LYNCH SYNDROME AND CANCER RISK

Mutations in genes that fix mismatched DNA have a well known association with colon and endometrial cancers, and now it appears they may also put people at extra risk for breast cancer and pancreatic cancer.

The mutations, known collectively as Lynch syndrome, "are very rare," according to Dr. Mark Jenkins, from the University of Melbourne. Researchers don't know exactly how common Lynch syndrome is, in part because people aren't generally tested unless they have a family history of colon or endometrial cancer.

Dr. Jenkins, senior author of a paper online Monday in the Journal of Clinical Oncology, said that at most one in 1,000 people probably has the condition.

Still, "the consequences for them are quite severe because the risks of cancer for them are quite high," Dr. Jenkins told Reuters Health.

His colleague Dr. Aung Ko Win led a team of researchers from Australia, New Zealand, Canada and the United States who followed 446 people with the gene mutations and 1,029 of their mutation-free relatives who were tested because someone in their family had colon or another cancer.

At the start of the study, none of the participants had been diagnosed with cancer themselves.

Among people with a family history of colon cancer, 4% of those with mismatch repair gene mutations were diagnosed with the disease during the next five years, compared to less than 0.5% of their mutation-free relatives.

Dr. Jenkins and his colleagues calculated that over five years, people with Lynch syndrome had 20 times the normal risk of colon cancer. Their risk was also 10-fold higher for pancreatic cancer, and four-fold higher for breast cancer.

People with the mutations also seemed to be at increased risk of endometrial, ovarian, stomach, bladder and kidney cancers.

In contrast, their relatives without the mutations didn't have an increased risk of any type of cancer, compared to expected rates of new diagnoses.

The link between Lynch syndrome and breast cancer in particular is still a controversial one, according to Dr. Albert de la Chapelle, a cancer geneticist from The Ohio State University in Columbus.

"It could be that there really is a slightly increased risk to get breast cancer," said Dr. de la Chapelle, who has worked with some of the authors before but wasn't involved in the new report.

But the conclusions, he said "are based on very small numbers," for example just 12 cases of breast cancer in mutation carriers and non-carriers combined.

Dr. Jinru Shia, from Memorial Sloan-Kettering Cancer Center in New York, told Reuters Health that the breast cancer result "goes along with our anecdotal experience" at her hospital.

The findings don't mean that everyone who tests positive for Lynch syndrome should get frequent screening for all cancers that were tied to the gene mutations, researchers agreed.

"Currently, screening is recommended for bowel cancer for people with this mutation, and we know that that screening works. For other cancers, there's less evidence that screening is effective," Dr. Jenkins said.

Meanwhile, Dr. Jenkins said the results are encouraging for the family members of people with Lynch syndrome who are themselves mutation-free and "don't need to worry" about any extra cancer risk.

That's been a concern because researchers have thought other genes, besides the four Lynch syndrome mutations, could be influencing cancer risks in those families.

"Now, one can say with confidence that those who turn out not to have the mutation, that their risk is the average risk," Dr. de la Chapelle told Reuters Health.

CANCER TREATMENT DURING PREGNANCY

Because cancer during pregnancy is a rare occurrence, with an incidence ranging from 0.02% to 0.10%, there is a scarcity of research to guide women and their physicians on treatment. Now, some experts have offered reassurance that it is possible to appropriately treat the mother without terminating the pregnancy.

Pregnancy should be preserved whenever possible with breast and gynecologic cancers, according to 2 separate review articles published in the February 11 issue of the Lancet. The most common malignancies diagnosed during pregnancy are gynecological (primarily uterine or cervical, and less frequently ovarian) and breast cancers; pregnancy does not have a deleterious effect on the prognosis of either.

Although prognosis and treatment success depends on the individual patient, it is possible to provide standard therapy to the mother while safeguarding the fetus.

Decisions about treatment for cancer in a pregnant woman can be difficult because of the conflict between the wellbeing of the mother and that of her unborn child, note Philippe Morice, MD, from the Institut Gustave Roussy, Villejuif, France, and colleagues in a comment accompanying the review papers.

They point out that the physician must define "when and how far to push back usual treatment limits to satisfy the patient's [ethical, legal, and/or personal beliefs]," but also must provide accurate information and consider the oncologic risks.

"The main goal is to offer pregnant patients the same optimum management (and therefore similar predicted survival) as nonpregnant patients," they write. Therefore, physicians must clearly define the real oncologic risk for each patient. Physicians need to stop thinking about cancer and pregnancy in general; instead, they need to focus on the particular cancer and its known characteristics.

Except for leukemia, true oncologic emergencies in pregnant women are rare, Dr. Morice and colleagues point out. This is fortunate because "time is required to deliberate and to draw up a personalized treatment plan that the patient will view as clear and balanced."

Treating cancer during pregnancy is still associated with unacceptable outcomes, such as the termination of pregnancies and the choice of an inadequate strategy for treatment of a tumor, they write.

"The treatment of every pregnant woman, and by extension every woman of childbearing age, should include a wider reflection on how to preserve the pregnancy or subsequent fertility, or both," Dr. Morice and colleagues explain. "Preservation of fertility in young women with cancer (an entirely new specialty, oncofertility) is every patient's right."

Pregnancy During Breast Cancer

In the review article on breast cancer during pregnancy, Frédéric Amant, MD, from the Multidisciplinary Breast Cancer Center, Leuven Cancer Institute, Katholieke Universiteit Leuven, Belgium, and colleagues note that a multidisciplinary focus and a cautious approach to radiotherapy are needed. A diagnostic strategy designed to reduce the burden of fetal radiation exposure needs to be established in a multidisciplinary setting.

Terminating the pregnancy does not improve the breast cancer prognosis, explained Dr. Amant. "We believe that fear of the toxic effects of chemotherapy should not be a reason for termination of pregnancy, and fear should not be a reason to delay maternal treatment or to induce prematurity," he told Medscape Medical News.

The therapeutic strategy should also be discussed within a multidisciplinary setting, and should adhere as closely as possible to standard protocols for nonpregnant women, say the authors, but fetal safety must also be considered.

Dr. Amant added that sometimes oncologists underestimate the long-term consequences of prematurity. "We believe children suffer more from prematurity than from antenatal exposure to chemotherapy," he said.

Until now, it was "easy to terminate pregnancy because the long-term effects were not known," said Dr. Amant. "With the current data, I believe it becomes unethical to terminate pregnancy when cancer is diagnosed."

A study recently published by Dr. Amant and colleagues showed that fetal exposure to chemotherapy was not associated with increased central nervous system, cardiac, or auditory morbidity. In addition, exposure did not appear to be associated with impairments to general health or growth, and cognitive development was age-adequate.

He added that if this trend is confirmed in more children with a longer follow-up, "I believe termination will be more difficult to defend."

In their review paper, Dr. Amant and colleagues explain that surgery, chemotherapy, and radiotherapy for breast cancer are possible during pregnancy, with the caveat that treatment should be tailored to the individual patient.

Generally, surgery can be conducted safely during any stage of pregnancy and most anesthetic agents seem to be safe for the fetus, they point out. The choice of surgery should follow the same guidelines as those for nonpregnant women, and radiation therapy after a breast-conservation procedure is rarely a concern; most women receive chemotherapy and delay radiotherapy until after delivery.

After the first trimester of pregnancy, chemotherapy can be either adjuvant or neoadjuvant, and the decision to use chemotherapy should follow the same guidelines as for nonpregnant women, the authors report. The goal should also be a term delivery (37 weeks or more), and premature birth should be avoided if possible.

Cervical and Ovarian Cancers During Pregnancy

In the review paper on gynecologic cancers, Dr. Morice and his colleagues from France and the United States focused on the 2 most common and complex gynecologic cancers — cervical and ovarian. As in breast cancer, a multidisciplinary discussion is essential for optimal disease management, note the authors. Physicians need to consider the possibility of saving the fetus and the effect of therapy on the woman's reproductive capacity.

Dr. Morice and colleagues point out that until the 1980s, cervical cancer diagnosed during the first 2 trimesters was managed by ending the pregnancy and radically treating the cervical neoplasm. The current trend is to try to preserve the pregnancy, especially in patients with early-stage disease with no nodal involvement.

The management of cervical cancer depends largely on 4 criteria: the extent of local spread, nodal status, pregnancy trimester, and histologic subtype. The authors explain that in early-stage cervical cancer, during the first and at the beginning of the second trimester, magnetic resonance imaging and laparoscopic lymphadenectomy can be used to help plan a conservative approach.

Among women with small tumors and without nodal spread, postponing treatment until fetal maturity and delivery can be discussed. In these cases, radical trachelectomy and neoadjuvant chemotherapy might be appropriate.

The treatment of patients with locally advanced disease is controversial — neoadjuvant chemotherapy with preservation of the pregnancy or chemotherapy and radiotherapy — and needs to be discussed on a case-by-case basis. Tumor size, radiologic findings, the term of pregnancy, and the patient's wishes must be taken into consideration, the authors note.

The management of ovarian cancer is dependent on histologic type, stage, and pregnancy trimester. In patients with peritoneal spread or high-risk early-stage disease, preservation of the pregnancy might be possible with neoadjuvant chemotherapy, according to Dr. Morice and colleagues.

Chemotherapy is generally necessary to achieve a cure in ovarian cancer, and the risk for a congenital malformation or miscarriage as a consequence is very high during the first trimester. In such cases, "consideration of a therapeutic abortion versus delayed treatment should be discussed with the patient," they write. However, treatment during subsequent trimesters can be given according to the usual standard chemotherapy guidelines for both germ-cell tumors and epithelial ovarian cancer; in most cases, there are generally no irreversible consequences for the fetus.

It is also usually not necessary to induce premature delivery if the cancer is controlled with chemotherapy.

"Clinical studies are needed, particularly for key issues in clinical management, such as an intentional delay in early-stage cervical cancer or radical trachelectomy and neoadjuvant chemotherapy, to establish the balance between the best chance of cure for the patient and preservation of a healthy fetus," Dr. Morice and colleagues emphasize.

Nefertiti duPont, MD, MPH, who was approached by Medscape Medical News for an independent comment, noted that this is "an excellent review of a difficult topic."

"When diagnosed early, gynecologic cancers in pregnancy can lead to good outcomes for the mother and infant," said Dr. duPont, who is assistant professor and director of the High Risk Ovarian Cancer Screening Clinic, Roswell Park Cancer Institute, Buffalo, New York. "The most important issues are close follow-up of the mother during her pregnancy and postpartum course, and long-term follow-up of the infant."

What is also critical is a multidisciplinary team to ensure that the mother and baby have the best possible outcomes, she explained.

Several areas in the review, however, could be strengthened, Dr. duPont noted. "Clinicians should provide psychosocial and emotional support to the mother during diagnosis and treatment," she said. "Also, most studies recommend postponing chemotherapy within 3 weeks of delivery to avoid neonatal myelosuppression."

MULTIDRUG RESISTANT TB IS SPREADING

Cases of multidrug-resistant tuberculosis (MDR-TB) hit an all-time high worldwide in 2009 and 2010, with 1 country reporting multidrug resistance in 65.1% of all previously treated TB cases, according to the latest World Health Organization (WHO) study, published in the February Bulletin of the World Health Organization.

Matteo Zignol, MD, MPH, from the Stop TB Department, WHO, Geneva, Switzerland, and colleagues analyzed data collected from 2007 to 2010 from 80 countries and 8 territories. The analysis showed that Eastern Europe and central Asia continue to record the world's highest proportion of MDR-TB. Still, there are no data on drug-resistant TB from much of Russia, India, and Africa, and from large portions of Eastern Europe and central Asia, the authors report.

"Surveillance of resistance to drugs is the cornerstone of TB control," Dr. Zignol said in a news release. "Following 15 years of intensive effort, we now have high quality data for two-thirds of countries in the world. At the same time, we don't know the full extent of the problem because we lack data from many countries, in particular India and most of Africa where the TB burden is high."

One bright spot in new surveillance efforts, the authors points out, is China, which conducted its first nationwide survey in 2007. Dr. Zignol and colleagues call China's efforts "a critical step towards addressing MDR-TB in one of the largest TB control programmes in the world." China, India, and Russia are home to more than half of the world's MDR-TB cases, the report states.

Worldwide, 3.4% (95% confidence interval [CI], 1.9% - 5.0%) of all new TB cases are multidrug-resistant, meaning Mycobacterium tuberculosis resists treatment with at least rifampicin and isoniazid. Among previously treated TB cases worldwide, 19.8% (95% CI, 14.4% - 25.1%) of TB cases are multidrug resistant, according to the report.

Some MDR-TB cases are considered extensively drug resistant (XDR), meaning they not only meet the criteria for multidrug resistance but also fail to respond adequately to fluoroquinolone and at least 1 second-line injectable agent, such as amikacin, kanamycin, or capreomycin. Worldwide, some 9.4% (95% CI, 7.4% - 11.6%) of MDR-TB cases are XDR cases. The number of MDR-TB cases considered to be XDR cases rose to more than 10% in South Africa (10.5%) and 3 former Soviet Union countries: Estonia (19.7%), Latvia (15.1%), and Tajikistan (Dushanbe city and Rudaki district, 21.0%).

However, only 38 countries and 3 territories reported surveillance data for XDR-TB. Among those, only 6 had more than 10 cases of XDR.

The Russian oblast of Murmansk, on the Kola Peninsula near Finland, had the highest level of newly diagnosed MDR-TB, at 28.9%. The Republic of Moldova, a landlocked country between Ukraine and Romania, had the highest rate of MDR-TB among previously treated TB cases, at 65.1%.

TB cases resistant to several treatment regimens require longer and more treatment regimens and are less likely to be cured. Despite the rising number of resistant cases, in 2010, only 16% of the world's patients with MDR-TB received appropriate treatment, the WHO report reveals.

In the United States, MDR-TB cases are in decline, falling even more quickly than new TB cases, the authors report. US TB cases have dropped 5.1% per year since 1996, and MDR-TB diagnoses declined 5.4% per year in the same period. Surveillance showed that 1.1% of new TB cases diagnosed in the United States were multidrug resistant in 2010, and 4.4% of previously treated cases were multidrug resistant.

Despite high MDR-TB rates in Latvia and Estonia, both those countries, along with the United States, have seen a decline in new TB cases and in MDR-TB cases during the last decade.

MDR-TB is increasing most rapidly in Botswana, at 10.9% per year; Peru, at 19.4% per year; and the Republic of Korea, with an increase of 4.3% per year. The Republic of Korea is also recording a 7.4% annual increase in new TB cases. Despite increases in MDR-TB rates, Botswana's overall new case rate is nearly stable, increasing at 0.3% per year, and Peru's rate of new cases is declining by 3.3% per year.

WHO began gathering drug resistance data from 127 countries in 1994 with the launch of the Global Project on Anti-tuberculosis Drug Resistance Surveillance. Today, 64 countries have continuous surveillance based on routine susceptibly testing of all patients with TB. The rest of the countries rely on special surveys of representative patient samples.

Among the report's other findings:

• Countries with new cases of MDR-TB at more than 12% include Belarus, at 25.7%; Estonia, at 18.3%; several oblasts of the Russian Federation, with Murmansk having the highest at 28.9%; and Tajikistan, with Dushanbe city and Rudaki district at 16.5%.
• Countries with MDR-TB in previously treated cases above 50% included Belarus, at 60.2%; Lithuania, at 51.5%; the Republic of Moldova, at 65.1%, 5 oblasts of the Russian Federation; and Tajikistan (Dushanbe city and Rudaki district), at 61.6%.
• Patients with TB who have HIV were no more likely to have a drug-resistant form of TB than those without HIV. In the 17 countries and 1 territory that looked at HIV status, odds of having MDR-TB among HIV-positive cases was 40% higher than among those without HIV (pooled odds ratio [OR], 1.4; 95% CI, 0.7 - 3.0; OR consistent across countries, I² = 23.2%; P = .19), but the difference was not significant.
• The sex of the patients with TB was not a factor in resistance. Among the 58 countries and 2 special territories that collected data on the sex of patients with MDR-TB, odds of MDR-TB were 10% higher among women (OR, 1.1; 95% CI, 0.8 - 1.4; OR heterogeneous across countries, I² = 32.9%; P = .009), which is not statistically significant.

PET-CT HAS PREDICTIVE VALUE AFTER RADIOCHEMOTHERAPY FOR HEAD AND NECK CANCERS

Oncologists at St. John Hospital in Grosse Pointe Woods, Michigan, routinely perform a surveillance positron emission tomography (PET)/computed tomography (CT) scan 6 to 9 weeks after the definitive chemoradiation treatment of patients with squamous cell carcinoma of the head and neck — even when a recurrence is not clinically suspected.
And these clinicians will continue to do so in light of the results from a small study conducted at their center, despite the "controversy" surrounding such routine follow-up, said study author Yasir Rudha, MD, MBChB, a radiation oncologist at the hospital.
"We will keep doing it because of the high negative predictive value," said Dr. Rudha during a press conference at the 2012 Multidisciplinary Head and Neck Cancer Symposium. He was referring to the fact that, in their study, about half of the patients with no clinical evidence of recurrence had a subsequent negative surveillance scan and that all of them remained free of locoregional recurrence on further follow-up.
"Almost all of those patients will be able to avoid neck dissection," predicted David Raben, MD, from the University of Colorado in Aurora, about patients with negative surveillance scans. He was moderator of the press conference. In the past, most of these patients would have automatically gone on to a neck dissection as part of treatment, he said.
The surveillance scans had another benefit — they identified patients with disease recurrence that preceded any clinical manifestation of recurrence. The rate for finding these "true positives" was 53%, Dr. Rudha reported. However, this benefit was somewhat offset by the "high false-positive rate" of 46%, he admitted.
"The routine use of PET/CT scanning in the follow-up of patients with squamous cell carcinoma of the head and neck may be useful for the detection of locoregional recurrences before they become clinically apparent," he summarized.
Study Results and Controversies
Dr. Rudha and colleagues identified 234 patients with head and neck cancer at their center who were treated with chemoradiation and then underwent a posttherapy PET/CT scan from 2006 to 2010.
A retrospective chart review was performed for 45 of those cases, all of whom had a "clinical no-evidence-of-disease " status at the time of the surveillance PET/CT scan.
Of these 45 patients, 30 had a negative PET/CT scan, and all 30 remained free from locoregional relapse at the time of last follow-up. However, the median time of follow-up for the 30 patients was not presented by Dr. Rudha.
The scans identified 15 patients with abnormalities requiring further evaluation. Biopsy showed malignancies in 8 of the 15 patients (53%). (Six of the 8 showed occult persistent disease at the primary site.)
The other 7 cases of abnormalities turned out to be false positives (46%). Thus, patients underwent "unnecessary work-up and/or biopsy evaluation," he said. "Caution should be shown when ordering biopsies after abnormal scans to prevent excessive unnecessary biopsies," he added.
However, overall, the study results provide "support for the routine use of PET scanning as a surveillance method following treatment of head and neck cancer," Dr. Rudha summarized.
Dr. Rudha suggested that this is an uncommon finding in the literature.
He acknowledged that, in most studies, PET scans are performed only when recurrent disease is clinically suspected. "Only a few publications report the value of PET examination at a fixed time after the end of treatment," he told reporters at the press conference.
Dr. Raben endorsed using PET after treatment. The scans are "absolutely critical" for the monitoring and follow-up of these patients. But he added that the use of PET scans in head and neck cancer "continues to evolve."

10% RATE OF ORAL HPV INFECTION

A major study of oral infection with human papillomavirus (HPV) — now known to cause of a subset of oropharyngeal cancer — has found a much higher incidence in men than in women and has established sexual transmission as the main way it spreads. It also raises questions about whether existing HPV vaccines offer protection.
There is a rising incidence in oral HPV infection and in HPV-positive oropharyngeal cancer in the United States. "The curves are a little bit frightening," said lead author Maura Gillison, MD, PhD, from Ohio State University in Columbus. But she pointed out that vaccines against HPV are already marketed, so "we have the means to prevent this already sitting on our pharmacy shelves."
The HPV vaccines (Gardasil and Cervarix) were developed to offer protection against cervical cancer after the link between cervical HPV infection and cervical cancer was firmly established, and are targeted mainly to girls.
The link between oral HPV infection and oral HPV cancer was established more recently; Dr. Gillison reported that the research is about 20 years behind that for cervical cancer. There is speculation — although no hard data — that the same vaccines could offer protection against HPV-associated oral cancer. Because this is more prevalent in men, it would make sense to vaccinate boys as well as girls.
"We need to have thorough and accurate discussions about HPV vaccination," Dr. Gillison said. "We have identified a new cancer...and we have identified its Achilles heel," she added.
Dr. Gillison spoke at a presscast at the 2012 Multidisciplinary Head and Neck Cancer Symposium, sponsored by the American Society for Therapeutic and Radiation Oncology and held in Phoenix, Arizona. The study was published online January 26 in JAMA: The Journal of the American Medical Association to coincide with its presentation.
Sexual Transmission
This the first major prevalence study of oral HPV infection in the United States, according to anaccompanying editorial, subtitled "Hazard of Intimacy."
Editorialist Hans Schlecht, MD, MMSc, from Drexel University College of Medicine in Philadelphia, Pennsylvania, writes that the "results are remarkable for a number of reasons," including the fact that they allow estimation of oral HPV prevalence based on sexual experience, smoking status, and immune suppression.
One of the main findings from this study is that the main method of transmission is sexual, and that the prevalence of oral HPV infection increases with the number of sexual partners reported.
Another finding is "a striking bimodal pattern with age" in men, with peaks in men 30 to 34 and 60 to 64 years of age.
During the presscast, Dr. Gillison speculated that these peaks in oral HPV infection might be partially explained by a "birth cohort" effect. The peak in older men could be related to the fact that they would have been making their sexual debut during the sexual revolution of the 1960s; the dip in middle-aged men could be the result of the dampening impact that the HIV epidemic had on sexual behavior. The peak in younger men could be related to one result of that epidemic — the perception that oral sex is "safe sex."
The new data showing a rising incidence of HPV oropharyngeal cancer raise questions about exactly how safe oral sex is.
In his editorial, Dr. Schlecht suggests that "clinicians should encourage their patients who engage in oral sex to use barrier protection."
First Major Prevalence Study
This study used 2009/10 data from the National Health and Nutrition Examination Survey (NHANES), and analyzed tissue collected from an oral rinse and gargle collected from 5579 people 14 to 69 years of age.
The overall prevalence of HPV oral infection was 6.9%; the particular strain associated with oropharyngeal cancer, HPV16, was found in 1%. "Although this 1% may sound small, this means that around 2.1 million individuals in the United States are infected," Dr. Gillison explained.
However, the incidence in men is significantly higher than it is in women (10.0% vs 3.6%; P < .001).
In addition, the bimodal distribution, with peaks in younger and older individuals, was seen only in men. Why the incidence of oral HPV infection in men is so much higher is not clear, Dr. Gillison said.
Men did report having more sexual partners than women, but this difference in sexual behavior explains only about 16% of the difference in prevalence, the authors note. Another explanation could be higher rate of transmission to men performing oral sex on woman than to women performing oral sex on men; there is some evidence for this in the data. But there are also many other factors, including the fact that women who have already been exposed to cervical HPV infection have greater protection against subsequent oral HPV infection.
The bimodal distribution of oral HPV infection in men is different than that of cervical HPV infection, which peaks in women in their 20s and then generally drops off, although a later peak in older women is seen in some populations.
"It is clear that the natural history of HPV is different in the 2 genders," Dr. Gillison reported.
There was a higher prevalence of oral HPV infection in black than in white people, although this did not reach statistical significance (10.5% vs 6.5%; P = .06). There was also a higher prevalence in current smokers and heavy consumers of alcohol (which increased with intensity of use for both), as well as in current and former marijuana users.
There was little HPV oral infection in individuals who had no history of any sexual contact. Compared with this group, the prevalence was 8 times higher in sexually experienced individuals, and increased significantly with the number of sexual partners. For instance, the prevalence was 20% in people who reported having more than 20 sexual partners.
"These data indicate that transmission by casual, nonsexual contact is likely to be unusual," the authors write.
They note that previous studies have suggested a link between oral sexual behavior and an increased risk for HPV-positive oropharyngeal cancer, but the way the data were collected in the current study precluded association with any particular behavior. However, the data did show that oral HPV infection is more common in sexually experienced people who do not report performing oral sex than in those who were not sexually experienced, which suggests that transmission occurs through other sexually associated contact, such as deep kissing.
This adds weight to the notion that HPV vaccination should be targeted at individuals who are 9 to 13 years of age, in an effort to reach them before any sexual behavior, including deep kissing, begins. This suggestion has been made previously by Dr. Gillison, although she emphasized that protection against oral HPV infection with the existing HPV vaccines has not been proven. She has been trying to conduct such a study for the past 5 years, but has run into funding problems; she hopes to hear soon about funding from the National Cancer Institute, she told journalists in the audience.
Extending HPV vaccination to offer protection against oropharyngeal cancer was discussed by several experts, in addition to Dr. Gillison, last year when it was highlighted by the American Society for Clinical Oncology.
The study was supported by an unrestricted grant from Merck, and was also funded by Ohio University and the Intramural Research Program of the National Cancer Institute. Dr. Gillison reports acting as a consultant to Merck and GlaxoSmithKline, both manufacturers of HPV vaccines. Dr. Schlecht has disclosed no relevant financial relationships.

RADIANT-2 MULTIFACTORIAL ANALYSIS-REFINING USE OF EVEROLIMUS IN NEUROENDOCRINE TUMORS

In patients with advanced neuroendocrine tumors that originate outside the pancreas, a new set of prognostic factors can help identify which patients are at greatest risk for progression and are more likely to need therapy sooner, say researchers.
The prognostic factors were identified in a reanalysis of the phase 3 multinational study known as RADIANT-2 (RAD001 in Advanced Neuroendocrine Tumors), said lead author James Yao, MD, assistant professor and deputy chair of gastrointestinal oncology at the University of Texas M.D. Anderson Cancer Center in Houston.
He spoke at a press conference hosted by the 2012 Gastrointestinal Cancers Symposium, which begins this week.
The significant prognostic factors include elevated levels of the blood biomarker chromogranin A (CgA), neuroendocrine tumors that originate in the lung, bone metastases, and a World Health Organization (WHO) performance status of 1 or more.
There have not been any "great" studies of this rare form of neuroendocrine tumors that have identified prognostic factors, said Dr. Yao. The RADIANT-2 data revealed that the patient population is "quite heterogenous," he said. The newly defined prognostic factors help identify who is "likely to progress in a short time" and "who actually needs treatment."
Dr. Yao said that the reanalysis had another potentially important finding — that everolimus might be more effective in the treatment of these tumors than originally reported.
In RADIANT-2, Dr. Yao and colleagues originally showed that progression-free survival was a median of 5.1 months longer with the combination of everolimus (Afinitor, Novartis) plus the carcinoid syndrome drug octreotide (Sandostatin, Novartis) than with octreotide alone (16.4 vs 11.3 months); the study results were reported last year by Medscape Medical News.
But the phase 3 study was found to have imbalances in its patient randomization, which put more patients with a poor prognosis in the everolimus group.
After adjusting for randomization imbalances, the researchers found in an exploratory analysis that the reduction in the risk for progression in patients treated with everolimus plus octreotide was 38% (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.51 to 0.87; P = .003). This is an improvement from the 23% risk reduction seen in the first analysis. Everolimus is likely "a little more active than previously thought," said Dr. Yao. A larger study to confirm these results is planned.
It is likely that the original study had randomization imbalances because the prognostic factors needed to stratify patients were not well defined at the start of the study, said Dr. Yao in a press statement.
In short, the researchers are learning as they go.
The subset of patients most likely in need of drug therapy is "all the more meaningful" because of the "limited treatment options" with this disease, said Morton Kahlenberg, MD, from the University of Texas Health Science Center at San Antonio, who moderated the press conference.
Everolimus was approved last year by the US Food and Drug Administration for the treatment of advanced pancreatic neuroendocrine tumors. The targeted therapy sunitinib (Sutent, Pfizer and Merck) was also approved for these tumors last year.
However, it is not known whether everolimus is effective in treating neuroendocrine tumors that do not originate in the pancreas. Currently, there are no approved therapies for the oncologic control of these types of neuroendocrine tumor, said Dr. Yao.
Study Details
In RADIANT-2, Dr. Yao and colleagues sought to assess the effectiveness of the combination of everolimus plus octreotide in patients with low- or intermediate-grade neuroendocrine tumors associated with carcinoid syndrome.
In the study, 429 patients with unresectable locally advanced or distant metastatic neuroendocrine tumors were randomized to receive either oral everolimus 10 mg daily (n = 216) or placebo (n = 213), both in conjunction with intramuscular octreotide LAR (long-acting repeatable) 30 mg every 28 days. Treatment was continued until disease progression, withdrawal from treatment because of adverse effects, or withdrawal of consent.
Of these patients, 357 discontinued study treatment and 1 was lost to follow-up.
The initial analysis of the study found that median progression-free survival was 16.4 months (95% CI, 13.7 to 21.2) in the combination group and 11.3 months (95% CI, 8.4 to 14.6) in the monotherapy group (HR, 0.77; 95% CI, 0.59 to 1.00; P = .026).
In the reanalysis, the investigators identified prognostic factors that predicted both good and poor outcomes in the trial.
They now report that median progression-free survival was significantly longer for patients with nonelevated CgA (27 vs 11 months; P < .001) and nonelevated 5-HIAA (17 vs 11 months; P < .001). The analyses also indicated the prognostic potential of age (14 vs 12 years; P = .01), WHO performance status of 0 vs 1 or more (17 vs 11; P = .004), liver involvement (14 vs not reached;P = .02), bone metastases (8 vs 15; P < .001), and lung as the primary site (11 vs 14; P = .06).
A multivariate analysis found that some factors were significantly associated with a greater likelihood of neuroendocrine tumor progression.
This analysis indicated that bone involvement (HR, 1.52; 95% CI, 1.06 to 2.18; P = .02) and lung as the primary site (HR, 1.55; 95% CI, 1.01 to 2.36; P = .04) were especially strong prognostic factors for progression-free survival, and that baseline CgA (HR, 0.47; 95% CI, 0.34 to 0.65; P < .001) and WHO performance status (HR, 0.69; 95% CI, 0.52 to 0.90; P = .006) were also significant.
Randomization in the trial also resulted patient group imbalances, especially in baseline CgA (median, 251 ng/mL for everolimus plus octreotide vs 137 ng/mL for octreotide alone), Dr. Yao reported.
Other randomization imbalances also favored the octreotide group, which had more patients with a WHO performance status of 1 or more and more with lung as the primary tumor site.
Dr. Yao reports receiving research funding and honoraria from Novartis, which sponsored the trial. Other authors report receiving research funding and honoraria or being employees of and owning stock in Novartis.
2012 Gastrointestinal Cancers Symposium (GICS): Abstract 157. To be presented January 20, 2012.

ASPIRIN IN PRIMARY CVD PREVENTION-BENEFITS AND RISKS

A new meta-analysis said to provide "the largest evidence to date regarding the wider effects of aspirin treatment in primary prevention" has shown that cardiovascular benefits are offset by an elevated risk of bleeding [1].
Senior author Dr Kausik Ray (St George's University of London, UK) commented to heartwire : "On a routine basis I would not recommend aspirin use in primary prevention. And it certainly should not be put in a polypill for mass use."
The current study did not find a significant reduction in cancer mortality. However, the lead author of a previous meta-analysis that did show a reduction in cancer death with aspirin says follow-up in the current study was not long enough to show such an effect.
The new analysis, published online January 9, 2012 in the Archives of Internal Medicine, included nine randomized placebo-controlled trials with a total of 100 000 participants. Results showed that during a mean follow-up of six years, aspirin treatment reduced total cardiovascular events by 10%, driven primarily by a reduction in nonfatal MI, but there was a 30% increased risk of nontrivial bleeding events. The number needed to treat to prevent one cardiovascular event was 120, compared with 73 for causing a nontrivial bleed.
Effect of Aspirin on Vascular and Nonvascular Outcomes or Death

Event	Odds ratio (95% CI)
Cardiovascular events	0.90 (0.85–0.96)
Nonfatal MI	0.80 (0.67–0.96)
Cardiovascular death	0.99 (0.85–1.15)
Cancer mortality	0.93 (0.84–1.03)
Nontrivial bleed	1.31 (1.14–1.50)

Possible Benefit in Those at High Risk
The authors conclude that the "rather modest benefits" and the significant increase in risk of bleeding do not justify routine use of aspirin in the primary-prevention population. They say that further study is needed to identify subsets that may have a favorable risk/benefit ratio. They note that their results suggest an increased risk of nontrivial bleeding in individuals receiving daily (vs alternate-day) aspirin treatment and a particularly unfavorable risk/benefit ratio for individuals at lower baseline cardiovascular risk.
An editorial accompanying the paper suggests that aspirin may be considered in patients with a CHD risk of more than 1% per year [2], but Ray said he thought that was an "oversimplification" of the results.
"There may be a benefit in higher-risk individuals, and there is a case for personalized medicine here. But we showed that as the event rate increased in the placebo group, the reduction in MI with aspirin also increased, but so too did the bleeding risk. The bleeding risk is always greater than the MIs prevented, but it depends on whether you think a nonfatal MI is worse than a significant bleed. So we could do better if we knew who would bleed and who would have an event. I think we need a dual risk score as is done for warfarin."
The cardiovascular results from this latest analysis are in line with those from the 2009 Antithrombotic Trialists' (ATT) Collaboration, and there seems to be agreement on the conclusions regarding heart disease. But there is less agreement on the use of aspirin for the prevention of cancer.
Disagreement Over Cancer Data
Lead author of last year's analysis showing a reduction in cancer mortality with aspirin, Dr Peter Rothwell (University of Oxford, UK) commented to heartwire : "This new meta-analysis just looks at the overall study results, and most of the studies only had three to four years of follow-up. That is not long enough to see a major effect on cancer mortality. In contrast, in our meta-analysis published last year we obtained individual patient data and followed patients long-term after the trials had finished, and in this way we were able to show a significant and impressive effect on cancer mortality."
Rothwell estimates that it takes at least five years to show an effect on cancer deaths, "but after this point you see quite an impressive effect." He noted that the new study also included both alternate and daily aspirin trials, but "all previous work has suggested that aspirin needs to be given every day to prevent cancer."
He added: "Their results are completely compatible with our results. They did show a trend toward a reduction in cancer mortality, which we believe would have become significant if they had longer-term data or if they looked at individual patient data."
The UK newspapers were today full of reports saying there is no benefit of aspirin in cancer prevention, exactly the reverse of the headlines after Rothwell's study came out last year. Rothwell says he is concerned about this. "The message today that aspirin does not prevent cancer is premature. The current study should not change advice on taking aspirin as a healthy person. It does not offer any additional information that we don't already know. We need to think about both risk of heart disease and cancer, and in general heart disease risk is coming down while cancer risk is increasing. There does appear to be a cancer benefit with long-term use, so if there is a family history of cancer I would think about taking aspirin. We have more studies with individual patient data coming out soon that will shed more light on the issue."
More Data Coming Soon
Rothwell says official guidance on primary prevention varies from country to country. "At the moment, the guidelines on primary prevention are just focused on heart disease. They have not looked at the cancer data. There are some new guidelines due to come out over the next year, and these should start to discuss the cancer findings. "
Ray, however, is not so convinced by the cancer data. "Our meta-analysis is much larger than Rothwell's. They had 25 000 individuals whereas we have more than 100 000 patients. As usual, in this situation, when you see the bigger picture, you see 'regression to the truth.' "
Ray commented to heartwire that assuming the trend toward fewer cancer deaths in the current analysis was real, the use of aspirin would produce three and half extra nontrivial bleeds for one cancer death prevented. But he suggested that the cancer data may be biased. "Cancer often shows up as bleeding, and if you are taking aspirin, you are more likely to bleed so are more likely to be investigated, which could affect survival." He also points out that Rothwell's study mixed primary- and secondary-prevention populations, while his study looked at only healthy individuals.
He added: "The cancer data are far from certain. The major reason to give aspirin is to prevent heart attacks and strokes, and in healthy people this benefit is outweighed by the risk of bleeding. Aspirin is not the same as statins, which are known to reduce mortality in primary prevention. Aspirin doesn't affect atherosclerosis; it modifies plaque rupture, which is the final step. That is why it works better in patients with established heart disease. Primary-prevention efforts are much better directed at the basics of diet, exercise, and smoking and reducing cholesterol and blood pressure."

A RARE MUTATION THAT INCREASE PROSTATE CANCER RISK

Researchers have discovered a "rare but recurrent" genetic mutation that is associated with a significantly higher risk for hereditary prostate cancer.
A report on the finding appears in the January 12 issue of The New England Journal of Medicine.
The discovery has no immediate impact on clinical practice because a commercial test is not available.
"Our findings need to be reproduced in additional populations before...there are sufficient data to support developing a clinical test," Kathleen Cooney, MD, one of the study's senior authors, toldMedscape Medical News. She is professor of internal medicine and urology at the University of Michigan Medical School in Ann Arbor.
Still, the discovery is big news. "This is the first major genetic variant associated with inherited prostate cancer," said Dr. Cooney in a press statement.
Prostate cancer has long been identified as having a "strong familial component," but identifying a genetic basis for the phenomenon has been elusive in the past, write Dr. Cooney and her coauthors in their paper.
In their preliminary work, the investigators found that in 4 selected families with a pronounced history of prostate cancer, all 18 males with the disease had a G84E mutation in the HOXB13 gene, which is important in prostate development.
This HOXB13 G84E mutation, now also identified as rs138213197, is novel; it has not been reported elsewhere in major gene sequencing databases.
Dr. Cooney and colleagues looked for the newly documented mutation in 5083 white men who had prostate cancer (but who were unrelated to each other) and in 1401 control subjects without prostate cancer.
They found the mutation in 72 men (1.4%) with and in 1 man without (0.1%) prostate cancer. Thus, the carrier rate was 20 times higher in men with than in men without prostate cancer.
The investigators analyzed these 5083 men with prostate cancer by age at disease onset and by the presence of any history of prostate cancer in their families. The mutation was significantly more common in men with early-onset familial prostate cancer (3.1%) than in those with late-onset nonfamilial prostate cancer (0.6%) (P = 2.0 × 10⁻⁶).
The HOXB13 G84E mutation is rare, the authors point out; it apparently occurs in only 1.4% of all men with prostate cancer. However, the relative rarity of the mutation has not dampened the spirits of the investigators.
"It's what we've been looking for over the past 20 years," said William B. Isaacs, PhD, the study's other senior author. He is professor of urology and oncology at the Johns Hopkins University School of Medicine in Baltimore, Maryland. "It's long been clear that prostate cancer can run in families, but pinpointing the underlying genetic basis has been challenging, and previous studies have provided inconsistent results."
The investigators hope that other groups will attempt to validate their findings. Dr. Cooney and her team are already doing further studies. But a test for the genetic mutation will have to overcome some hurdles, she explained.
"If our findings hold up, it may be possible to offer testing to unaffected men within a family in which the proband [the first member identified with prostate cancer] carries a HOXB13 mutation," she said.
But this is currently "premature," given the unknowns at the moment. "Because we do not know the penetrance of any of the HOXB13 mutations, we would not be able to offer clinical advice to men found to be mutation carriers. In other words, we would not be able to tell them the likelihood of being diagnosed with prostate cancer in their lifetime or if PSA testing would be useful," she said.
Other Rare Variants Could Be Found
This study might lead to more discoveries of the genetic causes of inherited prostate cancer, say the authors.
"This work suggests that future DNA sequencing studies using next-generation technology and study populations enriched for genetic influence (as evidenced by an early age at onset and positive family history) may identify additional rare variants that will contribute to familial clustering of prostate cancer," they write.
This "next-generation technology" was pivotal to the discovery of the HOXB13 G84E mutation.
Improved gene sequencing technologies allow for more "rapid and comprehensive" investigation of genomics, the authors say. In this case, the researchers sequenced the DNA of more than 200 genes in a human chromosome region known as 17q21–22. This has been "one of the most intensely investigated regions of the genome for prostate cancer susceptibility," they point out.
The study received funding support from William Gerrard, Mario Duhon, John and Jennifer Chalsty, P. Kevin Jaffe, and the Patrick C. Walsh Prostate Cancer research fund. The Department of Network and Computing Systems at TGen, with support from National Institutes of Health grants, facilitated the use of supercomputing resources.