary have developed a new way to predict the survival rate of patients who have squamous cell carcinoma of the head and neck, thanks to a study partially funded by a CPRIT grant. One of the problems with treating cancer is the degree of genetic heterogeneity within a tumor. What this means is that there are sub populations of tumor cells within a given tumor that have different mutations. This makes the cancer difficult to treat because some cells due to their different mutations will be resistant to the same treatment. According to Edmund Mroz, PhD at the MGH center for Cancer Research (lead author of a report in Cancer on May 20, 2013), this new method of measuring genetic heterogeneity can be applied to a wide range of cancers. (Additional co-authors included Curtis Pickering, PhD, and Jeffrey Myers, MD, PhD, both from the University of Texas M.D. Anderson Cancer Center.)


Prior to this study, genes and proteins that are involved with treatment resistance have been identified, however, there has been no way to measure tumor heterogeneity to predict patient survival. Mroz and his group of researchers working in the lab of James Rocco, MD, PhD at MGH developed this new measure by looking at advanced gene sequencing data to calculate a number that indicates the genetic variance found in sub populations of cells within a tumor. They dubbed this new procedure as the mutant-allele tumor heterogeneity (MATH). This measure of heterogeneity has the ability to predict not only the number of mutations present but how widely the particular mutations are shared within different sub populations of tumor cells. This research was published in Oral Oncology (March 2013) and was only able to demonstrate that patients with known factors predicting poor outcomes had lower survival rates or what is known as high MATH scores. So, further research was needed.

Mzor and colleagues have now looked at the tumors from 74 patients that had squamous cell head and neck cancer and analyzed their genetic data. These patients had completed their treatment and researchers had the outcome data as well. The MATH measure was applied and these researchers found that higher MATH scores were correlated with shorter survival and with patients who had genetic heterogeneity. This demonstrates that the MATH scores were well correlated with outcomes more so than earlier predictions based on what was known at the time as identifiable risk factors.

At the moment, the take home message is that MATH values along with clinical findings can help predict survivability based on tumor cell heterogeneity. Furthermore, MATH may be able to determine what type of therapy the patient is best suited for. For example, if their MATH score is high, this calls for therapies that are more aggressive to ensure tumor cell resistance doesn’t occur. On the hand, patients who have low MATH scores, need less aggressive therapeutic approaches.

Study examines role of DNA, HPV in oral cancer survival

Author: DrBicuspid Staff

High-risk types of human papillomavirus (HPV) are increasingly associated with oropharyngeal squamous cell carcinoma (OPSCC). However, HPV-positive OPSCC is highly curable, and patients with HPV have better survival compared with HPV-negative patients, whose cancers are usually associated with alcohol and tobacco use.

To better understand the molecular mechanisms underlying these differences, Jochen Hess, PhD, and colleagues at University Hospital Heidelberg monitored changes in DNA modifications in HPV-positive and HPV-negative OPSCCs (Journal of Clinical Investigation, May 1, 2013).

They applied an array-based approach to monitor global changes in CpG island hypermethylation between HPV-negative and HPV-positive OPSCCs, and identified a specific pattern of differentially methylated regions that critically depends on the presence of viral transcripts. This DNA modification pattern was significantly correlated with improved survival in three separate groups of OPSCC patients, the researchers noted.

“Our study highlights specific alterations in global gene promoter methylation in HPV-driven OPSCCs and identifies a signature that predicts the clinical outcome in OPSCCs,” they concluded.

HPV-positive African-Americans with throat cancer have better outcomes

Author: DrBicuspid Staff

African-Americans with throat cancer who are positive for the human papillomavirus (HPV) have better outcomes than African-Americans without HPV, according to a new study in Clinical Cancer Research (March 26, 2013).

African-Americans who are HPV-negative also fared worse than Caucasians both with and without HPV present in oropharyngeal cancer, concluded lead author Maria Worsham, PhD, from Henry Ford Health System in Detroit, and colleagues.

“This study adds to the mounting evidence of HPV as a racially-linked sexual behavior lifestyle risk factor impacting survival outcomes for both African-American and Caucasian patients with oropharyngeal cancer,” Worsham said in a statement about the study.

To compare survival outcomes in HPV-positive and HPV-negative African-Americans with oropharyngeal cancer, the researchers retrospectively evaluated 118 patients. Among the study group, 67 were HPV-negative and 51 were HPV-positive, and 42% of the patients were African-American.

The study results indicate the following, according to the researchers:

  • African-Americans are less likely to be HPV-positive.
  • Those older than 50 are less likely to be HPV-positive.
  • Those with late-stage oropharyngeal cancer are more likely to be unmarried and more likely to be HPV-positive.
  • HPV-negative patients had 2.7 times the risk of death compared to HPV-positive patients.
  • The HPV race groups differed, with significantly poorer survival for HPV-negative African-Americans versus HPV-positive African-Americans, HPV-positive Caucasians, and HPV-negative Caucasians.

Overall, the study showed that HPV has a substantial affect on overall survival in African-Americans with oropharyngeal cancer, Worsham and colleagues concluded.

April, 2013|Oral Cancer News|

The effect of treating institution on outcomes in head and neck cancer


Patients with head and neck cancer receiving radiation treatment at an academic center have a higher survival rate than those receiving treatment at a community center, according to a study in the December 2012 issue of Otolaryngology–Head and Neck Surgery.

“Despite similar rates of treatment completion and rate of treatment breaks between groups, patients treated in academic centers had more advanced cancer but better survival,” the authors state in their conclusion.

The study evaluated differences in patient characteristics, treatment, and cancer outcomes in the head and neck cancer population at the University of Minnesota from 2002 through 2008. Data were gathered on demographics, general medical data, tumor variables, insurance type, marital status and health behaviors.

The study analyzed 355 patients with mucosal head and neck cancer treated with radiation therapy from 2002 to 2008. One hundred forty-five (41%) received radiation treatment at community hospitals, and 210 (59%) were treated at academic hospitals. Within the academic hospitals group, 197 underwent radiation at the University of Minnesota, and 13 received radiation at an alternative academic center.

Both treatment groups shared similar characteristics in regard to sex, comorbidity, marital status, work status, insurance, and alcohol use. However, the community group had more current smokers and slightly older patients on average. Patients in the academic group were more likely to live in an urban location and had a higher median income. Patients undergoing radiation treatment at university centers had significantly more advanced cancer. After adjusting for these differences in patient characteristics, patients in the academic hospitals had about two-thirds the risk of dying compared with the community hospitals. The five-year survival rate was 53 percent for patients treated in academic centers compared with 33 percent for patients treated in community settings.

As a result of the study, the authors conclude that “more subtle differences in treatment administration and support at academic centers need to be investigated to understand the survival differences.” In addition, the authors note, “Potential disparities in care related to income, socioeconomic status, and geography should be further explored.”

Source: American Academy of Otolaryngology

December, 2012|Oral Cancer News|

Interim results from CEL-SCI’s Multikine Phase III study on head and neck cancer


CEL-SCI Corporation announced today that an interim review of the safety data from its open label, randomized, controlled, pivotal Phase III study of Multikine (Leukocyte Interleukin, Injection) investigational immunotherapy by an Independent Data Monitoring Committee (IDMC) raised no safety concerns. The IDMC also indicated that no safety signals were found that would call into question the benefit/risk of continuing the study. CEL-SCI considers the results of the IDMC review to be important since studies have shown that up to 30% of Phase III trials fail due to safety considerations and the IDMC’s safety findings from this interim review were similar to those reported by investigators during CEL-SCI’s Phase I-II trials. Ultimately, the decision as to whether a drug is safe is made by the FDA based on an assessment of all of the data from a trial.

IDMCs are committees commonly used by sponsors of clinical trials to protect the interests of the patients in ongoing trials especially when the trials involve patients with life threatening diseases, and when, as in cancer clinical trials, they extend over long periods of time (3-5 years). The committee’s membership should include physicians and clinical trial scientists knowledgeable in the appropriate disciplines, including statistics. The CEL-SCI IDMC includes prominent physicians and scientists from major institutions in the USA and abroad who are key opinion leaders in head and neck cancer and who are knowledgeable in all of the disciplines related to CEL-SCI’s study, including statistics.

The Multikine Phase III study is enrolling patients with advanced primary, not yet treated, head and neck cancer on 3 continents around the world. The objective of the study is to demonstrate a statistically significant 10% improvement in overall survival of enrolled patients who are treated with Multikine plus Standard of Care (SOC) vs. subjects who are treated with SOC only. The universally accepted current standard of care for the patient population being enrolled in the CEL-SCI study is surgery plus radiation or surgery plus concurrent radiation and chemotherapy, dependent on the risk factors for recurrence found after surgery. Multikine treated patients receive 15 local injections of Multikine over a 3 week period prior to standard of care treatment. Multikine injections are administered in the area around the tumor and in the area of the adjacent lymphnodes since those two areas are where the tumor is most likely to recur. Multikine is intended to create an anti-tumor immune response to reduce local / regional tumor recurrence and thereby increase the survival of these patients.

Multikine is the first immunotherapeutic agent being developed as a potential first-line treatment for advanced primary head and neck cancer. If it were to be approved for use following completion of our clinical development program, Multikine would become an additional and different kind of therapy in the fight against cancer: one that employs our body’s natural ability to fight tumors.

Source: CEL-SCI Corporation

October, 2012|Oral Cancer News|

Taiwan reports highest oral cancer survivor rate


Taiwan has reported the highest five-year survival rate for patients with oral cancer in the world, a hospital official said yesterday.

On average, more than 70 percent of the oral cancer patients treated at National Taiwan University Hospital (NTUH) live for more than five years after being diagnosed, said Ko Jeng-yuh, head of the hospital’s division of head and neck oncology.

Citing a survey carried out by the American Joint Committee on Cancer, Ko said the survival rate in the United States for such patients in late stages of the disease was lower than 30 percent in 2010.

The NTUH treated 1,288 patients with oral cancer between 2004 and 2009 and after complete treatment, more than 55 percent of the 476 stage-four patients lived for at least five more years, the hospital said.

Taiwan has the world’s highest number of patients suffering from oral cancer, as the majority of patients are middle-aged men who are also the bread winners for their families, said Lou Pei-jen, an NTUH doctor.

March, 2012|Oral Cancer News|

UT MD Anderson article offers one roadmap for defining value in health care, earns national award from leading journal

Author: University of Texas M. D. Anderson Cancer Center

A team from The University of Texas MD Anderson Cancer Center is receiving a national award for a research article tackling a question vital to the future of health care with reform regulations looming, competition growing and costs rising.

The MD Anderson study took on the complex question of defining value in health care and for its paper that outlines one approach, the team has been awarded the 2012 Edgar C. Hayhow Article of the Year Award.

Presented by the American College of Healthcare Executives (ACHE), the winning paper appeared in the organization’s publication, the Journal of Healthcare Management, in the November/December 2010 issue. The Hayhow Award was created in 1959 as a tribute to the organization’s 14th chair and the first practicing administrator to earn a doctoral degree. The award will be presented in March at the ACHE’s annual Congress on Healthcare Leadership in Chicago.

“The medical community understands how fundamental the concept of value is to improve the quality and delivery of care because it impacts patients, hospitals, physicians, insurance providers and regulators,” said Thomas W. Feeley, M.D., professor and head of the Division of Anesthesiology and Critical Care and the corresponding author of the study. “We’ve been looking at this complex question for many years and our paper outlines an approach that has been successful at MD Anderson and one that, we believe, can be applied throughout our institution. While we don’t assert that this approach will work for everyone, we think it’s important information to advance the national conversation.”

The study details MD Anderson’s method of testing the value proposition first described in 2006 by Professor Michael Porter of the Harvard Business School and his collaborator, Elizabeth Teisberg, and defines and measures outcomes and costs in a set of three specific head and neck cancers. It was Porter who first described value in health care as the balance between patient outcomes and costs.

With the Head and Neck Center as its clinical “lab,” the research team studied more than 2,400 patients diagnosed with cancers of the larynx, throat and mouth, and gathered data and costs to define quality in that single setting. Researchers looked at patient survival, the time it took for patients to go through treatment and return to work, and quality of life issues such as swallowing and speaking. The team then analyzed the costs of care based on the diagnosis and stage of disease and found, not surprisingly, that the majority of costs were incurred during treatment.

The model used in the Head and Neck Center for establishing outcomes and defining quality is one that the MD Anderson team believes can be replicated in other clinical areas, though each center will have its own outcomes. For example, while swallowing and eating are important measures for patients with head and neck cancer, for breast cancer survivors, the leading outcomes may be the cosmetic result of treatment and hormonal health.

The study also points out that the true measure of the value proposition lies in a patient’s ability to access accurate and useful information about a provider’s outcomes, costs and experience. As a result, researchers urge providers to seek patient feedback and learn what information is most valuable when making health care decisions.

In addition, the study notes the need for electronic medical records to better integrate and pull key information and a time-driven, activity-based cost accounting system that will detail true costs of treatment for specific conditions and diagnoses.

The team honored for the outstanding article includes Feeley; Heidi Albright, project director in the Department of Clinical Operations; Ronald Walters, MD, MBA, associate vice president for Medical Operations and Informatics and professor in the Department of Breast Medical Oncology; and Thomas W. Burke, MD, executive vice president and physician in chief and professor in the Department of Gynecologic Oncology and Reproductive Medicine.

These four people also form the leadership core of MD Anderson’s Institute for Cancer Care Excellence, a collaborative group that focuses its study on cancer economics, patient safety and quality improvement, information technology, education and outreach development. The institute recently launched initiatives to explore ways to eliminate waste, reduce costs and quantify quality care.

About MD Anderson
The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world’s most respected centers focused on cancer patient care, research, education and prevention. MD Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For eight of the past 10 years, including 2011, MD Anderson has ranked No. 1 in cancer care in “America’s Best Hospitals,” a survey published annually in U.S. News & World Report.

February, 2012|Oral Cancer News|

GP96 is over-expressed in oral cavity cancer and is a poor prognostic indicator for patients receiving radiotherapy

Author: Chien-Yu Lin et al.

Oral cavity cancers (ORC) are the most common cancers, and standard treatment is radical surgery with postoperative radiotherapy. However, locoregional failure remains a major problem, indicating radioresistance an important issue.
Our previous work has shown that GP96 contributed to radioresistance in nasopharyngeal and oral cancer cell lines. In this study, we determined clinical significance of GP96 in ORC by evaluation of GP96 expression and its association with disease prognosis in patients receiving radiotherapy

Total of 79 ORC patients (77 males, median age: 48 years old) receiving radical surgery and postoperative radiotherapy between Oct 1999 and Dec 2004 were enrolled.

Patients in pathological stages II, III and IV were 16.5%, 16.5% and 67%, respectively. For each patient, a pair of carcinoma tissue and grossly adjacent normal mucosa was obtained.

GP96-expression was examined by western blot analysis, and the association with clinicopathological status was determined.

Three-year locoregional control (LRC), distant metastasis-free survival (DMFS), disease-specific survival (DSS) and overall survival (OS) rates were 69%, 79%, 63% and 57%, respectively. We found that 55 patients (70%) displayed GP96-overexpression in the tumor tissue, which correlated with a higher pN stage (p=0.020) and tumor depth (>10 mm) (p=0.045).

Nodal extracapsular spreading (ECS) and GP96-overexpression predicted adverse LRC (p=0.049 and p=0.008). When stratified by nodal ECS, the adverse impact of GP96 remained significant in three-year LRC (p=0.004).

In multivariate analysis, GP96-overexpression was also an independent predictor of LRC, DSS and OS (p=0.018, p=0.011 and p=0.012).

GP96 may play roles in radioresistance which attributes to tumor invasiveness in oral cancer patients receiving radiotherapy. GP96 may serve as a novel prognostic marker of radiotherapy.

However, further independent studies are required to validate our findings in a larger series.

Authors: Chien-Yu Lin, Ting-Yang Lin, Hung-Ming Wang, Shiang-Fu Huang, Kang-Hsing Fan, Chun-Ta Liao, I-How Chen, Li-Yu Lee, Yan-Liang Li, Yin-Ju Chen, Ann-Joy Cheng, Joseph Chang

Source: Radiation Oncology 2011, 6:136

October, 2011|Oral Cancer News|

What accounts for racial differences in head/neck cancer?

Author: DrBicuspid Staff

Why are African-Americans more likely than Caucasians not only to be diagnosed with head and neck cancer, but also to die from the disease? While the answer isn’t a simple one, differences in lifestyle, access to care, and tumor genetics may be partly to blame, according to a new study from Henry Ford Hospital.

The study, which was presented September 14 at the American Academy of Otolaryngology – Head and Neck Surgery Foundation’s annual meeting in San Francisco, also found that African-Americans are more likely to be past or current smokers, one of the primary risk factors for head and neck cancer.

“We’re really trying to understand why African-Americans with head and neck squamous cell carcinoma do so poorly,” said lead author Maria Worsham, PhD, director of research in the department of Otolaryngology – Head and Neck Surgery at Henry Ford, in a news release. “Using a comprehensive set of risk factors that are known to have some bearing on the disease, we’re able to gain a better understanding of what contributes to racial differences and work to help improve patient care.”

This year alone, it’s estimated that 52,140 new cases of head and neck cancer will be diagnosed, and roughly 11,460 will die in 2011 from oral cavity and pharyngeal and laryngeal cancers, she and her team members noted.

African-Americans are more likely to be diagnosed with late-stage head and neck squamous cell carcinoma (HNSCC) and have a worse five-year survival rate than Caucasians. It’s unknown whether significant biological rather than socioeconomic differences account for some of the disparities in outcomes.

To get at the root of these differences, Worsham and her team used a large Detroit multiethnic group of 673 patients with HNSCC. Most notably, 42% of the study group was African-American.

The researchers took a broad approach to the study, examining many of the intertwined variables influencing health and disease to look for differences among African-Americans and Caucasians. In all, the study focused on 136 risk factors, including demographics (age, race, gender), smoking and alcohol use, access to care, and type of cancer treatment (radiation and/or surgery). Tumor characteristics, including stage, biology, and genetics, also were examined.

Among the study findings:

  • While 88% of African-Americans in the study had medical insurance, the majority had Medicare or Medicaid instead of private health insurance.
  • African-Americans also were more likely to be unmarried or living alone, both of which previous studies suggest have a negative impact on quality of life and survival.
  • In terms of cancer treatment, African-Americans in this study were more than two times more likely than Caucasians to receive radiation therapy. The study showed fewer African-Americans (43%) opted for surgery than Caucasians (49%).
  • African-American tumors were six to seven times more likely to present with lymphocytic response.
  • Compared to Caucasian tumors, African-American tumors were almost two times more likely to have loss of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene and gain of the small inducible cytokine A3 (SCYA3) gene. CDKN2A is important to cell cycle regulation, and the SCYA3 gene product has dual roles of tumor lymph node metastasis and local host defense against tumors in HNSCC.
September, 2011|Oral Cancer News|