Today, Erivedge (vismodegib) was approved by the U.S. Food and Drug Administration to treat adult patients with basal cell carcinoma, the most common type of skin cancer. The drug is intended for use in patients with locally advanced basal cell cancer who are not candidates for surgery or radiation and for patients whose cancer has spread to other parts of the body (metastatic).

Erivedge, reviewed under the agency’s priority review program, is the first FDA-approved drug for metastatic basal cell carcinoma. Erivedge was reviewed under the FDA’s priority review program that provides for an expedited six-month review of drugs that may offer major advances in treatment. The drug is being approved ahead of the March 8, 2012 prescription user fee goal date.

Basal cell carcinoma is generally a slow growing and painless form of skin cancer that starts in the top layer of the skin (epidermis). The cancer develops on areas of skin that are regularly exposed to sunlight or other ultraviolet radiation.

Erivedge is a pill taken once a day and works by inhibiting the Hedgehog pathway, a pathway that is active in most basal cell cancers and only a few normal tissues, such as hair follicles.

“Our understanding of molecular pathways involved in cancer, such as the Hedgehog pathway, has enabled the development of targeted drugs for specific diseases,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “This approach is becoming more common and will potentially allow cancer drugs to be developed more quickly. This is important for patients who will have access to more effective therapies with potentially fewer side effects.”

The safety and effectiveness of Erivedge was evaluated in a single, multi-center clinical study in 96 patients with locally advanced or metastatic basal cell carcinoma. The clinical study’s primary endpoint was objective response rate (ORR) or the percentage of patients who experienced complete and partial shrinkage or disappearance of the cancerous lesions after treatment. Of the patients with metastatic disease receiving Erivedge, 30 percent experienced a partial response and 43 percent of patients with locally advanced disease experienced a complete or partial response.

The most common side effects observed in patients treated with Erivedge were muscle spasms, hair loss, weight loss, nausea, diarrhea, fatigue, distorted sense of taste, decreased appetite, constipation, vomiting, and loss of taste function in the tongue.

Erivedge is being approved with a BOXED WARNING alerting patients and health care professionals of the potential risk of death or severe birth effects to a fetus (unborn baby). Pregnancy status must be verified prior to the start of Erivedge treatment. Male and female patients should be warned about these risks and the need for birth control.

Erivedge is marketed by South San Francisco based-Genentech, a member of the Roche Group.

Reported this week in The Lancet (Jan. 27, 2012), the two studies demonstrated how the test, which measures the activity of fourteen genes in cancerous tissue, improves the accuracy of prognosis. This in turn could guide treatments for patients with the most common form of the disease, non-squamous non-small cell lung cancer.

The two independent clinical trials included one blinded study involving the analysis of tissue samples from 433 people with early-stage lung cancer in northern California and another study involving 1,006 people with early-stage lung cancer in China. In both trials, the team showed that the test could accurately predict whether the odds of death within five years of surgery to remove a lung cancer were low, intermediate, or high.

“It’s quite exciting,” said David Jablons, MD, the Ada Distinguished Professor in Thoracic Oncology and leader of the Thoracic Oncology Program at the Helen Diller Family Comprehensive Cancer Center at UCSF. “This has the potential to help hundreds of thousands of people every year survive longer.” Jablons co-led the study with Michael Mann, MD, a UCSF Associate Professor of Cardiothoracic Surgery.

Today, doctors assess early-stage lung cancers by their size, location and microscopic appearance. This information, known as staging, is then used to guide the use of additional treatment following surgery. If doctors could more precisely gauge prognosis, more people who might benefit from additional therapy could receive it immediately after surgery, before any residual cancer has had a chance to grow.

Evidence from other studies suggests that chemotherapy given in early-stage lung cancer helps thwart recurrence when there is evidence of lymph node involvement. Such involvement increases the risk of other, undetectable metastasis.

The scientists plan to design a large clinical trial that would seek to confirm that using the algorithm to guide therapy helps people with lung cancer survive longer.

The study conducted in China is the first major clinical trial result to emerge from the China Clinical Trials Consortium (CCTC), a collaboration between hospitals and universities across mainland China that was founded with the help of leaders from the UCSF Thoracic Oncology Program to confront the epidemic of lung cancer in China.

“The CCTC represents a revolutionary new collaborative approach to clinical research among Chinese and Western experts,” said Mann. “It is fitting that this body’s first major effort may support a molecular personalization of lung cancer care, and yield one of the first examples that fundamental tumor biology reaches across ethnic lines and can be used to try to improve outcomes for a large percentage of patients.”

Problems with Lung Cancer Prognosis

Lung cancer is the most common cause of cancer death in both the United States and the world. More people die from the disease each year than from breast, colon and prostate cancers combined. It claims more than 150,000 American lives annually and accounts for some 1.4 million deaths around the world. About 85 percent of Americans with all types of lung cancer die within five years of diagnosis.

Most cases result from exposure to cigarette smoke, but other causes include exposure to asbestos, chemicals, environmental factors and genetic susceptibility.

One of the challenges of treating the disease is that it often goes undetected in its early stages, when it is most treatable, because it usually does not cause symptoms. Only about 30 percent of patients in the United States are detected in the earliest stage of the disease, contributing to the low overall survival rate.

Even people who have their cancer detected at the earliest stages, however, face serious odds. Unlike other types of cancer, where early diagnosis has significant survival advantages, some 35 to 45 percent of people with stage I lung cancer die within five years of recurrent disease, despite successful surgery. The prognostic test would address the inability to identify these patients, said Jablons.

Lung Cancer Treatment

For people with lung cancer that has metastasized to regional lymph nodes, the standard treatment is surgery followed by chemotherapy. For people without detectable lymph node involvement, the approach generally is surgery followed by clinical observation alone. With this “watch and wait” approach, doctors recommend additional treatment — surgeries, chemotherapy, or radiation therapy — only if the cancer recurs.

The challenge for doctors is that many people with early-stage lung cancer harbor tiny, undetectable clumps of cancer cells either in their lungs or throughout their bodies that grow into tumors in the months and years after surgery, giving rise to recurrent cancer. Almost half of all people with stage I lung cancer have these very early metastatic cancers.

Past studies involving people with stage II and III disease suggest that earlier treatment, before recurrent tumors can be detected, improves the chances of survival.

Given the danger of metastases even from stage I lung cancer, however, current guidelines also recommend the consideration of chemotherapy for a subset of stage I patients whose tumors have characteristics that are believed to put them at high risk for recurrence.

The data reported in The Lancet indicate that the new molecular assay does a better job at identifying patients at high risk of early death after surgery, and may therefore be a better guide for consideration of early chemotherapy.

How the Molecular Assay Predicts Lung Cancer Survival

The molecular assay is based on technology developed originally at UCSF. The assay itself was developed by Pinpoint Genomics, a company based in Mountain View, California, and relies on a standard laboratory technique known as quantitative polymerase chain reaction (qPCR).

The analysis begins with a piece of the patient’s cancerous tissue embedded in paraffin wax—the standard way of preserving all tissue samples removed during surgery. Material known as RNA, which reveals the relative activity level of genes within tissues, is then extracted from the tumors. The activity levels of 14 specific genes are then determined and compared to levels in normal lung. Eleven of these genes are linked to lung cancer biology, and the other three are common genes that are used to standardize the measurement of the cancer genes.

Pinpoint Genomics developed an algorithm for calculating risk of death after examining tissue taken from 361 patients at UCSF Medical Center who all had surgery to treat a common type of lung cancer called non-squamous, non-small cell lung cancer. The algorithm correlated the levels of these 14 genes with the clinical outcomes of these patients, the theory being that a molecular profile associated with a low, intermediate, or high risk of death in one patient could be used to predict a low, intermediate, or high risk in another patient.

To test their algorithm, the UCSF team partnered with Kaiser Permanente’s Division of Research in Oakland, CA and blindly examined lung samples taken from 433 other patients in northern California with the earliest stage of the same type of cancer. They also used a similar blinded approach to test the algorithm using tissue samples from 1,006 lung cancer patients in China, where lung cancer is one of the leading causes of death. No other clinical trial examining molecular prognostic indicators has ever demonstrated the same result in two different populations with different genetic make-ups on two continents, the team said.

The scientists found that the algorithm very accurately differentiated patients with high, intermediate or low risks of death in these larger cohorts of patients, even for patients with stage II and stage III lung cancer.

The total cost of asthma due to pollution is much higher than past traditional risk assessments have indicated and there is growing evidence that exposure to traffic-related air pollution is a cause of asthma and a trigger for attacks, so it should be included, say the authors. They conducted the study in Long Beach and Riverside, Calif., communities with high regional air pollution levels and large roads near residential neighborhoods.

Total additional asthma-specific costs there due to traffic-related pollution is about $18 million per year, almost half of which is due to new asthma cases caused by pollution, they report. Brandt worked with researchers at the University of Basel, Switzerland, Sonoma Technology, Inc. and the University of Southern California.

Using updated techniques that count asthma cases attributable to air pollution for the first time and including a broader range of health care costs such as parents’ missed work days, extra doctor visits and travel time along with prescriptions, the researchers found that a single episode of bronchitic symptoms cost an average $972 in Riverside and $915 in Long Beach. Bronchitic symptoms (daily cough, congestion or phlegm, or bronchitis for three months in a row) are a critical outcome for children with asthma.

Further, people who live in cities with high traffic-related air pollution bear a higher burden of these costs than those in less polluted areas, they say.

Brandt and colleagues say the total annual cost for a typical asthma case was $3,819 in Long Beach and $4,063 in Riverside, and “the largest share of the cost of an asthma case was the indirect cost of asthma-related school absences.” School absences are an important economic consequence, they add, because “they often lead to parents or caregivers missing work.”

Overall, Brandt points out that the results are relevant and applicable to many settings and “families with children who have asthma are bearing a high cost. The total annual estimate between $3,800 and $4,000 represents 7 percent of median household income in our study in these two communities. This is troublesome because that is higher than the 5 percent considered to be a bearable or sustainable level of health care costs for a family.”

Riverside and Long Beach account for about 7 percent of the total population of California, the authors say, which suggests that state-wide costs of asthma related to air pollution are “truly substantial.”

For this work, Brandt and colleagues analyzed several surveys on health care visits by children with asthma and their previous estimates of the number of asthma cases attributable to pollution to estimate the annual costs of childhood asthma. They also estimated the cost of asthma exacerbation due to regional air pollutants. They feel the new method does a better job of accounting for the full impact of traffic-related pollution and will be widely applicable in urban areas.

She points out, “Traditional risk assessment methods for air pollution have underestimated both the overall burden of asthma and the cost of the disease associated with air pollution. Our findings suggest the cost has been substantially underestimated and steps must be taken to reduce the burden of traffic-related pollution.”

The study, led by Durham University, found that the mechanism for using ‘inner speech’ or ‘talking things through in their head’ is intact in children with autism but not always used in the same way as typically developing children do.

The psychologists found that the use, or lack of, thinking in words is strongly linked to the extent of someone’s communication impairments which are rooted in early childhood.

However, the researchers suggest teaching and intervention strategies for children targeted at encouraging inner speech may make a difference. These strategies, which include encouraging children to describe their actions out loud, have already proven useful for increasing mental flexibility among typically developing children.

It is also suggested that children with autism spectrum disorder (ASD) could, for example, benefit from verbal learning of their daily schedule at school rather than using visual timetables as is currently a common approach.

The research by Durham University, Bristol University and City University London is published in Development and Psychopathology.

Lead author, Dr David Williams, lecturer in the Department of Psychology at Durham University, said: “Most people will ‘think in words’ when trying to solve problems, which helps with planning or particularly complicated tasks. Young typically developing children tend to talk out loud to guide themselves when they face challenging tasks.

“However, only from about the age of seven do they talk to themselves in their head and, thus, think in words for problem-solving. How good people are at this skill is in part determined by their communication experiences as a young child.”

One out of every 100 people in the UK has ASD, which is diagnosed on the basis of a set of core impairments in social engagement, communication and behavioural flexibility. Children with autism often miss out on the early communicative exchanges when they are young which may explain their tendency not to use inner speech when they are older. This relative lack of inner speech use might contribute to some of the repetitive behaviours which are common in people with autism.

In the study, those individuals with more profound communication impairments also struggled most with the use of inner speech for complex tasks. People with ASD did, however, use inner speech to recall things from their short-term memory.

Dr Williams said: “These results show that inner speech has its roots in interpersonal communication with others early in life, and it demonstrates that people who are poor at communicating with others will generally be poor at communicating with themselves.

“It also shows that there is a critical distinction between being able to express yourself verbally and actually using silent language for problem-solving. For example, the participants with ASD in our study were verbally able, yet did not use inner speech to support their planning.”

Caroline Hattersley, Head of Information, Advice and Advocacy at the National Autistic Society, said: “This study presents some interesting results and could further our understanding of autism. If the findings are replicated on a wider scale they could have a significant impact on how we develop strategies to support children with the disability.”

METHODS

In the study, 15 high-functioning adults with ASD and 16 comparison participants were asked to complete a commonly used task which measures planning ability, called the Tower of London task. This task consists of five coloured disks that can be arranged on three individual pegs. The aim of the task is to transform one arrangement of disks into another by moving the disks between the pegs, one disk at a time, in as few moves as possible. This type of complex planning task is helped by ‘talking to yourself in your head’.

The participants did the task under normal conditions as well as under an ‘articulatory suppression’ condition whereby they had to repeat out loud a certain word throughout the task – in this case, either the word ‘Tuesday’ or ‘Thursday’. If someone uses inner speech to help them plan, articulatory suppression prevents them from doing so and will detrimentally affect their planning performance, whereas it will have little impact on the planning performance of someone who doesn’t use inner speech.

The results showed that whilst almost 90 per cent of normally developing adults did significantly worse on the Tower of London task when asked to repeat the word, only a third of people with autism were in any way negatively affected by articulatory suppression during the task. This suggests that, unlike neurotypical adults, participants with autism do not normally use inner speech to help themselves plan.

The participants also completed a short-term memory task to asses the use of inner speech in short-term recall.

The research was funded by a City University London Research Fellowship to the lead researcher.

CASE STUDY

Jude Ragan OBE is Headteacher at Queensmill School in London. Queensmill School is one of the largest state funded schools for children with autism which has over 100 pupils and is accredited by the National Autistic Society.

Jude Ragan OBE said: “Complex planning ahead is not a strength of people with autism which means, for people most severely affected, that they can only comprehend the here and now. This can be hugely stressful and at times quite frightening. Everything that we do in an ASD specific school is to help our pupils recognise when something they are doing might finish, what might happen next and so on. Encouraging inner speech is very much part of that as it can work as a life-long support.

“In order to encourage children to use inner speech, we start with visual timetables when they are in nursery. This will have pictures for different activities, such as a nappy for toilet time and a spoon for lunch. We will change this as the child progresses, to symbols, then symbols with words and then words only. By the time we are using written tick lists for the child to know what they are doing when, this will be accompanied by speech to begin to build the foundations for inner speech to solve problems.

“We can then ask the child questions such as ‘What do you have next Tim? What will you need for that? Which room is it in? What happens after that? This is all scaffolding for inner speech which is naturally a more ‘normal’ way of planning and one that we would want a child to move to if they have the ability to do so.

“We also use ‘parallel talk’ whereby we play alongside the child and talk through what he or she is doing. That way, we are teaching them in a playful way to talk things through. We know that neurotypical children learn a great deal about how the world and social interaction works by naturally talking whilst they are playing but children with autism do not normally do this. It is important for us to show them how they can do that.

“Peer-reviewed research like this is very valuable as it informs the way we teach our pupils. As educators, we need to remind ourselves that whilst responding to visual cues is a strength of autism, we should never miss an opportunity to develop language, particularly inner language which I feel is more comfortable to a person with autism than spoken language.”

Excluding skin cancer, prostate cancer is the most common cancer diagnosed in American men, according to the Centers for Disease Control and Prevention. Open radical prostatectomy, or removal of the prostate, is a common treatment for the disease, but it carries substantial risks, including incontinence and impotence.

“I think preoperative MRI will be useful for surgeons who are uncertain whether to spare or resect the nerves,” said Daniel J. A. Margolis, M.D., assistant professor of radiology at the David Geffen School of Medicine at the University of California Los Angeles. “Our surgeons feel that, compared with clinical information alone, MRI is worthwhile for all patients, because it identifies important information leading to a change in the surgical plan in almost a third of patients.”

Robotic-assisted laparoscopic prostatectomy (RALP) is a newer treatment performed with the assistance of a surgical robot. RALP uses smaller incisions than those of open radical prostatectomy and offers improved cosmetic results, less blood loss and briefer postoperative convalescence. However, surgeons performing RALP lack tactile feedback, which may compromise their ability to evaluate neurovascular bundles—the collections of blood vessels and nerves that course alongside prostate. An aggressive surgical approach could unnecessarily damage the bundles and leave patients with loss of function, while an approach that is not aggressive enough may leave some cancer behind. There are no conventional preoperative urological techniques that provide information to take the place of tactile feedback.

Dr. Margolis and colleagues investigated endorectal coil MR imaging as a way to improve preoperative assessment of prostate cancer and the involvement of the neurovascular bundles. They prospectively evaluated 104 prostate cancer patients who underwent preoperative endorectal coil MRI of the prostate and subsequent RALP. The researchers determined the differences in the surgical plan before and after review of the MRI report and compared them with the actual surgical and pathologic results.

Preoperative prostate MRI data changed the decision to use a nerve-sparing technique during RALP in 28 (27 percent) of the 104 patients. The surgical plan was changed to the nerve-sparing technique in 17 (61 percent) of the 28 patients and to a non-nerve-sparing technique in 11 patients (39 percent). The decision to opt for nerve-sparing surgery did not compromise oncologic outcome.

Dr. Margolis cautioned that the study group represented a population of men with low to medium grade cancer and that the findings might not apply to all patients.

“There is a learning curve for prostate MRI,” Dr. Margolis said. “What we and others have found is that one has to select patients where there is likely to be a benefit from the imaging.”

For the approach to become more commonplace, Dr. Margolis said that two things were needed: a better way to stratify which patients would benefit from preoperative MRI, and a more standardized means of acquiring and interpreting prostate MRI results.

“The former is something we are investigating now,” Dr. Margolis said. “The latter is something that a number of leading experts in prostate MRI are working toward. However, most centers already have this technology, so this may become widespread relatively soon.”

The paper was published online in the journal Nature Materials on Jan. 22.

Currently all other adjuvants (substances added to vaccines to help to boost the immune response) are thought to enhance immunity at the skin site where the vaccine is injected rather than going to the lymph nodes, where the most effective immune reactions occur. The current study used mice to show it is possible to shift the delivery path directly to the lymph nodes.

The researchers based their strategy on their observation that mast cells, which are cells that are found in the skin that fight infections, also communicate directly to the lymph nodes by releasing nanoparticles called granules.

“Our strategy is unique because we have based our bioengineered particles on those naturally produced by mast cells, which effectively solve the same problem we are trying to solve of combating infection,” said St. John, who is in the Duke-NUS Program in Emerging Infectious Diseases.

The synthetic granules consist of a carbohydrate backbone that holds tiny, encapsulated inflammatory mediators such as tumor necrosis factor (TNF). These particles, when injected, mimic the attributes of the granules found in natural cells, and the synthetic particles also target the draining lymph nodes and provide for the timed release of the encapsulated material.

Traditional vaccine adjuvants may help antigens (the small part of a pathogen that is injected during vaccination that the body reacts to) to persist so the body can have an immune reaction and build antibodies so that when a real pathogen, such as the flu virus arrives, it will be conquered. Alternatively, adjuvants may activate cells called dendritic cells, which pick up pathogen parts and must travel from the skin to lymph nodes where immune reactions are initiated.

The Duke team, however, has created a vaccine adjuvant of nanoparticles that are capable of traveling from the point of injection to the lymph nodes where they act on many cell types of the immune system to spur the right reaction for a greatly increased immune response.

The researchers found that they could use this adjuvant in vaccinations of mice with the influenza A virus.

In levels of flu virus exposure that would be lethal in typical mice, the vaccinated mice were able to fight off the disease and had an increased survival rate, thanks to the effective immune response the particles stimulated.

The researchers also showed they could load the same type of particles with a different immune factor, IL-12, that directed a response toward a different set of lymphocytes. This is an important finding since certain types of infections require specialized responses to be overpowered by the body.

St. John said the flexibility of the synthetic particles and their ability to target certain lymph nodes represented a new avenue of personalized medical treatment – personalized vaccines.

Senior author Soman Abraham, Ph.D., professor of pathology, immunology and molecular genetics and microbiology at Duke in Durham, N.C., and emerging infectious diseases at Duke-NUS, is cautiously optimistic that the mast-cell-inspired synthetic particles could make their way into human use soon.

“It should not be long because all the individual cytokines (immune system factors) and additional materials loaded into these particles are already FDA approved for use in humans,” Abraham said. “There is a lot of interest in nanoparticle-based therapy, but we are basing our materials on our observation of mast cells in nature. This is an informed application to deliver the right material to the right place in the body to get the most effective immune reaction.”

“We know that low birth weight is associated with an increased risk of asthma symptoms in children, but the effects of specific fetal and infant growth patterns on this risk had not been examined yet,” said researcher Liesbeth Duijts, MD, PhD. “In our study, weight gain acceleration in early infancy was associated with an increased risk of asthma symptoms in children of preschool age, independent of fetal growth patterns, suggesting that early infancy might be a critical period for the development of asthma.”

The findings were published online ahead of print publication in the American Thoracic Society’s American Journal of Respiratory and Critical Care Medicine.

This study was embedded in the Generation R Study, a population-based prospective cohort study, and included 5,125 children who were followed from fetal life through the age of four. Information on asthma symptoms was obtained by questionnaires at the ages of 1, 2, 3, and 4.

No consistent relationships between fetal length and weight growth during different trimesters and the development of asthma symptoms were observed. Accelerated weight gain from birth to 3 months following normal fetal growth was associated with increased risks of asthma symptoms, including wheezing (overall odds ratio (OR) 1.44 (95% confidence interval (CI): 1.22, 1.70), shortness of breath: 1.32 (1.12, 1.56), dry cough: 1.16 (1.01, 1.34), and persistent phlegm: 1.30 (1.07, 1.58)). The associations between accelerated infant growth and risk of developing asthma symptoms were independent of other fetal growth patterns and tended to be stronger among children of atopic mothers.

“Our results suggest that the relationship between infant weight gain and asthma symptoms is not due to the accelerated growth of fetal growth-restricted infants only,” said Dr. Duijts. “While the mechanisms underlying this relationship are unclear, accelerated weight growth in early life might adversely affect lung growth and might be associated with adverse changes in the immune system.”

The study had a few limitations, including the possibility of measurement error in the estimation of fetal weight and the use of self-report for asthma symptoms.

“Further research is needed to replicate our findings and explore the mechanisms that contribute to the effects of growth acceleration in infancy on respiratory health,” concluded Dr. Duijts. “The effects of infant growth patterns on asthma phenotypes in later life should also be examined.”

The very action by which the pill works, blocking the mutated BRAF protein in melanoma cells, sets off a cellular cascade in other skin cells if they have another pre-disposing cancer mutation and ultimately accelerates the secondary skin cancers, said Dr. Antoni Ribas, co-senior author of the paper and a professor of hematology/oncology.

About 50 percent of patients who get melanoma have the BRAF mutation and can be treated with vemurafenib, Ribas said. Of those, a fourth of the patients develop skin squamous cell carcinomas. The squamous cell carcinomas were removed surgically, and vemurafenib was not discontinued for this side effect.

“We wondered why it was that we were treating and getting the melanoma to shrink, but another skin cancer was developing,” said Ribas, who studies melanoma at the Jonsson Cancer Center. “We looked at what was likely making them grow and we discovered that the drug was making pre-existing cells with a RAS mutation grow into skin squamous cell cancers.”

The 18-month study appears in the Jan. 19, 2012 edition of the New England Journal of Medicine.

The combined research team performed a molecular analysis to identify the oncogenic mutations in the squamous cell lesions of patients treated with the BRAF inhibitor. Among 21 tumor samples studied, 13 had RAS mutations. In a different set of 14 samples, eight had RAS mutations, Ribas said.

“Our data indicate that RAS mutations are present in about 60 percent of cases in patients who develop skin squamous cell cancers while treated with vemurafenib,” Ribas said. “This RAS mutation is likely caused by prior skin damage from sun exposure, and what vemurafenib does is accelerate the appearance of these skin squamous cell cancers, as opposed to being the cause of the mutation that starts these cancers.”

Ribas’ group found that blocking the non-mutated BRAF in cells with mutated RAS caused them to send signals around BRAF that induced the growth of the squamous cell cancers.

The discovery of the squamous cell cancer mechanism has led to strategies to inhibit both the BRAF mutation with vemurafenib and block the cellular cascade with a different drug, a MEK inhibitor, before it initiates the secondary skin cancers, said co-senior author Professor Richard Marais from the Institute of Cancer Research in London, who developed the animal model for the study.

“By understanding the mechanism by which these squamous cell cancers develop, we have been able to devise a strategy to prevent the second tumors without blocking the beneficial effects of the BRAF drugs,” Marais said. “This may allow many more patients to benefit from these important drugs.”

Ribas said that this is one of the very few times that oncologists understand molecularly why a side effect to cancer treatment is happening.

“The side effect in this case is caused by how the drug works in a different cellular setting,” he said. “In one case it inhibits cancer growth, and in another it makes the malignant cells grow faster.”

Studies currently are under way testing BRAF and MEK inhibitors in combination in patients with metastatic melanoma, Ribas said.

“Our data provide a molecular mechanism for the clinical toxicity of a targeted oncogene inhibitor that apparently contradicts the intended effects,” the study states.

A new report by the Cochrane Collaboration says Roche’s refusal to provide full access to all its data leaves critical questions about how well the drug works unresolved.

A BMJ investigation, published to coincide with today’s report, also raises serious concerns about access to drug data, the use of ghost writers in drug trials, and the drug approval process.

Meanwhile, Tamiflu has become the mainstay of influenza treatment in the UK. It has also made it onto the World Health Organisation’s list of Essential Medicines and Roche’s claims continue to be supported by influential health agencies.

The Cochrane researchers set out to test Roche’s claim that Tamiflu prevented complications and reduced the number of people needing hospital treatment. But their investigation was hampered by Roche’s refusal to provide all of its trial data for analysis. The team obtained some clinical study reports from the European Medicines Agency (EMA), but found inconsistencies with published reports and possible under-reporting of side effects.

When previously questioned by the BMJ, Roche also admitted that some of the published papers had been ghost written.

The BMJ investigation reveals how different regulators took different approaches to the data submitted to them, leading to conflicting messages about it effectiveness.

For example, the EMA released a proportion of the clinical study reports relating to the Tamiflu trials to Cochrane, but it admits that it did not ask for the remainder from the manufacturer, although it was legally entitled to do so. The EMA has since told the BMJ that it plans to start publishing reports for all drugs submitted for approval in the next few years.

Dr Fiona Godlee, BMJ Editor-in-Chief says: “We hope very much that the EMA will indeed take this important step in making the full study reports available. But we are still a long way away from having a full trial history for all drugs in clinical use. Public safety and the proper use of public money demands that we should stop at nothing less than this.”

Meanwhile, the US Food and Drug Administration (FDA), which has reviewed the Tamiflu trial programme in perhaps more detail than anyone outside of Roche, chose not to review the largest ever trial of Tamiflu when considering the drug for approval. It states that “Tamiflu has not been shown to prevent such complications [serious bacterial infections].”

However, the US Centers for Disease Control and Prevention (CDC) continue to cite key published trials of Tamiflu, claiming a reduced risk of influenza complications, even after Roche admitted that some of these trials have been ghost written.

Dr Godlee says: “The discrepancies between the conclusions reached by different regulators around the world highlights the absurd situation we find ourselves in. In a globalised world, regulators should cooperate and pool their limited resources. Otherwise we will continue to waste money and risk people’s health on drugs that don’t work.”

The investigation also raises questions about Tamiflu’s clinical effects. After careful evaluation of trial data, the Cochrane group say that Tamiflu appears to affect antibody production – a claim that Roche refutes. This is important, say Cochrane, because influenza vaccination relies on an antibody response to be effective. But when asked by the BMJ, Roche refused to explain how the drug works.

As such, the Cochrane group say that “until more is known about the mode of action of neuraminidase inhibitors, health professionals, patients and other decision makers need to reflect on the findings of this review before making any decision about the use of the drug.”

Cochrane also argue that Tamiflu’s ability to prevent the spread of influenza has not been demonstrated in trials. Yet this is one of the main reasons governments around the world have spent billions of dollars stockpiling Tamiflu in case of a pandemic.

Roche maintain they provided the Cochrane team with enough information to conduct their evaluation, but the Cochrane team say this is not the case. Dr Peter Doshi from Johns Hopkins University School of Medicine says: “In the BMJ in December 2009, Roche promised full study reports to any legitimate investigators. They have not provided a single full study report to Cochrane, despite our repeated requests.”

“This is the first demonstration that adding a second anti-HER2 therapy, lapatinib, to trastuzumab is superior to trastuzumab alone in patients with early breast cancer,” says José Baselga, MD, PhD, chief of Oncology at Massachusetts General Hospital (MGH) Cancer Center, who led the study. “It opens up the concept of dual HER2 blockade as a better approach for patients with early, non-metastatic, HER2 breast cancer.”

Approximately 20 to 30 percent of breast cancers are driven by overexpression of HER2, and such tumors are particularly aggressive. Both trastuzumab and lapatinib are agents that target HER2 and have been shown to improve the outcome of patients with HER2-positive breast cancer. Trastuzumab is currently approved in the U.S. for postoperative treatment and in Europe for both pre- and postoperative therapy; lapatinib is used in combination with chemotherapy for patients whose tumors have stopped responding to trastuzumab. Since the two drugs have different mechanisms of action, combination therapy is being investigated to reduce the development of treatment-resistant disease.

The current investigation – the NeoAdjuvant Lapatinib and/or Trastuzumab Treatment Optimization (NeoALTTO) study – enrolled 455 patients in 23 countries. Participants had early-stage, nonmetastatic HER2-positive breast tumors that had not yet been treated and were randomized to one of three treatment arms: anti-HER2 treatment with either intravenous trastuzumab, oral lapatinib or both for 6 weeks. For all participants the same anti-HER2 therapy was continued for another 12 weeks, with the addition of a weekly dose of paclitaxel (Taxol). Tumors were removed surgically within 4 weeks of the last paclitaxel dose. At the completion of surgery, patients received additional chemotherapy and then continued to receive the same anti-HER2 therapy, for a total of one year of anti-HER2 treatment.

More than half the participants receiving combined anti-HER2 therapy achieved a pathological complete response, which means is they had no visible cancer cells in pathologic samples of the removed tissue, a standard measure of the success of preoperative – also called neoadjuvant – therapy. Similar results were seen in less than a third of those receiving a single anti-HER2 agent. The impact of these protocols on patients’ postsurgical survival will be reported in a future study. The authors conclude that, compared to the standard trastuzumab treatment, the combined approach statistically improved the rate of complete remissions.

“We are also conducting a companion study, comparing dual HER2 blockade to single-drug therapy in adjuvant [postoperative] treatment of 8,000 patients,” Baselga says. “If that study’s results confirm our current findings, the implications could be profound for the way we design clinical trials, suggesting that we could answer important questions with much smaller trials.” Baselga is a professor of Medicine at Harvard Medical School. The study was supported by GlaxoSmithKline, which manufactures lapatinib.