Christin Melton

Over the past few decades, the annual incidence of oropharyngeal squamous cell carcinoma (OPSCC) has increased sharply in several countries, including in the United States.

A closer look at the data shows that the rise in human papilloma virus (HPV)positive OPSCC accounts for most of the increase.

The Role of Oral Human Papilloma Virus in OPSCC

&ldquo;The proportion of HPV-positive oropharyngeal cancers has increased over the past 20 to 30 years in the US,&rdquo; said Anil K. Chaturvedi, PhD, an investigator in the Infections and Immunoepidemiology branch of the National Cancer Institute (NCI), who has conducted extensive research into the prevalence and natural history of HPV-related OPSCC. Chaturvedi said the proportion of HPV-positive OPSCC was only 16% during the 1980s but climbed to 72% during the 2000s. He and several colleagues have predicted that in 20 years HPV-positive OPSCC will be the predominant head and neck cancer in the US.

Maura L. Gillison, MD, PhD, is a professor of internal medicine and the Jeg Coughlin Chair of Cancer Research, division of medical oncology, at The Ohio State University, and one of the first clinicians to discover the link between oral HPV and oral cancer. It was 1996, and HPV was already recognized as the primary cause of cervical cancer and a driver of other anogenital cancers.

&ldquo;My thesis mentor, Keerti V. Shah, MD, PhD, at John Hopkins School of Public Health, was intrigued by a single case report that found HPV DNA in a cell line derived from an oral cancer. He and I decided to investigate the association further to determine if this was just a one-time rare occurrence or indicative of a more frequent event than was appreciated at the time,&rdquo; Gillison explained.

Since then, Gillison has conducted numerous studies and published several articles on the link between oral HPV and OPSCC. Not surprisingly, the increase in HPV-positive OPSCC coincides with an increase in the prevalence of oral HPV.

&ldquo;Data through 2009 from the Centers for Disease Control and Prevention (CDC) and the NCI indicate an ongoing increase in the rate of oral HPV to that time,&rdquo;

Gillison said. Her research shows that 7% of US men and women 14 to 69 years of age are infected with oral HPV.

The rate of oral HPV is significantly greater among men than among women (10.1% vs 3.6%, respectively;

<.001), and Gillison said she and her colleagues will soon publish a paper that shows men are more susceptible than are women to HPV-positive oral cancer.

Age is also a significant risk factor for oral HPV infection, with higher rates in people 30 to 34 years of age (7.3%; 95% confidence interval [CI], 4.6%-11.4%) and in those 60 to 64 years of age (11.4%; 95% CI, 8.5%-15.1%). Gillison and colleagues found no racial differences in prevalence of oral HPV infection. However, a recent study reported lower rates of HPV-positive OPSCC in black people than in white or Hispanic people or in Asian Pacific Islanders.

More studies are needed to explain these racial differences.

the prevalence of oral HPV infection was 8 times greater in individuals who had experienced sexual intercourse than in people who had not, and having a higher number of partners was associated with a higher likelihood of having oral HPV infection. Approximately 20% of people who reported having had more than 20 sexual partners had oral HPV.

&ldquo;Just like genital HPV, oral HPV seems to be a sexually transmittable disease, and cultural changes in sexual practices over time are certainly having an effect,&rdquo; said William H. Westra, MD, Johns Hopkins. Although oral-to-anogenital contact is strongly believed to be the primary transmission route for oral HPV, the risk of contracting oral HPV this way or through kissing is unclear; the few studies investigating the subject report conflicting results.

More than 200 types of HPV have been identified.6 With most types, the body is able to fight off the infection. However, type 16 and type 18 are highly carcinogenic and responsible for most cervical cancers.

&ldquo;Probably around 95% of HPV-positive OPSCC is due to HPV-16,&rdquo; Westra said, who recommends testing patients with OPSCC for oral HPV infection.

&ldquo;Even if you just tested for HPV-16, you would pick up the vast majority of HPV-related tumors,&rdquo; he explained.

Pathologists at Johns Hopkins automatically test biopsy specimens from suspected oropharyngeal cancer for HPV.

&ldquo;HPV status probably represents the most powerful prognostic indicator for patients with HPV-positive tumors,&rdquo; Westra said, explaining that HPV-negative OPSCC is associated with worse outcomes than HPV-positive disease. Another reason to test OPSCC cancer for HPV is that it may be used to guide therapy in the near future, according to Westra.

&ldquo;Clinical studies right now are looking at de-intensification therapy for patients with HPV-positive tumors, which would minimize the side effects of therapy,&rdquo; he explained.

Although current guidelines do not call for routine HPV testing in patients with OPSCC, oncology consensus groups are moving in that direction, according to Westra.

&ldquo;I&rsquo;m currently working with the College of American Pathologists, and we hope to put out our recommendations within the next year or two,&rdquo; said Westra. He recently published a review on the different modalities available for HPV testing and said the many options make it easy to accurately determine the HPV status of almost all OPSCC tumors.

Although some physicians test all head and neck cancers for HPV, Westra said the published data do not support this.

No medical treatment is available for oral HPV. Many people manage to fight off HPV infection or clear the disease, but without being able to predict who those individuals are, prevention of oral HPV is essential for reducing the risk of OPSCC. Although studies have not specifically tested whether or not HVP vaccination prevents OPSCC, Chaturvedi said, &ldquo;A recent analysis from the NCI-sponsored Costa Rica HPV Vaccine Trial indicated that current vaccines had high efficacy against the presence of HPV in the mouth 4 years after vaccination.&rdquo;

He added: &ldquo;Because vaccination is currently done at younger ages (9 to 26 years), it will take several decades to observe declines in oropharyngeal cancer rates.&rdquo;

Without clear data on how oral HPV is transmitted, physicians may struggle with how to advise their patients on how to prevent oral HVP infection.

&ldquo;For other sexually transmitted infections transmitted through oral sex, such as oral gonorrhea, use of condoms or other barrier methods has been shown to reduce transmission,&rdquo; said Gillison.

Over the past few decades, incidence OPSCC increased sharply worldwide.

HPV-positive OPSCC was 16% during 1980s but 72% during 2000s.

Prevalence of oral HPV was 8 times greater in individuals who had sexual intercourse than in people who had not.

HPV type 16 and type 18 are highly carcinogenic and responsible for most cervical cancers.

HPV status represents prognostic indicator for patients with HPV-positive tumors.

Current guidelines do not call for routine HPV testing in patients with OPSCC, but oncology consensus groups are moving in that direction.

Recent analysis indicated that current vaccines have high efficacy against the presence of HPV in the mouth 4 years after vaccination.

Several clinical trials in patients with HPV-positive OPSCC are ongoing.

Gillison and others have identified smoking as a risk factor for oral HPV, which offers patients another reason to quit. She said it is not clear whether smoking increases the risk of HPV-positive OPSCC but that, &ldquo;preliminary studies suggest smoking mediates the effect of oral HPV infection by promoting persistence of the infection.&rdquo;

What this means, said Gillison, is that, &ldquo;If a person has acquired an oral HPV infection through sexual behavior and they also happen to smoke, their immune system may not clear the infection as effectively as someone who does not smoke.&rdquo;

Several clinical trials in patients with HPV-positive OPSCC are ongoing, and results are expected to be available in the next few years. Oncologists looking for treatment alternatives for their patients with HPV-positive oral cancer can search for an open trial at ClinicalTrials.gov.

Chaturvedi AK, Anderson WF, Lortet-Tieulent J, et al. Worldwide trends in incidence rates for oral cavity and oropharyngeal cancers.

Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States.

Gillison ML, Broutian T, Pickard RKL, et al. Prevalence of oral HPV infection in the United States, 2009-2010.

Steinau M, Saraiya M, Goodman MT, et al. Human papillomavirus prevalence in oropharyngeal cancer before vaccine introduction, United States.

Centers for Disease Control and Prevention. Human papillomavirus (HPV) and oropharyngeal cancerfact sheet. http://www.cdc.gov/std/hpv/STDFact-HPVandoropharyngealcancer.htm. Updated November 22, 2013. Accessed January 22, 2015.

Oral Cancer Foundation. The HPV connection. http://www.oralcancerfoundation.org/hpv. Accessed January 22, 2015.

Westra WH. Detection of human papillomavirus (HPV) in clinical samples: evolving methods and strategies for the accurate determination of HPV status of head and neck carcinomas.

Herrero R, Quint W, Hildensheim A, et al. Reduced prevalence of oral human papillomavirus (HPV) 4 years after bivalent HVP vaccination in a randomized clinical trial in Costa Rica.

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Over the past few decades, the annual incidence of OPSCC has increased sharply in several countries, including in the United States.

Epidemic in Sex-Related Oral Cancer Highlights Need for Guidelines

Precision, personalized, individualized, targeted

 most oncologists are well acquainted with these terms, often used interchangeably to describe a model of care in which a treatment plan is based on patient characteristics and the molecular and genetic profile of the patient&rsquo;s tumor. On Tuesday, President Obama introduced this concept to the nation in his State of the Union Address. &ldquo;Tonight, I&rsquo;m launching a new Precision Medicine Initiative to bring us closer to curing diseases like cancer and diabetes&mdash;and to give all of us access to the personalized information we need to keep ourselves and our families healthier,&rdquo; Obama said.

Other than describing the Precision Medicine Initiative as &ldquo;delivering the right treatment at the right time,&rdquo; the president provided few specifics. However, Jo Handelsman, associate director for science at the White House Office of Science and Technology, offered a few details on the administration&rsquo;s website.

Handelsman referred to the therapeutic approach for most ailments as &ldquo;one-size-fits-all&rdquo; and ineffective.

She described precision medicine as &ldquo;an emerging approach to promoting health and treating disease that takes into account individual differences in people&rsquo;s genes, environments, and lifestyles.&rdquo; As an example of the potential of precision medicine to improve lives, Handelsman and the president mentioned the case of Bill Elder, a 27-year-old medical student who is benefitting from a new targeted therapy designed for the 4% of cystic fibrosis patients who have a rare

In her statement on precision therapy, Handelsman mentioned cancer treatment &ldquo;entering a new era.&rdquo; However, cancer treatment crossed the threshold of this &ldquo;new&rdquo; era decades ago. In the late 1980s, researchers at various institutions independently identified a subtype of aggressive breast cancer that overexpressed the HER2 protein.

In 1998, the US Food and Drug Administration (FDA) approved trastuzumab to treat women with metastatic breast cancer that overexpressed HER2, making it the first cancer treatment with a molecular target.

Despite the success with trastuzumab, in the decade that followed, molecular or genetic factors were seldom a consideration when enrolling patients in clinical trials of novel cancer drugs. If outcomes from a trial evaluating an investigational drug proved disappointing, companies moved onto the next candidate.

In some clinical trials, such as cetuximab for colorectal cancer or imatinib for chronic myeloid leukemia, the prevalence of an as-yet undiscovered resistance mutation was low enough that outcomes for patients with these genetic aberrations did not compromise overall outcomes and the manufacturer was able to secure FDA approval. Only later did researchers delve into why a stubbornly consistent percentage of patients failed to respond to certain therapies. For cetuximab, the problem was a

mutation. Today, drug developers have come to appreciate the benefit of sequencing a cancer&rsquo;s genetic profile, engineering a drug that targets a specific biomarker, and restricting the trial to patients whose tumors test positive for the biomarker of interest. This formula may allow a targeted drug to provide a meaningful clinical response even if it does not prolong survival, and the FDA has approved several oncology drugs on that basis.

The National Cancer Institute (NCI) has already thrown its weight behind precision medicine. In September of last year, the agency launched the &ldquo;Exceptional Responders Initiative.&rdquo; The purpose of this program is to revisit failed early-phase trials of a novel drug candidate to determine whether or not any patients had an exceptional response to the treatment.

The NCI hopes to analyze tissue specimens from these patients for any molecular biomarkers that might account for the surprising response.

Trials being considered for inclusion are those in which less than 10% of patients achieved a complete or durable partial response that persisted for at least 6 months. The NCI has already identified 100 cases eligible for analysis and has also received reports of other exceptional patients from investigators of various cancer drug trials. According to the NCI, the impetus for the program was the surprising response of 1 bladder cancer patient who took part in a trial of everolimus. She achieved a complete response and maintained it for 2 years. Subsequent genetic sequencing of her tumor and the tumors of other trial participants who had partial responses identified several

regulates a signaling pathway targeted by everolimus.

Another new approach to precision medicine in oncology is to pair patients with a drug trial based on their tumor&rsquo;s genetic or molecular profile instead of their tumor type. Novartis recently launched &ldquo;Signature,&rdquo; a clinical trial program that matches investigational cancer drugs or approved cancer drugs being studied for new uses to patients according to predefined genetic alterations, regardless of whether they have breast cancer, lung cancer, or some other tumor type. Novartis describes this as &ldquo;Protocol to the Patient&rdquo; trials because the trial site will be established wherever the patient with the preselected genetic marker has been identified. Treatments being investigated in these trials include buparlisib, dovitinib, binimetinib, encorafenib, and sonidegib.

Memorial Sloan Kettering Cancer Center (MSKCC) is taking a similar approach, which the center describes as &ldquo;basket trials.&rdquo; Patients with any of several types of cancer who possess the requisite molecular target will be enrolled in the same trial.

Oncology, which continues to advance personalized cancer care, has undoubtedly paved the way for specialists in other disease states to move forward with precision medicine initiatives. Although curing the underlying genetic aberration behind a disease like cystic fibrosis or muscular dystrophy may be years away, precision therapy offers the potential to make these and other diseases more manageable and with greater odds of survival. More details on the president&rsquo;s &ldquo;Precision Medicine Initiative&rdquo; are expected in the coming weeks, and the program is likely to be included in his proposed budget for 2016.

Handelsman J. Precision medicine: improving health and treating disease. http://www.whitehouse.gov/blog/2015/01/21/precision-medicine-improving-health-and-treating-disease. Published January 21, 2015. Accessed January 21, 2015.

Somander T. Meet William Elder, Jr., a guest of the first lady at the State of the Union. Published http://www.whitehouse.gov/blog/2015/01/19/meet-william-elder-jr-guest-first-lady-state-union. January 19, 2015. Accessed January 21, 2015.

FDA approves Kalydeco to treat a rare form of cystic fibrosis [press release]. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm289633.htm. Published January 31, 2012. Accessed January 21, 2015.

Herceptin (trastuzumab) timeline. http://www.gene.com/media/product-information/herceptin-development-timeline. Accessed January 21, 2015.

American Society of Clinical Oncology. Extraordinary responders drive concept of basket trial design. http://am.asco.org/extraordinary-responders-drive-concept-basket-trial-design. Published June 24, 2014. Accessed January 22, 2015.

Fauber J, Chu E. FDA approves cancer drugs without proof they&rsquo;re extending lives. http://www.jsonline.com/watchdog/watchdogreports/fda-approves-cancer-drugs-without-proof-theyre-extending-lives-b99348000z1-280437692.html. Published October 26, 2014. Accessed January 22, 2015.

National Cancer Institute. Exceptional responders initiative: questions and answers. http://www.cancer.gov/newscenter/newsfromnci/2014/ExceptionalRespondersQandA. Published September 24, 2014. Accessed January 22, 2015.

Slosberg ED, Kang B, Beck JT, et al. The Signature program, a series of tissue-agnostic, mutation-specific signal finding trials.

Memorial Sloan Kettering Cancer Center. 2013 Annual report: traditional clinical trials versus basket trials. http://www.mskcc.org/annual-report/2013/traditional-clinical-trials-versus-basket-trials. Published February 2014. Accessed January 22, 2015.

Precision, personalized, individualized, targeted â€” most oncologists are well acquainted with these terms.

Precision Medicine: President's New Initiative Is Established Practice in Oncology

The start of 2015 brought news from Novartis that it had signed an agreement with Intellia Therapeutics and Caribou Biosciences to license its proprietary CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 gene editing platform to develop novel treatments for chronic genetic-based diseases. Intellia is a private Massachusetts-based biotechnology company cofounded in November 2014 by Caribou and Atlas Venture to develop new therapies for inherited diseases using Caribou&rsquo;s proprietary CRISPR/Cas9 platform.

Under the 5-year agreement with Intellia, Novartis gains exclusive rights to develop all collaborative programs using Intellia&rsquo;s CRISPR platform to engineer chimeric antigen receptor (CAR) T-cells ex vivo. Together, Novartis and researchers from the University of Pennsylvania have already been evaluating CAR T cells in the oncology setting and have reported positive preliminary results from early phase trials conducted in patients with acute lymphoblastic leukemia and chronic lymphocytic leukemia. Jeff Lockwood, global head of communications, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, explained that, &ldquo;The ability to gene edit CAR-Ts gives us the opportunity to potentially broaden the application of CAR-T therapy. Selective gene targeting allows us to explore allogeneic CAR-T approaches and modulate the efficacy and tolerability of CAR-T therapy.&rdquo;

The agreement also commits Novartis to working with Intellia on developing targets for ex vivo editing of hematopoietic stem cells (HSCs). However, the agreement does not prevent Intellia from pursing its own pipeline of HSC-based therapies. Findings from successful in vitro experiments that used CRISPR/Cas9 to edit genes in HSCs suggest the platform might have strong potential in the development of HSC-based therapies for hereditary blood disorders like sickle cell anemia or hemophilia.

In Novartis&rsquo; agreement with Caribou, Novartis agreed to fund a 1-year collaborative research program and make additional undisclosed investments in exchange for nonexclusive licensing rights to use the Caribou CRISPR/Cas9 platform. In a press release, Novartis said its agreement with Caribou is &ldquo;focused on using Caribou&rsquo;s foundational CRISPR platform and intellectual property as a research tool for drug discovery.&rdquo;

The CRISPR/Cas system is an immune defense mechanism first discovered in

bacteria. Various bacteria and archaea (another type of single-celled microorganism) use the CRISPR/Cas system to defend themselves against invading viruses and foreign DNA. A few different CRISPR systems have been identified, but the one currently generating the most enthusiasm among researchers is the type II CRISPR/Cas9 protein complex, sometimes dubbed the &ldquo;molecular scissors&rdquo; approach. Cas9 is an RNA-guided enzyme that cleaves double-stranded DNA at specific sites in the genome upstream of a protospacer adjacent motif (PAM).

The DNA sequence for every gene has a complementary RNA sequence, and scientists Jennifer Doudna and Emmanuelle Charpentier found a way to program guide RNA to direct Cas9 to highly specific DNA sequences in a cell targeted for editing. Cas9 triggers DNA repair within the cell and can be used to knockout a gene, insert or delete a gene, or even introduce a random mutation. The CRISPR gene editing platform is a cheaper, faster, easier method of gene editing than earlier platforms, and it allows more precise targeting. Doudna and Charpentier have won several accolades for their efforts to unravel the mysteries of CRISPR, and some have speculated a Nobel Prize may be in their future.

Since CRISPR/Cas9 was discovered, it has been studied in several commonly used research organisms, including yeast, zebra fish, flies, nematodes, and mice. In 2014, researchers at the Massachusetts Institute of Technology (MIT) used CRISPR to treat a mouse model of type I tyrosinemia, a condition that results from by a mutation in the gene that codes for the FAH enzyme. The MIT group used guide RNA and Cas9 to deliver a template containing the correct DNA sequence for the FAH gene to cells in the liver. The complex succeeded in inserting a copy of the correct gene into several hepatocytes, which replicated themselves and ultimately replaced enough diseased liver cells to cure the mice.

The start of 2015 brought news from Novartis that it had signed an agreement with Intellia Therapeutics and Caribou Biosciences to license its proprietary CRISPR/Cas9 gene editing platform to develop novel treatments for chronic genetic-based diseases.

Christin Melton | Authors

Articles

Epidemic in Sex-Related Oral Cancer Highlights Need for Guidelines

Precision Medicine: President's New Initiative Is Established Practice in Oncology

Novartis Buys Into Gene Editing With CRISPR/Cas9