HPV-16

OralDNA Labs introduces OraRisk HPV salivary diagnostic test

Source: www.rdhmag.com
Author: press release

OralDNA Labs , a leader in advancing wellness in dentistry through salivary diagnostics and a subsidiary of Quest Diagnostics, recently introduced a OraRisk HPV test.

The test is a noninvasive, screening tool to identify the type(s) of oral human papillomavirus (also called HPV). Oral HPV is a mucosal viral infection that is a known risk factor for oral, head, and neck cancers.

High-risk types of HPV that persist present an increased risk for cancers in these regions. This test will provide the dental clinician with the ability to establish risk for HPV-related cancers of the oral, head, and neck regions, and determine appropriate referral and monitoring conditions.

Squamous cell carcinoma of the head and neck, which can be found in the oral cavity, tongue, tonsils, oropharynx, and larynx, affects approximately 40,000 individuals in the United States each year.

The most common symptoms of SCCHN include sore throat, earache, hoarseness–and often–enlarged lymph nodes in the neck. Early detection of oral HPV presents an important opportunity to detect those at risk for these types of cancers before symptoms appear.

According to OralDNA Labs’ Medical Director Ronald C. McGlennen, MD, “The availability of the OraRisksm HPV test marks an important and timely advance in oral diagnostics, because the at-risk profile for oral cancer is rapidly changing.”
The use of tobacco and heavy alcohol consumption has traditionally been considered to be the primary risk factor for SCCHN, but an alarming number of new cases are being diagnosed each year among persons who do not fit the tobacco and alcohol user profile.

“In fact, a new high-risk profile for SCCHN has emerged,” explained Dr. McGlennen. “Recent research studies have identified several high-risk strains of the human papillomavirus, especially the variant known as HPV-16, as potential etiologic agents in the development of SCCHN.”

It is now estimated that 50% of all diagnosed cases of oral cancer in the United States are attributed to the HPV virus. It has been well documented that HPV transmission is associated with sexual contact with the risk of contracting HPV higher among those with multiple sex partners.

“Oral HPV is a silent, serious infection that can now be detected and closely monitored by the dental professional,” stated OralDNA Labs’ Chief Dental Officer, Thomas W. Nabors, DDS.

“Specifically, the laboratory report derived from the OraRisksm HPV salivary diagnostic test helps dental professionals identify the specific types(s) of oral HPV present, as well as the associated risk profile for each type of HPV variant detected in the patient’s oral cavity.”

Strong candidates for the OraRisksm HPV test include patients with the following profile characteristics:
* Sexually active
* Family history of oral cancer
* Signs and symptoms of oral cancer
* Traditional risk factors for oral cancer
* Suspicious oral lesions

Salivary diagnostic tests from OralDNA Labs are fundamental elements of a patient’s wellness plan. OraRisksm HPV is the third molecular salivary DNA test that OralDNA Labs has introduced to the dental profession in less than a year. In 2009, the company launched two tests for periodontal disease named MyPerioPath and MyPerioID PST.

Specifically, MyPerioPath identifies the type and concentration of specific perio-pathogenic bacteria that are known to cause periodontal disease and helps support clinicians with better risk assessment and personalized treatment options for more predictable patient outcomes.

MyPerioID PST identifies an individual’s genetic susceptibility to periodontal disease and enables clinicians to establish which patients are at increased risk for more severe periodontal infections due to an exaggerated immune response.

March, 2010|Oral Cancer News|

New vaccine against HPV approved in Canada

Source: www.ctv.ca
Author: staff

Canadian women have a choice of two vaccines against HPV, the family of viruses that can cause cervical cancer, now that Health Canada has approved GlaxoSmithKline’s vaccine, Cervarix.

The vaccine, which is expected to be available by the end of the month, will compete against Gardasil, a product of Merck Canada, which has been on the Canadian market since 2006.

Cervarix has been available in Europe since 2007, and was approved in the U.S. this past fall. Health Canada said its approval was based on a review of clinical trials on nearly 30,000 women.

The competing vaccines will be similarly priced, at about $400. Each vaccine requires three doses and are meant for girls and women aged 10 to 25, ideally before they become sexually active.

While there are differences between the two vaccines, each offers good protection against infection with the most dangerous strains of HPV, the Society of Gynecologic Oncology of Canada (GOC) said in a statement Tuesday. The GOC added that each vaccine has had an excellent safety profile both in pre-market testing and after extensive use worldwide.

Cervarix is designed to protect against two human papillomavirus strains: HPV 16 and 18. Those strains are responsible for more than 70 per cent of cases of cervical cancer.

It also offers some protection against three other cancer-causing strains HPV 31, 33 and 45. Between them, the four strains account for more than 80 per cent of cervical cancer cases.

Gardasil also prevents infection with four strains of HPV 16 and 18, as well as HPV 6 and 11. The latter two strains cause about 90 per cent of cases of genital warts.

In all, there are almost 200 strains of HPV, some that cause common warts on the skin, others that cause genital warts and that are sexually transmitted, and some that cause no symptoms at all.

While a number of strains have linked to cervical cancer, others have been linked to throat cancer, cancer of the head and neck, anal cancer, penile cancer and other cancers of the female genital tract such as vulvar and vaginal cancer.

In Canada, every province and territory now offers school-based HPV vaccination although the age group targeted varies by jurisdiction, from Grade 4 in Quebec through to Grade 8 in Ontario. Currently, all school-based programs use Gardasil. But GSK officials say they are in discussions with several provinces and territories.

The GOC stresses that neither vaccine offers 100 per cent protection and women and sexually active girls should still go for regular Pap screening, regardless of whether they’ve been vaccinated.

“With vaccination, in combination with continued cervical screening, cervical cancer and its precursors are now highly preventable,” the group said in a statement.

In Canada, there are approximately 1,400 new cases of cervical cancer and 420 deaths annually.

February, 2010|Oral Cancer News|

HPV-associated base of tongue squamous cell carcinoma incidence increasing in Sweden

Source: www.hemonctoday.com
Author: staff

The incidence for base of tongue squamous cell carcinoma increased significantly in Sweden between 1998 and 2007, and by 2007, more than 80% of these cases were HPV-positive.

Various studies during the past 20 years have indicated that HPV is a risk factor for oropharyngeal cancer. However, few studies have assessed the specific sub-sites of the oropharynx.

In this study, researchers assessed the increased incidence of base of tongue cancer and the association of HPV in 109 patients diagnosed with base of tongue cancer between 1998 and 2007 in Stockholm, Sweden.

The researchers obtained diagnostic pretreatment paraffin-embedded tumor biopsies from 95 patients. DNA samples were obtained from 30-mcm paraffin-embedded base of tongue biopsy slices. Age at diagnosis ranged from 41 to 85 years.

From 1970 to 2007, the age-standardized incidence of base of tongue squamous cell carcinoma increased from 0.15 per 100,000 person-years between 1970 and 1974 to 0.47 per 100,000 person-years between 2005 and 2007.

HPV DNA was found in 75% of base of tongue cancer cases during this time. Of the HPV-positive tumors, 86% were HPV-16–positive and seven were HPV-33–positive.

During the study period, the incidence of HPV-positive base of tongue cancers persistently increased (see chart). A significant increase was found in the proportion of HPV-positive cancer between 1998 and 2001 compared with 2004 and 2007 (58% vs. 84%; P<.05).

When compared with patients with HPV-negative tumors, patients with HPV-positive tumors were likely to be stage IV (P<.02) and had less advanced T-stage (P<.05 for T2; P<.01 for T3); however, these patients had more advanced N-stage (P<.01 for N0; P<.01 for N2a-c).

Source: Attner P. Int J Cancer. 2010;doi:10.1002/ijc.24994.

February, 2010|Oral Cancer News|

Liverpool scientists working on vaccine for mouth cancer

Source: www.liverpoolecho.co.uk
Author: Liza Williams

ONE central project the scientists and doctors are working on is a vaccine for mouth cancer. Liverpool researchers have found some cases are caused by the HPV virus – the same bug which causes cervical cancer. They have discovered that two-thirds of tonsil cancer tumour samples showed evidence of the HPV-16 gene.

The work is particularly important because the researchers are also seeing the rates of tonsil cancer doubling in non-smokers and non-drinkers – two of the main causes of the disease.

They have found a DNA test helps to predict whether a patient has HPV. This could be used to decide which treatment is best for the patient, because both chemo and radiotherapy are more successful in patients with the virus.

They are now developing a clinical trial for a HPV vaccine for head and neck cancer, like the jab given to teenage girls to prevent cervical cancer.

January, 2010|Oral Cancer News|

Vaccines plus screening could end cervical cancer

Source: www.cancernetwork.com
Author: Fram Lowry

Out with the old and in with the new is a commonly followed maxim in medicine given the rapid pace of developments in diagnosis and treatment. Human papillomavirus vaccines are relative newcomers to the cervical cancer armamentarium, but they cannot be relied on to do the job on their own; screening is still a must.

Richard B. Roden, PhD, from Johns Hopkins University in Baltimore, and Carlos L. Santos, MD, from the Instituto Nacional de Enfermedades Neoplasicas in Lima, Peru, discussed the merits and drawbacks of HPV vaccines and standard screening during a session on female malignancies at ASCO 2009 in Orlando


Long-term protection

The widespread vaccination of adolescents against HPV will be critical to the eradication of cervical cancer, said Dr. Roden, an associate professor in the department of pathology. “HPV virus-like particle [VLP] vaccines are very effective in preventing genital HPV infection and neoplastic disease,” he explained. “Solid protection has been observed for more than six years after vaccination, suggesting vaccine protection is likely to be long-term, although the need for a booster is not out of the question.”

To date, two HPV vaccines are FDA-approved: Gardasil from Merck, produced in yeast, and Cervarix from GlaxoSmithKline, produced in insect cells. In October 2009, Gardasil was approved by the FDA for use in boys and men (aged 9-26) for the prevention of genital warts caused by HPV-6 and HPV-11.

Both vaccines target HPV-16 and HPV-18, the two most common oncogenic HPV types. Gardasil also targets HPV-6 and HPV-11, which cause benign genital warts.

Two types of trials, efficacy trials and immunogenicity bridging trials, have contributed to the licensing of these HPV VLP vaccines. All of the six efficacy trials have been placebo-controlled (randomized 1:1 between vaccine and placebo) and double-blinded, and they have included young women.

“Some of the results from these trials have been confusing to some people, and that reflects the different types of analyses that were done,” Dr. Roden said. The cohorts analyzed were:

• According to protocol (ATP)
• Intention to treat (ITT)
• Modified intention to treat (MITT)

The most clearcut study results came from ATP trials that were conducted with no protocol violations. Also, the endpoints were not counted until the intervention was completed. In ITT, endpoints were counted from the start of enrollment; these trials offer a better estimation of the impact of general use. Finally, in MITT trials, protocol violations were still counted as were endpoints that occurred after one intervention/dose. In the trials with Gardasil and Cervarix, efficacy in the ATP cohort was consistent and impressive, ranging from 96% to 100%. However, the efficacy dropped off in the MITT cohort: between 94% and 100% for the Gardasil trials and between 76% and 94% for Cervarix trials. Based on MITT/ITT analysis for any HPV type, vaccine efficacy came in at 34% in the FUTURE I study, 17% in the FUTURE II study, and 52% in the GSK 001/07 study.

“Why is this efficacy so low? These are really the expected results. The prophylactic vaccine produces somewhat type-restricted protection,” Dr. Roden said. “The vaccine does not induce the regression of established infection. Disease from prevalent infection dominated disease from incident infection in the trials that had a relatively short follow up.” In short, the vaccines are not therapeutic, he added.

The HPV vaccine has been shown to be effective in other groups, Dr. Roden said. ATP data on Gardasil have demonstrated a 90% reduction in HPV-6 and HPV-11 in women aged 24 to 45. It has also been deemed effective in adolescent boys and men (aged 16 to 23), with an approximately 85% reduction in incident, persistent six-month infection and a near 90% reduction in incident external warts caused by the main HPV types.

Finally, immunobridging studies provide rationale for vaccination in groups that were not included in the major trials, such as adolescent girls, he said. Solid protection for more than six years after vaccination suggests that the benefits are long-term.

Screening remains main option in many countries
While the evidence for the efficacy of vaccination may be solid, its widespread, global distribution is less certain at this time. In developing areas with limited resources, vaccination with the current HPV vaccines may not be an option, said Dr. Santos, who is a gynecologic oncologist at his institution. This is particularly problematic because cervical cancer is prevalent in these areas, with the highest incident mortality rates in sub-Saharan Africa, Latin America, and some Asian countries, Dr. Santos said. In half of Latin American countries, cervical cancer is the number one female malignancy.

“Let’s take a look at the development of cervical carcinogenesis in order to understand the place for secondary prevention,” he said. “This is a long-lasting process, starting with HPV infection and ending up in invasive carcinoma capable of killing the host. Fortunately, we have a long period of precancerous or premalignant lesions, usually five to 15 years, and these are easily treatable.”

There are two ways to establish a cervical cancer screening program, Dr. Santos said. An opportunistic program takes advantage of any visit that a female patient makes within her healthcare system as a chance for screening. An organized program is promoted by a central public health institution, which ensures coverage to all at risk.

The standard methodology for screening is cytology, followed by colposcopy if it is deemed necessary, followed by biopsy. This system has proved very effective in industrialized nations, Dr. Santos pointed out. He cited data from Scandinavia as an example. “Sweden and Finland get the best results in terms of reduction of the mortality rate because they have long-standing and very well organized screening programs,” he said. “Norway started screening a bit later compared to its neighbors. In Denmark, there is a mixture of opportunistic and organized screening and their results are not as good.”

Unfortunately, developing nations cannot claim such success rates, Dr. Santos said. Some of the reasons that screening has failed include:

• Failure to reach the population at risk
• Lack of sensitivity of cytologic screening
• Infrequency of repeated screening
• Inadequate management of abnormalities found at screening
• Ineffective treatment

However, some countries are having success with screening programs that work outside the confines of traditional, cytology-based methods. In Peru, a “see and treat” approach has been effective, Dr. Santos said. The 10-minute screening starts with the application of a solution of 5% acetic acid on the cervix, which will demarcate the borders of any lesion in the transformation zone. Any lesions that are found are considered high-grade and are treated immediately with cryotherapy, he said, adding that the advantage of cryotherapy is that it is an outpatient procedure that requires no anesthesia.

While HPV vaccination may not happen in developing nations for some time, HPV DNA testing is coming to the forefront as the primary screening method. HPV DNA testing offers many advantages, according to Dr. Santos. “It has a sensitivity over 95%, although it is less specific than cytology,” he said. “Another virtue of HPV DNA testing is that it has very good predictive value: having a negative HPV test means that there is little or no probability of developing a lesion in the next 10 years.”

The obstacle to using HPV testing in the developing world is cost, with the price tag on an individual test ranging from $70 to $80. But a less expensive reliable test—the careHPV at $5 per test—is on the horizon, Dr. Santos said. “This is the plan for developing countries. Women will be screened with careHPV. Those with negative studies will return in three to five years for follow-up testing. Those with positive results will be triaged the same day to visual inspection, and if necessary, will be treated with cryotherapy.”

Even after HPV vaccination goes global, screening will still be necessary, he said. Women who have been vaccinated will undergo screening with HPV DNA testing or biomarker testing later in life (around age 30), and the interval between screenings may be as long as a decade, Dr. Santos predicted.

December, 2009|Oral Cancer News|

Cervarix® vaccination against HPV lasts at least six years

Source: professional.cancerconsultants.com
Author: staff

Researchers affiliated with the GlaxoSmithKline Vaccine HPV-007 Study Group have reported that Cervarix® [human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine] has “high and sustained immunogenicity, and a favorable safety” profile for up to 6.4 years following administration. The details of this study appeared in an early online publication in the Lancet on December 3, 2009.[1]

Cervarix is approved by the U.S. Food and Drug Administration for the prevention of cervical pre-cancers and cervical cancer associated with HPV types 16 and 18. It is approved for use in girls and women between the ages of 10 and 25 years.

Human papillomaviruses consist of more than 100 different viruses. Some types of HPV cause warts on the hands or feet; others cause genital warts; and some have been linked with cancer, most notably cervical cancer. The types of HPV most commonly linked with cervical cancer are HPV 16 and HPV 18, but several other high-risk types contribute to cancer as well.

The types of HPV that cause cervical cancer or genital warts are transmitted sexually. HPV infection is extremely common and generally occurs soon after an individual becomes sexually active. Although most infections resolve on their own, some persist and can lead to precancerous or cancerous changes to the cervix, vulva, vagina, penis, and anus. HPV infections have also been linked with some head and neck cancers.

The first HPV vaccine to be approved in the United States was Gardasil®, which protects against HPV types 6 and 11 (linked to genital warts), as well as the cancer-associated types 16 and 18. Cervarix also protects against HPV types 16 and 18. Both Gardasil and Cervarix are intended to prevent infection with certain types of HPV and do not treat existing HPV infections or cervical abnormalities. It’s also important to keep in mind that these vaccines do not protect against all types of HPV; women who are vaccinated should continue to be screened for cervical cancer.

The current report presents the results of follow-up analyses of young women participating in two randomized controlled trials of Cervarix for prevention of cervical cancer with follow-ups extending to 6.4 years. These authors reported that prevention of HPV 16/18 was 95.3% and prevention of persistent infection was 100%. Cervarix was 100% effective in preventing cervical intraepithelial neoplasia (CIN) 2+ associated with HPV 16/18in young women. Cervarix was 72% effective in preventing lesions independent of HPV DNA. They also reported that antibody concentrations remained 12 times higher than in control women. There were also no more side effects to the vaccine than to the placebo.

Comments:
This is important information, as durability of vaccination is a necessity for application to underdeveloped countries, where the risk of cervical cancer is the highest. An accompanying editorial suggests that this new information provides an impetus to develop methods to vaccinate more young women before sexual activity in order to prevent the 0.5 million new cases of cervical cancer that occur worldwide each year.[2]

References:
[1] The GlaxoSmithKline HPV-007 Study Group. Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebo-controlled trial up to 6.4 years. Lancet [early online publication]. December 3, 2009.

[2] Clifford GM. Global access to HPV vaccination: what are we waiting for? Lancet [early online publication]. December 3, 2009.

December, 2009|Oral Cancer News|

HPV vaccine clears viral infection and may reduce cancerous lesions

Source: www.newswise.com
Author: staff

Breakthrough study reports complete and partial remissions following vaccination

A new vaccine designed to stimulate an immune response against a cancer-causing human papillomavirus (HPV-16) can eliminate chronic infection by the virus and may cause regression of precancerous genital lesions in women who receive the vaccine.

According to a report published in the November 5 issue of the New England Journal of Medicine (2009;361:1838-47), the vaccine successfully induced HPV-specific immune responses in 100% of patients with advanced vulvar intraepithelial neoplasia (VIN3), a life-threatening disease that in the majority of cases results from HPV infection and for which there is as yet no satisfactory standard therapy.

Among the women who participated in the study, the majority (79%) experienced measurable regression of their VIN3 lesions within 1 year of vaccination. Nine of the women (47%) experienced complete disappearance of lesions and were still symptom-free two years following vaccination. The virus was undetectable in four of five women whose disease had regressed completely after the first year.

According to researchers who conducted the phase II study at the Leiden University Medical Center in Leiden, The Netherlands, spontaneous regression of HPV-16 positive VIN3 lesions is very rare, occurring in less than 1.5% of patients. The induction of HPV-specific T-cell immune responses following vaccination, and the researchers’ observation that stronger vaccine-induced immune responses correlated with better clinical outcome indicate that the vaccine is the most likely cause of the high response rate among the patients treated in the study.

Unlike recently approved vaccines that prevent against infection by HPV, such as Merck’s Gardasil® and GlaxoSmithKline’s Cervarix®, this is a therapeutic HPV vaccine for people who have already been exposed to HPV and who are unable to clear the virus on their own and are at high risk of developing HPV-related cancer.

The vaccine is composed of HPV synthetic long peptides (SLP®), a proprietary technology developed by Dr. Cornelis Melief and others at Leiden University in The Netherlands in partnership with ISA Pharmaceuticals. In recognition of this and his other important contributions to the development of immune-based therapies for cancer, Dr. Melief received in June of this year the 2009 William B. Coley Award for Distinguished Research in Tumor Immunology from the Cancer Research Institute (CRI), a nonprofit organization based in the United States dedicated exclusively to harnessing the power of the immune system to treat, control, and prevent cancer.

To accelerate the testing and refinement of synthetic long peptides in the treatment of cancers that are not of viral origin, the Cancer Research Institute awarded Dr. Melief a grant of $300,000 for the establishment of a Good Manufacturing Practice (GMP) facility at Leiden University. The facility will produce clinic-grade synthetic long peptides for use in clinical trials within the Cancer Vaccine Collaborative (CVC), a joint program of the Cancer Research Institute and the Ludwig Institute for Cancer Research Ltd (LICR) in 2009.

The CVC is a global network of academic clinical trial sites and immune monitoring laboratories that is carrying out a coordinated program of early stage trials of therapeutic cancer vaccines. To date, the CVC has conducted more than 40 trials of various combinations of therapeutic vaccines targeting highly immunogenic cancer antigens, chiefly the NY-ESO-1 antigen. NY-ESO-1 is a prototypic member of the cancer-testis (CT) family of antigens, which are expressed in cancer but not normal adult tissue. In a recent publication, the National Cancer Institute prioritized this antigen among the top 10 most promising cancer immunotherapy targets available. NY-ESO-1 has been the central focus of CVC and other CRI or LICR sponsored studies for more than a decade.

Dr. Melief will supply CVC investigators with synthetic long peptides derived from XAGE antigens, which have properties similar to other CT antigens including NY-ESO-1. XAGE antigens are expressed in a number of cancers, particularly adenocarcinoma of the lung. CVC investigators will test the efficacy of delivering XAGE in the form of synthetic long peptide as compared to vaccines that deliver XAGE in the form of whole protein or DNA.

Upon completion of the GMP upgrade to Leiden University’s synthetic long peptide production facility, it will be the second of two academically funded and operated bioproduction facilities within the CVC network. The first, at Cornell University in Ithaca, New York, recently completed production of clinic-grade recombinant NY-ESO-1 protein for CVC trials in melanoma and ovarian cancer, and is now producing clinic grade Melan-A/MART-1 protein for CVC clinical trials.

About vulva epithelial neoplasia
An epithelial neoplasia occurs when cells lining the outer layers of the body (for instance the skin and inside the mouth, intestines and the genitalia) start dividing and growing in an unusual way. An epithelial neoplasia can manifest itself as a wart or a lump, and in some cases it can develop into cancer, if left untreated. A majority of epithelial neoplasias of the vulva (the outer parts of the female genitalia) are caused by an infection of human papilloma virus type 16. Symptoms of the disease include discomfort, itching, irritation, pain and local bleeding. Epithelial neoplasia of the vulva is chronically debilitating and life-threatening due to the associated symptoms and the high risk of developing invasive cancer. (Source: ISA Pharmaceuticals)

About the CRI/LICR Cancer Vaccine Collaborative
The Cancer Vaccine Collaborative is a partnership between two not-for-profit institutions, the Cancer Research Institute (CRI) and the Ludwig Institute for Cancer Research (LICR). Each of these institutions has a long and distinguished history in the field of cancer immunology and each is committed to translating laboratory discoveries in this field into therapeutic cancer vaccines. Begun in 2001, the CRI/LICR Cancer Vaccine Collaborative supports and coordinates a network of early phase cancer vaccine trials at nineteen hospitals and medical centers around the world. Driven by a scientific agenda, these parallel, single-variable trials use defined antigens, standard treatment protocols, uniform monitoring methodologies, and centralized data collection to provide comparable results that are teaching us how to effectively immunize against cancer.

About the Cancer Research Institute
The Cancer Research Institute (CRI) is the world’s only non-profit organization dedicated exclusively to the support and coordination of scientific and clinical efforts that will lead to the immunological treatment, control, and prevention of cancer. Guided by a world-renowned Scientific Advisory Council that includes four Nobel Prize winners and twenty-nine members of the National Academy of Sciences, CRI supports leading-edge cancer research at top medical centers and universities throughout the world. The Cancer Research Institute is ushering in a new era of scientific progress, hastening the discovery of effective cancer vaccines and other immune-based therapies that are providing new hope to cancer patients.

The Cancer Research Institute has one of the lowest overhead expense ratios among non-profit organizations, with more than 85 percent of its resources going directly to the support of its science, medical, and research programs. CRI meets or exceeds all 20 standards of the Better Business Bureau Wise Giving Alliance, the most comprehensive U.S. charity evaluation service, and according to Charity Navigator exceeds or meets industry standards and performs as well as or better than most cancer charities. CRI has also received an ‘A’ grade for fiscal disclosure and efficiency from the American Institute of Philanthropy as well as top accolades from other charity watchdog organizations. For more information, visit http://www.cancerresearch.org.

November, 2009|Oral Cancer News|

Human papillomavirus infection and cancers of the oropharynx

Source: www.ajho.com
Author: Robert Haddad, MD

Dana Farber Cancer Institute, Boston, MA
The author was invited to contribute his thoughts on the topic of human papillomavirus and cancers of the oropharynx.

Squamous cell carcinoma of the head and neck (SCCHN) is a major public health problem, affecting nearly half a million individuals worldwide each year. These cancers can arise from the oral cavity, oropharynx, nasopharynx, hypopharynx and larynx.1 Treatment of head and neck cancer is often multidisciplinary, involving chemotherapy, radiation therapy, and surgery. Patient symptoms can include a sore throat, ear pain, odynophagia, or hoarseness. Most patients will present with stage III or IV disease. The major risk factors are smoking tobacco and alcohol abuse. A large number of patients diagnosed with oropharynx cancer, however, have no history of smoking or drinking, and increasing epidemiological, molecular, and clinical evidence suggests that high-risk human papillomavirus (HPV), especially HPV-16, account for the development of these cancers.2-5 Most individuals are unaware of their infection and have no symptoms.

HPV is one of the more common virus groups in the world, and more than 80 types of HPV have been identified. Some types (eg, HPV 6 and 11) are known to cause benign conditions such as genital warts, while other types (eg, HPV 16 and 18) are known to be associated with malignant, cancerous transformation. Although different types of HPV are known to infect different parts of the body, HPV usually infects the epithelial cells of skin and mucosa. The epithelial surfaces include all areas covered by skin and/or mucosa such as the tonsil, tongue base, vagina, penis, and anus. Transfer of the virus between individuals can occur with any type of skin-to-skin or skin-to-mucosa contact. HPV infection is known to be a necessary infection for the development of cervical cancer in women and is a risk factor for the development of anal, penile, and vulvar cancer. It is noteworthy that the site mainly associated with HPV infection in the head and neck area is the oropharynx, particularly the tonsils and tongue base. Other sites, including the oral cavity and larynx, are not. Nasopharynx cancer is associated with another type of virus, Epstein Barr Virus (EBV). It is not clear why the oropharynx is more susceptible to HPV transformation. It is well established that the transmission of genital HPV infections is associated with sexual contact and its prevalence increases among individuals with multiple sexual partners. The means by which HPV is transmitted to the oral cavity is less well understood at this stage but sexual behavior and practices are one possible mode of transmission.3 Oropharynx cancer can be placed in the category of “virally mediated cancers” along with cervical cancer, anal cancer, vulvar cancer, and penile cancer (all associated with HPV), and nasopharyngeal cancer and lymphomas (both associated with EBV).

There is an emerging consensus that 2 pathways exist in oropharynx cancer’s development, one caused by smoking and/or alcohol and another caused by HPV infection. The absence of genetic changes in HPV-positive head and neck cancer contrasts to what is observed in HPV-negative head and neck cancer. In the typical squamous cell carcinomas not caused by HPV, p53 mutations are frequently present. In contrast, HPV-related carcinomas usually do not contain any p53 mutations, and predominantly occur in patients with no excessive tobacco and/or alcohol consumption history, implying that HPV-positive and HPVnegative head and neck cancer represent distinct entities. Furthermore, it has been shown that the outcome of patients with HPV-related tumors is better compared to those with a smoking-related tumor. Indeed, we have enough evidence at this stage to support the notion that patients who have an oropharynx cancer related to HPV will have a longer survival than those whose cancer is not related to HPV. This is likely due to a higher response to chemotherapy and radiation than is seen with HPV-associated tumors. Recently, new evidence has emerged showing that African Americans have a lower incidence of HPV infection, likely accounting for the worse prognosis seen in head and neck cancer affecting these patients.6

The first prospective report of improved outcome in HPV-positive SCCHN comes from the Eastern Cooperative Oncology group (ECOG).7 In a single-arm phase 2 study performed by ECOG, 96 patients with stages III or IV oropharynx or larynx cancer received induction chemotherapy with carboplatin and paclitaxel followed by concurrent chemoradiotherapy with weekly carboplatin and paclitaxel and standard radiation. The presence or absence of HPV oncogenic types in tumors was determined by multiplex polymerase chain reaction (PCR) and in situ hybridization. The authors were able to show that patients with HPV-positive tumors had higher response rates after induction chemotherapy (82% vs 55%) and after chemoradiation treatment (84% vs 57%) compared with patients with HPV-negative tumors. After a median follow-up of more than 3 years, patients with HPV-positive tumors had significantly improved overall survival (2-year overall survival, 95% vs 62%) and, after adjustment for age, tumor stage, and ECOG performance status, lower risks of progression and death from any cause than those with HPV-negative tumors.

A surrogate for HPV infection, p16 positivity, has also recently been found to have a major impact on treatment response and survival in patients treated with radiotherapy alone in the Denmark. Indeed, patients with p16 positive tumors had a 5-year survival of 62%; the survival for those with p16 negative tumors was only 26%.8

RTOG 0129 is a large randomized study comparing chemoradiotherapy with 2 different radiation fractionation schedules. A correlative study presented at the 2009 American Society of Clinical Oncology meeting looked at the association of tumor HPV status and survival for the oropharynx group in this phase 3 study.9 HPV status was evaluable for 73% of oropharynx cases and 60% were HPV16 positive. After median follow-up of 4.4 years, cases with HPV-positive oropharynx cancer had better overall survival (2 year, 87.5% vs 67.2%) and progression-free survival (2 year, 71.9% vs 51.2%). Overall, patients with HPV-positive cancer had a 59% reduction in risk of death and a 46% reduction in risk of progression or death. Second primary tumors were less common among HPV-positive cases and patterns of first failure were similar. Another interesting finding from this study is that smoking status is important for patients with HPV-positive tumors. Mortality was higher for those patients that were smokers compared with nonsmokers in the HPV-positive group. It is likely, based on recent data, that 3 categories of oropharynx cancer patients exist:

Group 1: Oropharynx cancer, HPV positive, no active or prior smoking history. These patients have an excellent prognosis and the vast majority of those are cured with radiation-based therapy. Cure rate: 80% to 90%.

Group 2: Oropharynx cancer, HPV positive, current or former smoker. This is considered an intermediaterisk group with survival that is better than the HPV negative group but inferior to group 1. Cure rate: 50% to 60%.

Group 3: Oropharynx cancer, HPV negative. This group has a poor prognosis and is clearly different than the first 2 groups. Cure rate: 30% to 40%.

The findings regarding HPV and head and neck cancer have yet to be translated into clinical practice. Indeed, treatment recommendations have not changed so far and chemotherapy/radiation therapy and surgery remain mainstays of therapy. Currently, we do not recommend that treatment be tailored to HPV status unless this is done as part of a clinical trial. Going forward, HPV stratification should and would be required in all head and neck cancer clinical trials. There will also be HPV-related oropharynx trials where only patients with this entity are enrolled. This is important since this group is clearly distinct for the HPV-negative group and has a different prognosis. The most interesting option will be “dose de-intensification” for chemotherapy, radiation therapy, or both. Many imminent clinical trials will be looking at a lowered radiotherapy dose or at a radiation therapy alone option (without chemotherapy) for patients. The implications are significant in term of side effects and quality of life. Decreasing the radiation dose will have significant positive impact for patients. It will be crucial as these trials develop to make sure that the high cure rates for these patients are not compromised. HPV-related oropharynx cancer could be the equivalent of Hodgkin disease, for which radiation dose has been lowered significantly or even eliminated from treatment paradigms. Until this is studied in prospective, well-designed clinical trials, oncologists should continue to treat patients with the current standards and only use HPV status as a prognostic factor. Testing for HPV is rapidly becoming a standard approach with oropharynx cancer and in situ hybridization (ISH) appears to be the preferred method, even though a much simpler and more easily performed test (p16 immunohistochemistry) is likely to be as reliable as ISH.

Finally, HPV vaccination is an important tool in fighting cervical cancer in women and undoubtedly will become a tool in the fight against oropharyngeal cancer. Clinical trials looking at expanding vaccination strategies to boys and girls will be crucial in this fight.

References
1. Haddad RI, Shin DM. Recent advances in head and neck cancer. N Engl J Med. 2008;359(11):1143-1154.
2. Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst. 2000;92(9):709-720.
3. D’Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. 2007;356(19):1944-1956.
4. Gillison ML, Lowy DR. A causal role for human papillomavirus in head and neck cancer. Lancet. 2004;363(9420): 1488-1489.
5. Chaturvedi AK, Engels EA, Anderson WF, Gillison ML. Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol. 2008;26(4):612-619.
6. Settle K, Posner MR, Schumaker LM, et al. Racial survival disparity in head and neck cancer results from low prevalence of human papillomavirus infection in black oropharyngeal cancer patients. Cancer Prev Res (Phila Pa). 2009 Jul 29 [Epub ahead of print].
7. Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst. 2008;100(4):261-269.
8. Lassen P, Eriksen JG, Hamilton-Dutoit S, et al. Effect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck. J Clin Oncol. 2009;27(12):1992-1998.
9. Gillison ML, Harris J, Westra W, et al. Survival outcomes by tumor human papillomavirus (HPV) status in stage III-IV oropharyngeal cancer (OPC) in RTOG 0129. J Clin Oncol. 2009;27:15(suppl;abstr6003).

Author disclosures: No relationships with industry were reported.

October, 2009|Oral Cancer News|

DNA test could be key to targeting treatments for head and neck cancer

Source: news.biocompare.com
Author: staff

It is estimated that more than 7,000 people are diagnosed with head and neck cancer each year in the UK and approximately 3,500 cases result in death. These cancers include tumours of the mouth, lips, throat and voice-box, and some have been linked to the sexually transmitted infection, HPV-16. Scientists at Liverpool analysed the DNA of more than 90 cancerous tissue samples to look for genes that indicated infection.

The team found that nearly two thirds of tonsil tumour samples showed evidence of the HPV-16 gene. It is thought that chemical alterations in the virus’s DNA trigger the production of proteins that can alter the rate at which cells grow and repair. This strongly increases the possibility of subsequent cancer development. Recent studies have found, however, that patients who have the HPV infection when they are diagnosed with cancer, respond better to chemotherapy or radiation therapy than those that do not have the infection. The work will be presented at the National Cancer Research Institute’s (NCRI) Cancer Conference in Birmingham today.

Mr Richard Shaw, from the School of Cancer Studies, explains: “Recent evidence demonstrates the possible involvement of HPV in the development of tonsil cancer, particularly in non-smokers. Interestingly, the treatment efficiency of chemotherapy and radiation, seems to differ between HPV positive and negative cases. We also need to find out why only a small percentage of people with this common infection develop this cancer. Our study, however, gives us a new lead towards a risk marker.

“It is thought that HPV interacts in the cell with genes controlling the chemical modification of DNA, which affects gene expression and tumour behaviour. Our study shows that HPV may be a trigger of tonsil cancer, independent of the known common causes, such as smoking or drinking. The work also suggests that a DNA test to determine the activity of HPV, could be used to identify the most effective treatment for each individual patient.

“Liverpool has the largest centralised head and neck oncology practice in the UK and our data show a doubling in the rate of non-drinkers and non-smokers presenting with tonsil cancer. As head and neck cancer is one of the cornerstones of the new CR-UK Cancer Centre in Liverpool, we are pleased to be making real progress in this area of research.”

Researchers are now working to develop a clinical trial for a therapeutic HPV vaccine in head and neck cancer.

Note:
1.The study, supported by the Royal College of Surgeons, is presented at the NCRI Cancer Conference on Monday, 5 October.

2. The Liverpool Cancer Research UK Centre focuses on understanding how cancers start and behave, how to develop better treatments with fewer side effects and how to tackle cancer in low-income communities where survival is lowest. As one of the first CR-UK Centres, Liverpool will set the pace for national and international progress in cancer of the pancreas, head and neck and blood. It will also concentrate on pioneering the latest techniques in surgery, radiotherapy and the treatment of children’s cancers.

3. The School of Cancer Studies brings together the considerable cancer research activities of the Divisions of Haematology, Pathology and Surgery & Oncology. The School forms a major part of the recently formed Liverpool CR-UK Cancer Centre..

4. The National Cancer Research Institute (NCRI) was established in April 2001. It is a UK-wide partnership between the government, charity and industry which promotes co-operation in cancer research among the 21 member organisations for the benefit of patients, the public and the scientific community. NCRI Cancer Conference is the UK’s major forum for showcasing the best British and international cancer research.

5. The University of Liverpool is a member of the Russell Group of leading research-intensive institutions in the UK. It attracts collaborative and contract research commissions from a wide range of national and international organisations valued at more than £93 million annually.

October, 2009|Oral Cancer News|

Scientists identify common HPV genotypes In Northern India, encourage vaccination

Source: www.sciencedaily.com
Author: press release

Although a wide spectrum of human papillomavirus is seen across the population of India, HPV-16 and HPV-18 are the most common types and a vaccination targeting these types could eliminate 75 percent of the cervical cancers in the region, according to data presented at the American Association for Cancer Research Frontiers in Basic Cancer Research Meeting.

Cervical cancer caused by HPV is the most common cancer among Indian women, with an estimated 132,000 new cases and 74,000 deaths annually.

“In terms of cancer death, India has one fourth of the global burden and when you standardize for age it is the highest in the world,” said A. Raj Kumar Patro, a doctoral student in the Department of Microbiology at the All India Institute of Medical Sciences in New Delhi. “Most women present with an advanced state of the disease and compliance with treatment is very poor.”

To effectively vaccinate against HPV, scientists need a greater understanding of the genotype. More than 100 HPV genotypes have been identified in humans and at least 40 are found in the anogenital tract, which makes HPV a moving target.

Patro and colleagues examined 106 women with invasive cervical cancer, 524 women with an unhealthy cervix and a community-based population of women who underwent HPV testing.

Among the women with invasive cervical cancer, 83 percent were linked with HPV-16 or HPV-18. Of those who presented with an unhealthy cervix, 15.5 percent had HPV. HPV-16 and HPV-18 were associated with 34.3 percent of normal disease, 45.4 percent of low-grade disease and 65.7 percent of high grade disease. Overall HPV prevalence in the community cohort was 7 percent.

Patro said the HPV vaccine is generally well received in India, with none of the moral or religious objections like those seen in the United States. However, economics remains a significant barrier.

“The vaccine is better accepted than screening in most cases, but it is difficult for most of the population to purchase it at the current price,” said Patro. “At present it is purchased by the upper classes and if it becomes freely available through advocacy and outreach efforts, it could reach the general population.”

Note:
1. Adapted from materials provided by American Association for Cancer Research.

October, 2009|Oral Cancer News|