Monthly Archives: March 2018

Accurately identifying aggressive head and neck cancers

Source: www.eurekalert.org
Author: press release

The Case Western Reserve-led research team will analyze computerized images of tissue samples for patterns which could become “biomarkers,” or predictors, for determining relative risk for recurrence in one particularly common type of head and neck cancers.

Those tumors, known as oropharyngeal cancers, occur primarily at the base of the tongue and in the tonsils.

Currently, however, oncologists tend to treat all of these tumors with the same aggressive level of therapy. This is the case even though many of the oropharyngeal tumors which are caused by the human papilloma virus (HPV) tend to have favorable outcome-regardless of treatment-while another subset of the tumors progress and metastasize, or spread.

“Right now, it’s a one-size-fits-all therapy for all of these patients with HPV head and neck cancers,” said Anant Madabhushi, MD, the F. Alex Nason Professor II of Biomedical Engineering, founding director of the CCIPD at the Case School of Engineering and primary investigator in the new research.

“There are currently very few validated biomarkers and approaches that are accurate enough to be able to identify which of these cancers are more aggressive or which ones are less aggressive,” he said. “That has limited the ability of clinicians to even hold clinical trials to find out if they can de-escalate therapy for some of these patients-or who needs more aggressive therapy.”

The National Cancer Institute (NCI) recently awarded a $3.15 million, five-year academic-industry partnership grant to Madabhushi and his team to pursue the research and build toward establishing those clinical trials.

Co-primary investigator on the grant is Vanderbilt University’s James Lewis Jr., MD, whose specialty is head and neck pathology, while Cleveland Clinic’s Shlomo Koyfman, MD, and David Adelstein, MD, are co-investigators with expertise in radiation and medical oncology.

Additionally, Pingfu Fu, an associate professor of population and quantitative health statistics at Case Western Reserve, brings expertise in biostatistics. Cheng Lu, a senior research associate in CCIPD is also involved with the project.

Madabhushi’s team is again working with Mark Lloyd, MD, of industry partner Inspirata Inc., the Florida-based company also teaming up with the lab on studies of breast and lung cancer-work supported by more than $6.3 million in NCI funding.

The team presented its data at the 2018 United States and Canadian Association of Pathology (USCAP) meeting in Vancouver this month and has generated data to suggest that the approach could soon become a clinically actionable tool.

Initial results on almost 400 oropharyngeal cancer patients suggests that the technology is independently prognostic of disease progression-meaning that it could stand alone in helping clinicians figure out how aggressive the disease is and then make a more informed decision on how aggressively to treat the cancer.

“In those cancers, they’ve established whether you can modulate your therapy based on the risk profile for those tumors,” Madabhushi said. “But in head and neck, clinicians might have a sense that there are different risk profiles for different patients, but nobody knows for certain. We want to change that by giving them the risk stratification tools to better help the patient.”

March, 2018|Oral Cancer News|

A better understanding of how genetics influences responses to mouth cancer drugs could lead to improved treatment

Source: medicalxpress.com
Author: provided by Agency for Science, Technology and Research (A*STAR)

A single letter DNA mutation is a big determinant of whether patients with advanced oral cancer respond to treatments. Researchers from the National Cancer Centre Singapore (NCCS) and A*STAR who uncovered the mechanisms behind this effect hope their findings will help doctors target treatment more effectively.

Oral squamous cell carcinoma (OSCC) is characterized by the uncontrolled growth of thin, scale-like squamous cells in the outer layer of the mouth. Only around 50 per cent of patients who are treated through surgery or radiotherapy are cured, and the average duration of survival of those with advanced OSCC that recurs following treatment is just 6 to 9 months.

Epidermal growth factor receptors (EGFRs) play important roles in driving the progression of some OSCCs. Drugs that target them, however, only work in a small number of patients.

A 2012 clinical trial led by Daniel Tan at NCCS and A*STAR’s Genome Institute of Singapore had found that the EGFR-blocking drug gefitinib worked well in two patients with two copies of the EGFR coding gene with an adenine (A) nucleobase in place of the more common guanine (G) at a particular location.

More recently, tests by Gopal Iyer, also at NCCS, and Tan showed that OSCC patient-derived cells with the above A/A genotype were sensitive to gefitinib and erlotinib, another EGFR blocker. Those with the G/G or G/A variants exhibited resistance to the drugs.

Editing the DNA of the G/G genotype cells to become G/A at the same location increased their sensitivity to the drugs 70-fold. “We were pretty surprised it had such a dramatic effect,” says Iyer.

The genetic mutation occurs in a section of DNA that modulates the stability of a long non-coding RNA (lncRNA) known as EGFR-AS1. Gene expression tests showed that levels of this lncRNA were significantly higher in G/G genotype cells than in A/A cells.

When cells with the G/G genotype were exposed to small interfering RNAs that reduced their production of EGFR-AS1, their sensitivity to EGFR-blocking drugs increased significantly.

They also found that the tumors of seven patients with the A/A genotype shrank following treatment with EGFR-inhibiting drugs.

While the mechanism underlying this effect is not fully understood, the group has demonstrated that cells of the G/A and A/A genotypes produced higher ratios of one of four variants of EGFR relative to another, and that EFGR-AS1 helps mediate this difference.

Iyer said that new RNA-interference therapies could be developed to target cancers dependent on EGFR signaling. The group is conducting a larger human trial to better understand the biomarkers that could provide for improved targeting of existing treatments.

Source:
Daniel S W Tan et al. Long noncoding RNA EGFR-AS1 mediates epidermal growth factor receptor addiction and modulates treatment response in squamous cell carcinoma, Nature Medicine (2017). DOI: 10.1038/nm.4401

March, 2018|Oral Cancer News|

Management strategies for oral potentially malignant disorders

Source: www.medscape.com
Author: Joel M. Laudenbach, DMD

Oral potentially malignant disorders (OPMDs) include oral leukoplakia (OL), oral erythroplakia, oral submucous fibrosis, oral lichen planus, proliferative verrucous leukoplakia, and actinic keratosis. Once an OPMD has been clinically diagnosed, execution of management strategy is critical. When formulating the strategy, healthcare providers should consider histopathology, lesion characteristics (ie, surface texture, unifocal, multifocal), lesion location in the mouth (ie, tongue, floor of mouth), patient risk factor assessment, and a detailed medical/cancer history.

In this newly published article, Nadeau and Kerr[1] detail various parameters surrounding evaluation and management of OPMDs. The authors make it clear that OPMDs are challenging, each with their own nuances regarding risk for malignant transformation. For example, when OL is unifocal, nonhomogeneous, nodular, or verrucous, there is a much higher chance of the OL becoming dysplastic (12.63-fold) or demonstrating a focus of carcinoma (8.9-fold) when compared with homogeneous types of OLs.[1]

Provider knowledge of these variables is critical when counseling patients about their diagnosis and management options and when selecting interventions along with follow-up care. Although progression to malignancy is difficult to predict with OPMDs, clinicians can account for multiple risk factors such as smoking/alcohol status, high-risk location in the oral cavity, and size of lesion (>200 mm2) to help formulate a tailored management plan for each patient. Consultation with an oral pathologist to discuss the histologic appearance in the context of specific patient history and lesion characteristics can provide additional perspective and/or recommendations.

Modifiable oral cavity cancer risks related to tobacco and heavy alcohol use should be communicated to patients with OPMDs so that they are able to make changes that may lead to regression/disappearance of certain lesions such as OL. Providers confronted with patients who use tobacco and/or heavy alcohol can integrate recommendations for cessation of tobacco[2] and alcohol[3] because they are both established, independent, causative agents for oral cavity cancer and OPMDs.

Available treatment strategies for OPMDs include surgical removal/ablation, photodynamic therapy, and surveillance. The authors make a clear point with supportive studies that traditional surgical excision of dysplastic OPMDs may decrease malignant transformation (MT) risk, yet it does not fully eliminate that risk and, in some instances, has not changed the MT risk when compared with surveillance alone. Appropriate surgical margin identification for OPMDs is clinically challenging. The authors note that smaller excisional margin sizes (1-2 mm) without marginal histologic assessment are common surgical management goals for OPMDs.[1]

Viewpoint
Nadeau and Kerr carefully outline updated considerations for all OPMDs. Healthcare providers involved in screening, diagnosing, referring, and/or managing patients with OPMDs should be well versed in standards of care, including baseline biopsy goals, tobacco/alcohol cessation, currently available interventions, and surveillance care.

Clinicians should also develop a local team of practitioners who are experts in diagnosis and management of OPMDs to help patients obtain the best opportunity for positive outcomes. I encourage readers with interest to retrieve and review the full article by Nadeau and Kerr as a strategy to update your knowledge base and to continue to improve overall morbidity, mortality, and survival rates related to OPMDs.

References:
1. Nadeau C, Kerr AR. Evaluation and management of oral potentially malignant disorders. Dent Clin North Am. 2018;62:1-27.

2. US Preventive Services Task Force. Final recommendation statement. Tobacco smoking cessation in adults, including pregnant women: behavioral and pharmacotherapy interventions. September 2015. https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/tobacco-use-in-adults-and-pregnant-women-counseling-and-interventions1 Accessed March 1, 2018.

3. US Preventive Services Task Force. Final recommendation statement. Alcohol misuse: screening and behavioral counseling interventions in primary care. May 2013. https://www.uspreventiveservicestaskforce.org/Page/Document
/RecommendationStatementFinal/alcohol-misuse-screening-and-behavioral-counseling-interventions-in-primary-care Accessed March 1, 2018.

March, 2018|Oral Cancer News|

The Sate of Liquid Biopsy

Author:Pam Harrison
Date: March 5, 2018
Source: Medscape.com

So called “liquid biopsies” — which can detect circulating tumor DNA (ctDNA) in blood samples — are not yet ready for prime time in the diagnosis or management of early-stage or advanced solid tumors, a new expert review concludes.

These assays are also not useful, outside of clinical trials, for monitoring patients for minimal residual disease following definitive treatment of cancer, nor for cancer screening, the expert review concludes.

The review was prepared jointly by the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) and was published online March 5 in the Journal of Clinical Oncology.

“This is an area of great interest to both pathologists and oncologists, [and] it’s also an area where we see a lot of commercial advertisement and a lot of enthusiasm from the public,” Jason Merker, MD, PhD, cochair of the expert panel, who was representing the CAP, said in a statement.

“We thought it was a good time to look at the literature and take an evidence-based approach to various uses for ctDNA assays,” he added.

“Like all new things in medicine, the use of ctDNA assays in routine cancer care requires evidence of clinical utility. At present, there is insufficient evidence of clinical validity and utility for the majority of ctDNA assays in advanced cancer, including those that interrogate a panel of genes,” said Daniel F. Hayes, MD, coauthor of the review, who was representing ASCO.

“What is promising is that this area of research is rapidly evolving, so there should be enough evidence soon to formulate evidence-based guidance for a variety of clinical scenarios,” Hayes suggested.

Review Based on Literature Review

For the review, panel members identified 77 relevant articles in the literature. They limited their analysis to variants in ctDNA for solid tumors and to sequence or copy number variants in DNA.

 

They assessed overall evidence of the ability of a test to reliably detect the variant or variants of interest (analytic validity); whether a test accurately detects the presence or absence of a pathologic state or predicts outcomes for patients (clinical validity); and whether the use of the test improves patient outcomes compared with not using it (clinical utility).

The authors focused largely on the use of ctDNA assays in the setting of metastatic cancer, because that is the area for which there is most evidence. Much less research supports the use of liquid biopsy in other settings.

Advanced Cancer

“Fundamentally, there are two paradigms to demonstrate clinical utility and the adoption of ctDNA as a clinically useful test,” the panel members write.

The most reliable strategy is to conduct a prospective clinical trial designed to evaluate how well the test performs as a stand-alone diagnostic test. However, no such trial has yet been carried out, they write.

The second approach is to assess whether the ctDNA test in question delivers the same information that physicians would seek through tissue genomic evaluation.

“[D]emonstrating that a ctDNA assay has high agreement with tumor tissue genotyping may provide sufficient evidence of utility for ctDNA assays in driving patient treatment decisions,” the panel members explain.

They go on to document how far short ctDNA assays fall with respect to meeting this high level of agreement.

First, only one polymerase chain reactin–based ctDNA test has been approved by the US Food and Drug Administration and the European Medicines Agency. That test is the COBAS assay for the detection of EGFR genetic variants in non–small cell lung cancer (NSCLC).

Another assay is available in Europe for the detection of the KRAS mutation in colorectal cancer (CRC).

“These assays have demonstrated clinical validity but the clinical utility in this setting is based on retrospective analyses,” the panel members point out.

Even in light of these approvals, the panel members note that physicians should continue to rely on tissue sample analysis if nothing is detected on ctDNA testing.

They also point out that ctDNA levels may drop while a tumor is still responding to treatment, and as a result, the sensitivity of the test may be compromised.

As for tumor types other than NSCLC and CRC, there is limited evidence to support the clinical validity of ctDNA analysis, the panel members conclude.

The clinical utility of assays developed for the detection of other potentially targetable variants, such as BRAF in melanoma, is not yet established, they add.

Further confounding the diagnostic potential of ctDNA testing is the fact that advanced cancers may be “genetically heterogeneous.”

Although ctDNA tests may be able to pick up subclonal variants in cancer, these variants may not predict how well patients will respond to treatments that theoretically target the variant.

“[S]ubclonality may undermine the clinical utility of ctDNA assays,” the panel members state.

 

Monitoring Response to Therapy

Ideally, liquid biopsies could help physicians monitor patients’ response to treatment, as some tumor-associated proteins now enable them to do.

This, too, remains a challenge, because quantifying changes in ctDNA over time is not as simple as determining whether or not a variant is present. Nor has the best unit by which to measure DNA burden been established.

“Correlations between changes in ctDNA levels and tumor responses or outcomes have been demonstrated in small proof-of-principle studies in a variety of cancer types,” the panel members acknowledge.

“However, currently there is a lack of rigorous evidence on clinical validity, let alone clinical utility, because few large, prospective validation studies have been performed on ctDNA-based monitoring,” they conclude.

 

Use to Monitor Residual Disease

Researchers expressed hope that after curative treatment of a solid tumor, ctDNA assays could be used to monitor patients for minimal residual disease, much as is done in hematogic malignancies using assays to detect leukemic cells in blood following completion of chemotherapy.

However, there is not enough evidence to support the ability of ctDNA tests to detect low levels of minimal residual disease in a manner similar to assays used in the management of diseases such as leukemia, the panel members conclude.

Moreover, “[t]he false-negative rate of ctDNA analysis in…patients who relapse without ctDNA being detected and the false-positive rate [in] patients who do not relapse despite the ctDNA assay being positive have not been established sufficiently for any assay,” they caution.

There is also no evidence that treatment based on detection of ctDNA improves patient outcomes, a major metric of clinical validity.

Screening for Cancer

In an ideal world, ctDNA tests could be used in the early detection of cancer in patients who have no signs of disease.

However, the feasibility of using ctDNA tests to screen asymptomatic individuals has not been demonstrated.

“[D]iagnosing the presence of cancer in a patient without cancer, and determining tissue of origin, have not been established,” the authors point out.

There is also a risk that such tests might be positive for cancers in cases in which none exists and thus lead to overdiagnosis. Currently, overdiagnosis is a major problem with, for example, mammography in breast cancer and prostate-specific antigen screening for prostate cancer, the panel members observe.

Dr Merker has served as a consultant to or in an advisory role for Bio-Rad Laboratories, Rainbow Genomics, and Genoux and has received patents or royalties or has other intellectual property in the measurement and monitoring of cell clonality. Dr Hayes owns stock or has other ownership interests in OncImmune and InBiomotion and has served as a consultant or as an advisor to Cepheid. He has also received research funding, mostly for his institution, from AstraZeneca, Puma Biotechnology, Pfizer, Eli Lilly, Merrimack Pharmaceuticals, Parexel, and Menarini Silicon Biosystems (aka Veridex/Johnson & Johnson). He also holds a number of patents and receives royalties for some of them.

 

 

March, 2018|Oral Cancer News|

Australia may become the first country to eliminate one form of cancer

Author: Brad Jones
Date: March 8, 2018
Source: flipboard.com

The International Papillomavirus Society has announced that Australia could become the first country to eliminate cervical cancer entirely.

According to a new study, Australia’s efforts to distribute a human papillomavirus (HPV) vaccine for free in schools have been a resounding success. The sexually transmitted infection causes 99.9 percent of cases of cervical cancer.

In 2007, the Australian federal government began offering the vaccine to girls aged 12-13, and in 2013 it was made available to boys, too. Girls and boys outside of that age bracket but under nineteen are also entitled to two free doses of the vaccine.

Between 2005 and 2015, the percentage of Australian women aged between 18 and 24 who had HPV dropped from 22.7 percent to just 1.1 percent. Immunization rates have increased further since 2015, contributing to what’s being described as a “herd protection” effect.

Coupled with a more advanced screening test that was introduced by the Australian government in December 2017, there are hopes that no new cases of cervical cancer will be reported within ten or twenty years.

THE WORLD ISN’T CATCHING UP

In the US, the HPV vaccine is not free. It can cost as much as $450 for the full regimen, according to the Association of Reproductive Health Professionals, although financial assistance is often available. In 2016, 78.6% of 15-year-old Australian girls, and 72.9% of 15-year-old Australian boys were vaccinated – but only 50% of American girls between 13 and 17, and 38% of American boys between 13 and 17 had received the vaccination, as per data published by the Henry J. Kaiser Family Foundation.

The situation is much worse in the developing world, where papillomavirus incidence rate remains high. “Two-thirds of the world’s population of women don’t get access to what Australian women do,” said Joe Tooma, the chief executive of the Australian Cervical Cancer Foundation. “Unless we do something, it will still be one of the major cancer killers in developing countries.”

Administering the HPV vaccine in schools has also proven to be effective in a trial that took place in Bhutan. Offering this kind of free access to the vaccine in other developing countries may seem like an expensive measure, but as the Australian example shows, it could ease the burden of cervical cancer down the line.

 

March, 2018|Oral Cancer News|

Non-smokers with oral precancerous lesions at increased risk of cancer

Source: www.eurekalert.org
Author: press release

Precancerous lesions in the mouths of non-smokers are more likely to progress to cancer than those in smokers, new research from the University of British Columbia has found.

Although tobacco use is still one of the strongest risk factors associated with mouth cancers, UBC dentistry PhD candidate Leigha Rock found that oral precancerous lesions in non-smokers are more than twice as likely to progress to cancer. Furthermore, lesions in non-smokers progressed to cancer faster than smoking-associated lesions. The study was published this week in Oral Oncology.

“This is the first published study where the main focus was to examine the difference in risk of progression to oral cancer between non-smokers and smokers with oral precancerous lesions,” said Rock, lead author of the study. “While other studies have also reported a higher rate of transformation among non-smokers, we looked at multiple risk factors including genetic markers.”

Rock and colleagues looked at case history of 445 patients with oral epithelial dysplasia (OED), a type of precancerous oral lesion, enrolled in the B.C. Oral Cancer Prediction Longitudinal study. One-third of the patients were non-smokers.

“As smoking rates decline, we are seeing an increase in the proportion of these types of lesions in non-smokers,” said Rock.

Among the scientists’ findings were that lesions on the floor of the mouth in non-smokers were 38 times more likely to progress to cancer than in smokers. The study is also the first to report on quicker progression to cancer in non-smokers: both three-year and five-year rates of progression were seven per cent and 6.5 per cent higher than smokers, respectively.

The researchers suggest that the marked difference in outcomes is due to a difference in the root causes of the lesions. In smokers, the OED is likely the result of environmental factors, whereas in non-smokers, genetic susceptibility or mutations are likely to blame.

“Our findings show that molecular genomic markers can identify high risk lesions, regardless of risky habits like smoking, and should be an important consideration in patient management,” said Rock.

The study’s results stress the importance of taking oral lesions seriously, especially when they occur in non-smokers: “If you see a lesion in a smoker, be worried. If you see a lesion in a non-smoker, be very worried. Don’t assume it can’t be cancer because they’re a non-smoker; our research indicates non-smokers may be at higher risk.”

March, 2018|Oral Cancer News|

HPV is causing an oral cancer epidemic in men by outwitting natural defenses

Source: www.philly.com
Author: Marie McCullough, staff writer

Five years ago, when actor Michael Douglas candidly revealed that his throat cancer was linked to having oral sex, two things happened.

He made headlines that mortified his family. And he helped publicize the fact that a pervasive, sexually transmitted virus called HPV was unleashing an epidemic of oral cancer among men.

Since then, scientists have made headway in figuring out why HPV, the human papillomavirus, has this glaring gender bias. Men are four times more likely than women to be diagnosed with oral cancer, a hard-to-detect, hard-to-treat disease that has overtaken cervical cancer as the most common HPV-related malignancy in the United States.

To be sure, changes in sexual norms over the last few generations have played a role in this alarming trend. But research increasingly shows the real problem is something men have practically no control over: their immune response.

Compared with women, men are more likely to get infected with HPV — including “high-risk” cancer-causing strains. They also are less able to wipe out infection on their own, and more likely to get reinfected. The reasons are unclear.

“There is good evidence that men acquire oral infections more readily than women, even if they have similar sex practices,” said Ashish A. Deshmukh, a University of Florida HPV researcher. “And more than the acquisition, it’s the persistence of the virus. The clearance rate is not that fast in men.”

Michael Becker of Yardley has stepped up as the face of this immunological inequity. The 49-year-old former biotech executive is health-conscious, clean-living, happily married for 26 years – and battling terminal oropharyngeal cancer, the medical term for malignancies in parts of the mouth and throat.

He’s also battling the misconceptions and ignorance that keep too many parents from protecting their pubescent children — especially boys — against HPV-driven cancers. Two shots. That’s all it takes for the leading vaccine, Gardasil, to prevent most cervical cancers, less common genital malignancies, and the disease that is killing Becker.

“I can’t tell you how many emails I got from parents after the CBS segment,” he said, referring to a national television interview last month. “They said, ‘What do you mean this vaccine is for boys?’ and ‘What do you mean oral cancer incidence has eclipsed cervical cancer?’ ”

An inescapable virus
HPV is a family of more than 100 virus types that can live in the flat, thin cells on the surface of the skin, cervix, vagina, anus, vulva, penis, mouth, and throat. The virus is spread through contact with infected skin, mucous membranes, and bodily fluids. Some types can be passed during intercourse or — as Douglas pointed out — oral sex. While virtually all sexually active people will get infected at some point, the virus is usually wiped out by the immune system without so much as a symptom.

But not always.

In the cervix, persistent infection with high-risk HPV types can lead to precancerous changes that, left alone, slowly turn malignant. Fortunately, the Pap smear enables the detection and removal of abnormal cells before cancer develops. What’s more, age-related changes in cervical cells reduce the risk that HPV will take hold there as women get older.

No such screening test exists for oropharyngeal sites – the tongue, soft palate, tonsils, the throat behind the nasal cavity – and symptoms usually don’t appear until cancer is advanced. Becker, for example, had metastatic disease by the time he noticed a lump under his jaw line in late 2015.

Traditionally, smoking and heavy alcohol use are the big risk factors for oral cancer, but the non-HPV tumors linked to these bad habits have been declining in recent years. HPV-related tumors, in contrast, have increased more than 300 percent over the last 20 years. The virus is now found in 70 percent of all new oral cancers.

About 13,200 new HPV oral cancers are diagnosed in U.S. men each year, compared with 3,200 in women, according to federal data. Treatment — surgery, chemotherapy, radiation — can have disfiguring, disabling side effects. About half of late-stage patients die within five years.

Natural defenses go awry
Oral HPV infection rates are skewed by gender, just like the resulting cancers. The latest national estimates of this disparity, published in October, come from Deshmukh and his University of Florida colleagues. They used a federal health survey that collected DNA specimens to estimate that 7.3 percent of men and 1.4 percent of women have oral infections with high-risk HPV types. That translates to 7 million men and 1.4 million women.

The chance of oral infection increases for women as well as men who have simultaneous genital HPV infections or a history of many sex partners, but male infection rates still far surpass female rates.

Patti Gravitt, an HPV researcher at George Washington University, believes these estimates are a bit oversimplified because women counted as uninfected may actually have undetectably low virus levels, or HPV may be hiding in a dormant state in their cells.

Still, Gravitt said the study is in line with others that suggest “men are more susceptible to HPV viral infection than women.”

In women, an HPV infection usually sets off the body’s defense mechanisms. The immune system makes antibodies that kill off the invader, then immune cells remain on guard, ready to attack if the virus reappears.

But in men, something goes awry. The HIM study — for HPV in Men — documented this by collecting genital, anal, and oral samples from 4,100 unvaccinated men in Florida, Mexico and Brazil between 2005 and 2009. The samples were tested for the presence of two high-risk HPV types and two that cause genital warts.

Among 384 men who developed infections during a 24-month period, only 8 percent produced antibodies. But this response rate varied depending on the site of infection; none of the small number of orally infected men produced antibodies.

Rather than putting the immune system on guard and protecting men from the virus, infection sharply increased the chance of getting infected again with the exact same HPV type. And many men who got reinfected were celibate at the time.

How could this be? Anna R. Giuliano, the researcher at the Moffitt Cancer Center in Tampa, Fla., who led the HIM study, said recurring infections may be due to reactivation of dormant virus, or to auto-inoculation – the man spreads infection from one part of his body to another. Or to something else entirely.

While the scientific understanding of this puzzle is evolving, one implication is clear. “HPV vaccination is the only reliable method to ensure immune protection against new HPV infections and subsequent disease in males,” Giuliano and her co-authors declared in a recent paper.

Becker hammers that message – when he is not being hammered by chemotherapy – using his self-published memoir and his blog. This week’s blog gave a shout-out to Sunday’s first-ever International HPV Awareness Day, declared by Giuliano and other members of the International Papillomavirus Society.

Becker realizes that the novelty of the vaccine, the complexity of HPV, and its link to sex are obstacles to immunization. But he focuses on the life-saving aspect.

“Parents are being asked to vaccinate their 11-year-old child and they can’t imagine 30 or 40 years down the line, it will prevent cancer,” Becker said. “If you don’t know it’s connected to six cancers, you’re not going to care. So it really should be cast as an anti-cancer vaccine.”

March, 2018|Oral Cancer News|

Immunotherapy: beyond melanoma and lung cancer treatment

Author: David Crow
Source: www.ft.com
Date: March 4, 2018
In the late 1800s, William Coley, a surgeon in New York, developed what scientists now think was the first cancer immunotherapy.

Coley noticed one of his patients, Fred Stein, had started recovering from cancer after catching a serious infection. The observation made him wonder whether the bacteria had somehow stimulated the patient’s immune system and recruited the body’s natural “resisting powers” in the fight against Mr. Stein’s tumours.

The surgeon began treating inoperable cancer patients with bacterial injections — known as “Coley’s toxins” — and recorded some success, but his poorly documented findings were dismissed by contemporaries who favoured radiation and chemotherapy.

Mr. Coley died in 1936 and his theories were all but forgotten: it would take almost 80 years for oncologists to take cancer immunotherapy seriously.

Today, immunotherapies are among the world’s best selling drugs and they have dramatically improved the survival prospects for some of the sickest patients, especially those with melanoma and lung cancer.

“Immunotherapy is here to stay,” says Jill O’Donnell-Tormey, chief executive of the Cancer Research Institute. “It’s not just a blip, it’s not overhyped — I think it is going to become the standard of care for many cancer types.”

The most common immunotherapy drugs are known as checkpoint inhibitors, which work by removing brakes in the immune system so the body can attack cancer.

Their discovery was made possible by the research of James Allison, now a professor at the MD Anderson Cancer Center in Texas, who spent the 1990s and early 2000s working on immunotherapy even as many other scientists dismissed it as an intriguing but futile sideshow.

60 percentage of advanced melanoma patients who survive three years when they take a combination of two checkpoint inhibitors Checkpoint inhibitors have proven remarkably effective in people with advanced melanoma, a disease once known as the “cancer that gave cancer a bad name” because it had such a terrible prognosis, with most patients dying within three to 18 months.

Today, almost 60 per cent of advanced melanoma patients survive three years if they take a combination of two checkpoint inhibitors, both made by Bristol-Myers Squibb, the US pharmaceutical group that bought Yervoy, the drug based on Dr Allison’s findings, in 2009.

A rival drug made by Merck, known as Keytruda, can significantly boost survival in lung cancer patients when added to a type of chemotherapy, according to early findings from a trial that is due to be published shortly. Other companies, including Roche and AstraZeneca, make competing versions.

It was not until 2013 that checkpoint inhibitors gained widespread acclaim among oncologists, but the drugs were soon being hailed as the biggest breakthrough in cancer treatment since the advent of chemotherapy.

The hype served to cloud some uneasy truths.

When checkpoint inhibitors work, they are remarkably effective, helping patients live for months or years longer than expected with less severe side-effects than other drugs. However, with the exception of the remarkable impact in melanoma and, to a lesser extent, lung cancer, most patients do not respond.

Although immunotherapies have now been approved in a long list of cancers from bladder and gastric to liver, the response rates in these illnesses is lower, with as many as 4 out of 5 patients deriving no benefit at all.

When the second generation of checkpoints, known as PDL1 inhibitors, were approved in 2014, researchers and pharma executives confidently predicted they would quickly push response rates higher by combining them with newer experimental immunotherapies.

So far no one has come up with the magic combination, despite running hundreds of trials.

Giovanni Caforio, chief executive of Bristol-Myers Squibb, hails “unprecedented progress” with immunotherapies, but concedes the next step, which he describes as finding “intelligent combinations”, has not moved as quickly.

“I think that it is not growing at the same speed, but I wouldn’t call it stalling,” he says. “I think it’s moving at a speed that is probably more typical of the speed of [traditional] cancer research.”

Sean Bohen, chief medical officer of AstraZeneca, says the quick advent of checkpoint inhibitors was all the more remarkable because immunotherapy “had been a disappointment for decades”. Yet he cautions progress might become slower because the “science is going to harder places”.

That is not necessarily a bad thing, says Dr. Bohen, because it encourages companies and researchers to work in a more methodical way rather than making speculative guesses: “I believe it’s a healthier way to do drug development”.

The challenge now is finding new drugs that can be added to checkpoints and boost the immune response to cancer without putting patients at risk or causing intolerable side effects.

One hope is a so-called IDO inhibitor, which suppresses an enzyme that tumours use to hide from the immune system. Both Merck and Bristol-Myers are testing their checkpoints in combination with this type of medicine in a partnership with Incyte, a US biotech group that is developing the most advanced IDO inhibitor. The first trials are due to complete in May.

Regardless of whether drugmakers and scientists find the right combination any time soon, the remarkable progress in recent years means the field is unlikely to languish as it did after Mr. Coley’s early discoveries.

 

March, 2018|Oral Cancer News|