Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin’s lymphoma: a phase 1, open-label, dose-escalation study.


Summary

Background

Roughly 70–80% of patients with advanced stage Hodgkin’s lymphoma are cured with various first-line and second-line treatments, including ABVD, BEACOPP, and stem-cell transplantation. Brentuximab vedotin has shown significant clinical activity, with a manageable safety profile, in patients with relapsed or refractory Hodgkin’s lymphoma. We aimed to assess the safety and early clinical efficacy of this drug as first-line treatment in combination with standard or modified-standard treatment in patients with previously untreated Hodgkin’s lymphoma.

Methods

We did a phase 1, open-label, dose-escalation safety study comparing brentuximab vedotin in combination with standard (ABVD) or a modified-standard (AVD) treatment. Patients were enrolled into the groups sequentially. Main entry criteria were newly diagnosed, treatment-naive, CD30-positive patients with Hodgkin’s lymphoma who had histologically confirmed stage IIA bulky disease or stage IIB–IV disease and an Eastern Cooperative Oncology Group performance status of two or less. Patients received doses of 0·6, 0·9, or 1·2 mg/kg brentuximab vedotin by intravenous infusion every 2 weeks with either ABVD (25 mg/m2 doxorubicin, 10 units/m2 bleomycin, 6 mg/m2 vinblastine, and 375 mg/m2 dacarbazine) or AVD (ABVD modified regimen without the inclusion of bleomycin) for up to six cycles. Our primary objectives were to assess the safety profile and establish the maximum tolerated dose (MTD) of brentuximab vedotin in combination with ABVD and AVD. The safety profile and MTD was assessed for the safety population. The study has completed and the final analysis is presented. This study was registered with ClinicalTrials.gov, number NCT01060904.

Findings

Between Jan 29, 2010, and Sept 17, 2012, 51 patients were enrolled and received at least one dose of brentuximab vedotin. The maximum tolerated dose of brentuximab vedotin when combined with ABVD or AVD was not exceeded at 1·2 mg/kg. 21 (95%) of 22 patients given brentuximab vedotin and ABVD achieved complete remission, as did 24 (96%) of 25 patients given brentuximab vedotin and AVD. Adverse events were generally grade 1 or 2; however, an unacceptable number of patients in the brentuximab vedotin and ABVD groups had pulmonary toxic effects (11 [44%] of 25), which exceeded the historical incidence for ABVD alone. No patients experienced pulmonary toxic effects when treated with brentuximab vedotin plus AVD. The most common grade 3 or worse events were neutropenia (20 [80%] of 25 patients in the brentuximab vedotin and ABVD group vs 20 [77%] of 26 patients in the brentuximab vedotin and AVD group), anaemia (five [20%] vs three [12%]), febrile neutropenia (five [20%] vs two [8%]), pulmonary toxic effects (six [24%] vs 0), syncope (three [12%] vstwo [8%]), dyspnoea (three [12%] vs one [4%]), pulmonary embolism (three [12%] vs 0), fatigue (one [4%] each), and leucopenia (one [4%] each). Serious events occured in 41% of all patients (14 [56%] in the brentuximab vedotin and ABVD group and seven [27%] in the brentuximab vedotin and AVD group). Serious events occurring in 10% of patients or more overall were febrile neutropenia (four [16%] in the brentuximab vedotin and ABVD group vs two [8%] in the brentuximab vedotin and AVD group), and, in the brentuximab vedotin and ABVD group only, pulmonary toxic effects (six [24%]).

Interpretation

Brentuximab vedotin should not be given with bleomycin in general or specifically as first-line therapy for patients with treatment naive, advanced stage Hodgkin’s lymphoma. 1·2 mg/kg brentuximab vedotin combined with AVD given every 2 weeks was generally well tolerated by patients. At present, a phase 3 trial comparing brentuximab vedotin plus AVD to ABVD alone is ongoing (ClinicalTrials.gov, number NCT01712490) and will formally assess whether brentuximab vedotin plus AVD might redefine therapy in treatment-naive patients with Hodgkin’s lymphoma.

Source:http://www.thelancet.com

Should we screen extensively for cancer after unprovoked venous thrombosis?


What you need to know

  • The prevalence of occult cancer in patients with a first unprovoked venous thromboembolism seems to be lower (~4%) than previously reported (10%)

  • There is limited evidence to recommend extensive cancer screening with computed tomography in such patients

  • Consider history and physical examination, basic laboratory tests, and results from routine age-specific cancer screening to guide further testing as an alternative to extensive screening

How far to go in screening patients with an unprovoked venous thromboembolism (VTE) for an occult cancer is a clinical dilemma. Unprovoked VTE, either deep vein thrombosis or pulmonary embolism, can be the first manifestation of an undiagnosed cancer. Until recently, the literature suggested that up to 10% of such patients would be diagnosed with a cancer in the year after their diagnosis of VTE.1 However, the incidence of occult cancer in patients studied in two recent, high quality, randomised controlled trials was only about 4%.23 This drop in the proportion of people with occult cancer may require an adjustment in the clinical approach.

Fig 1⇓ outlines a conservative approach and a more detailed approach to investigating such patients. Extensive screening has become the standard of care, though it is based on limited data.

 However, high quality data from recently completed trials discussed below suggest that extensive screening strategies may not provide additional value over routine cancer screening in the frequency of cancer detection in these patients.

What is the evidence of uncertainty?

Search strategy and study selection

We searched PubMed (from inception to 31 December 2016) for randomised controlled trials and systematic reviews using the search terms “cancer screening,” “venous thromboembolism,” “unprovoked,” “meta-analysis,” and “randomized controlled trial.” We reviewed articles published in English between 2012 (publication of NICE guidelines) and 2016.

Source:BMJ

Bad Luck Causes Most Cancer, New Study Finds


Cancer cells in a culture from human connective tissue.

Humans want to believe we control our own destinies. If we exercise for 30 minutes every day, eat healthy, avoid cigarettes, alcohol, and drugs, meditate, and participate in the health trend du jour, it seems logical that we will live longer, be happier, and avoid diseases like cancer. Unfortunately, it seems fate is more chaotic than that. A new study published in Science suggests that most cancers are unavoidable. They’re caused more often by bad luck than anything else.

Mutation, which drives cancer, is actually totally normal. In fact, its the engine of evolution–if not for mutation, our genes wouldn’t make the random changes that once in a while end up giving us a new, important skill–like making enzymes that break down lactose, or resistance to disease. But often, those mutations get out of control. Cells divide and divide until they overpower the useful cells in our body and kill us. That’s what cancer is.

According to Bert Vogelstein and Cristian Tomasetti at the Johns Hopkins Kimmel Cancer Center, many of these cancers are unavoidable. They’re just part of nature.

“We all agree that 40 percent of cancers are preventable,” Vogelstein said at a press conference. “The question is, what about the other cancers that aren’t known to be preventable?”

Vogelstein explained that each time a cell’s DNA is copied, mistakes are made. Most of these mistakes are harmless, and as noted above, some of them can even be beneficial. “But occasionally they occur in a cancer driver gene. That’s bad luck,” Vogelstein says. Several of these bad-luck mistakes can add up to a cancerous cell.

Their study sets out to determine how often these mistakes are preventable–whether by not smoking or maintaining a healthy weight–how often they are genetic, and how often they occur by chance. The answer may surprise people who have spent decades believing they can control the development of cancer in their bodies. According to the paper, 66% of cancerous mutations are random, 29% are preventable, and only 5% are genetic.

The numbers vary depending on the type of cancer. Lung cancer is indeed usually caused by cigarette smoke, while childhood cancer is often random. The authors hope that these statistics will help some parents feel less responsible for their children’s disease.

An earlier paper by the authors on the same topic stirred up controversy in the scientific community. Some feel that publicizing this viewpoint will make people less likely to follow advice about cancer prevention. This new study is likely to be even more controversial.

Of course, cancer science is incredibly complicated. Mutations are not the only thing that matter in driving cancer. Factors like hormones can also play a role in determining who the disease hits hardest. “We’re not saying the only thing that determines the seriousness of the cancer, or its aggressiveness, or its likelihood to cause the patient’s death, are these mutations,” Vogelstein told NPR. “We’re simply saying that they are necessary to get the cancer.”

Source: Science via NPR

The effect of different radiological models on diagnostic accuracy and lung cancer screening performance.


Abstract

High false-positive (FP) scan rates associated with low-dose computed tomography (LDCT) lung cancer screening result in unnecessary follow-up tests and exposure to harm. The definition of a ‘positive’ scan can impact FP rates and screening performance. We explored the effect of Lung Imaging Reporting and Data System (Lung-RADS) criteria, PanCan Nodule Malignancy Probability Model and varying nodule size thresholds (≥4 mm, ≥6 mm, ≥8 mm) on diagnostic accuracy and screening performance compared with original trial definitions (National Lung Screening Trial (NLST) criteria) in a secondary analysis of a lung cancer screening cohort. We found Lung-RADS criteria and the PanCan Nodule Malignancy Probability Model could substantially improve screening performance and reduce FP scan rates compared with NLST definitions of positivity but that this needs to be balanced against possible risk of false-negative results.

source: BMJ THORAX

Two thirds of cancer mutations result from completely random DNA mistakes


An increased focus on early detection will be needed to effectively treat the disease

a yellow breast cancer cell on a red background

A breast cancer cell, photographed by a scanning electron microscope, which produces a 3-dimensional images.

Humans have forever questioned what causes human cancer. And we’ve come a long way: Early theories proposed by Hippocrates in the middle ages suggested the disease arose from supposed “black bile” accumulating in the body. This and other subsequent theories—like cancer cells themselves as infectious, contagious agents—have been debunked by modern research. Scientists now understand cancer arises from mutations created in our DNA when cells replicate and three factors cause those mutations: Environmental, hereditary, and random ones. However, the influence of one of those factors over another is still largely unknown.

Now, a group of researchers at The Johns Hopkins University used new statistical models to figure this out. After analyzing 32 common cancer types, the researchers estimate that 66 percent of cancer mutations are from random ones that occur when cells divide, 29 percent from environmental factors, and 5 are inherited. This means that for people with these cancers, about two thirds of all mutations that eventually result in cancer happen not because of factors in their environment or what they inherit from their parents, but rather as a direct result of how healthy cells grow and divide. The geneticists say researchers should use this new understanding to focus more efforts to detect and treat cancer as early as possible.

 

Cell division, in which one cell breaks apart into two cells in an effort to create new, needed healthy ones, is a natural process. But as this occurs, random mutations happen to the DNA within the cells. Other factors can cause these mutations, too. Environmental ones like smoking or eating a diet low in fiber increase the rate that these errors occur. When enough of these mutations accumulate—no matter what their cause—that’s when the cells begin dividing uncontrollably. That uncontrolled division is what we call cancer.

The researchers wanted to know how much of an influence each mutation-causing factor had on the occurrence of cancer. For 32 cancer types, they pulled together medical information from patients around the world, including those patients’ DNA sequences, information about their lifestyle, and what type of cancer they had. They combined these data sets to understand the influence of each mutation factor. Here’s how one analysis, for lung cancer, would go: Researchers already know the average number of random mutations that happen to an otherwise healthy person who eats well and never smokes. Say that number is 100. From those data sets, and from previous research, they found smokers have cell mutation rates that are three times higher than healthy, non-smokers. So you would expect to find 300 mutations in smokers. So, probabilistically, you can attribute that extra 200 to smoking. They did a similar analysis for 31 other cancers by comparing the mean number of mutations from healthy individuals to mutations attributed to known environmental and heritable causes of those cancers.

 Comparing the 32 types of cancers further demonstrated the effect random mutations have. Cancer is more common in tissues that divide often. For example, cells in the colon divide much more frequently than cells in the brain, which is why colon cancer is much more common in the population than brain cancer is. But overall, the numbers they got—66 percent random, 29 percent environmental, and 5 percent inherited—told the researchers that a majority of cancers occur from random, unpredictable “mistakes” that can’t be predicted.

causes of cancer in the body

DNA mutations, which ultimately cause cancer, result from three causes: they’re inherited, they happen randomly as cells divide, or they occur due to environmental factors like smoking. Researchers found that the cause is different for each organ, charted above. Lung cancer, for example, has a larger percentage of environmental mutations because of smoking whereas brain cancer is almost entirely a result of random errors stated in the graph as “Replicative”.

It offers comfort to the millions of patients who have developed cancer but have led near perfect lives, says Bert Vogelstein, a co-author of the study and professor of pathology and oncology at Johns Hopkins. “We want it to help people avoid feeling guilty about their cancers. These cancers would have occurred not matter what they did.” The researchers say the results could also help guide future research: Understanding how to recognize cancer early on, when its first developing, could offer a better chance at successfully treating it.

So is there anything we can do to slow down, or even completely eliminate these random mutations? Right now, the researchers say most are unavoidable, but it may be possible that some of them could become avoidable in the future. There are four ways that cells randomly mutate during cell division. One of them, called reactive oxygen species or “free radicals” could theoretically be reduced by exposing cells to special antioxidants. Vogelstein says a better understanding of these mutations could open up areas of research to develop these kinds of antioxidant preventative therapies. “It’s similar to our understanding of cholesterol,” Vogelstein says. “Before we knew about cholesterol, we didn’t know we could try to lower it to prevent cardiovascular disease.”

And perhaps this type of research couldn’t come soon enough. The researchers think that in the future, as populations continue to age, the percent of cancer cases attributable to random mutations is only going to increase. As bodies get older, their cells will have experienced more division, which increases the chances of mutations and cancer. Vogelstein says the way we are going to keep up with this increase is finding better ways to detect cancer in its early stage.

Evaluation of Biomarkers for HER3-targeted Therapies in Cancer


Integration of biomarkers into the majority of drug development programs has led to a need for robust measurements and assay validation techniques for analyses of biological samples. The importance of solid methodologies for biomarker assessment is heightened by the fact that new drugs frequently only offer modest benefit and that many potential biomarkers are continuous variables, the application of which relies on data interpretation, with the risk of subjectivity bias, to establish thresholds. Patritumab is a fully human anti-human epidermal growth factor receptor 3 (HER3) antibody that inhibits HER3 from binding to HRG (Mendell et al., 2015). In the HERALD phase II trial, before data unblinding but after subject enrollment, heregulin (HRG) was prospectively declared to be the predictive biomarker for patritumab efficacy. Advanced non-small cell lung cancer (NSCLC) patients previously treated with at least one chemotherapy regimen were randomized to erlotinib plus patritumab (high- or low-dose) or erlotinib plus placebo (Mendell et al., 2015). Testing a single primary predictive biomarker hypothesis to identify those patients most likely to benefit from patritumab was a secondary objective of the trial and HRG was identified as a continuous biomarker to predict outcome.

Members of the HER family of receptor tyrosine kinases (RTK) and their respective ligands constitute a robust biologic system that plays a key role in the regulation of cell-proliferative growth, survival, and differentiation (Ma et al., 2014). HER3 transactivation via dimerization with other RTKs is frequently observed in various malignancies, including NSCLC. Binding of the alpha and beta forms of neuregulin 1, collectively known as HRG, exposes a dimerization arm in the extracellular domain of HER3 and promotes receptor–receptor interactions (Ma et al., 2014, Carraway et al., 1994). HER3 contains six phosphotyrosine binding sites for the p85 subunit of PI3K, the greatest number of all HER family members, and is a major cause of treatment failure in cancer therapy (Ma et al., 2014, Fedi et al., 1994). Recently, the role of HER3 in primary and acquired resistance to EGFR-targeted or other targeted therapies in NSCLC patients has attracted considerable attention (Ma et al., 2014, Torka et al., 2014). Since HER3 lacks or has weak intrinsic kinase activity, targeting it with blocking antibodies that inhibit HRG binding is one strategy currently being investigated in order to overcome therapeutic resistance (Ma et al., 2014).

In the study by Mendell et al., although no progression-free survival (PFS) benefit was observed overall with the addition of patritumab to erlotinib, when patients were stratified according to HRG mRNA levels HRG-high patients treated with patritumab and erlotinib had significantly improved PFS compared with patients treated with erlotinib alone in both the high- and low-dose arms (Hazard Ratio (HR), 0.37 [95%CI, 0.16–0.85] and 0.29 [95%CI, 0.13–0.66]) (Mendell et al., 2015). No PFS benefit was observed in HRG-low patients. An exploratory analysis suggested that high HRG expression might also be a negative prognostic factor in patients treated with single-agent erlotinib (Mendell et al., 2015).

The role of HRG expression as a marker of HER3 activity has been previously reported. Constitutive activation of HER3 signaling can occur in the absence of direct genetic activation of HER3 or HRG while HER3 activation does not occur as a result of mutation or amplification of the HER3 co-receptors EGFR or HER2. Chronic HER3 signaling is driven by high level and potentially autocrine expression of HRG (Holmes et al., 1992). When HRG and HER3 expressions were profiled in more than 750 patients with head and neck squamous cell carcinoma, high-level expression of HRG was associated with constitutive activation of HER3, defining an actionable biomarker for interventions targeting HER3 (Shames et al., 2013).

Since the arrival of erlotinib and gefitinib, metastatic EGFR positive lung cancer patients can be offered therapeutic alternatives with proven superiority over standard platinum-based chemotherapy (Rosell et al., 2013). Testing for EGFR mutations to guide patient selection for EGFR inhibitors, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, is highly recommended (Lindeman et al., 2013). As commented by Mendell et al., the use of a prospective–retrospective approach applied to a single predictive biomarker hypothesis has the advantage of avoiding a high false-positive rate due to multiple comparisons when multiple biomarker hypotheses are evaluated on an equal footing in an exploratory fashion (Mendell et al., 2015). But are statistical simulations able to dismiss the confounding interactions that EGFR-sensitizing mutations could have on the HRs observed in the study? Some readers may also wonder why, in a study of primarily erlotinib treatment where samples were obtained from most patients, EGFR mutations were not assessed? Clinical trials with EGFR inhibitors designed without using EGFR mutation status, as an enrolment criterion should not be an acceptable practice anymore. Finally, having lost >50% of samples for analyzing HRG mRNA, can we safely conclude that high HRG mRNA and not HER3 expression levels are correlated with patritumab efficacy?

Although technological improvements in terms of specimen acquisition and processing have been made, much work remains to be done to ensure the quality of biospecimens and harmonization of tissue collection, processing and storage procedures, attributable largely to the long-standing success of formalin-fixed paraffin-embedded tissue analysis as the standard in diagnostic pathology. There is an ongoing trend to improve standardization of procedures for biomarker development in oncology that involves academia, professional organizations, and industry. Identification and widespread use of biomarkers will ensure that patients receive the best possible therapeutic strategies, thereby avoiding unnecessary treatments and associated toxicities, and reducing total health costs. Increased awareness of HER3 function in cancer progression and tumor recurrence following drug resistance has several implications for future lines of investigation. High expression of HRG seems to accurately define a population of tumors that may have an oncogenic dependency on ligand-activated signaling via HER3 (Mendell et al., 2015). Based on the results of the Mendell et al. study, a two-part phase III study (NCT02134015) has been initiated to examine patritumab plus erlotinib treatment in EGFR wild-type patients with advanced NSCLC. Part A will enroll subjects with any HRG value to further refine the HRG cutoff level while evaluating the efficacy of patritumab plus erlotinib versus erlotinib in the HRG-high group. Part B will enroll only HRG-high (as per revised criteria) patients to evaluate efficacy and safety of patritumab plus erlotinib versus erlotinib.

Source:http://www.ebiomedicine.com

Clinical Translation and Validation of a Predictive Biomarker for Patritumab, an Anti-human Epidermal Growth Factor Receptor 3 (HER3) Monoclonal Antibody, in Patients With Advanced Non-small Cell Lung Cancer


Highlights

  • High heregulin levels predict benefit from patritumab treatment in patients with NSCLC.

    A prospective–retrospective approach provisionally validated a predictive biomarker.

    Post hoc analyses can be used to test underlying assumptions in biomarker validation.

    The median may be a reasonable initial cutoff for a unimodal continuous biomarker.

Abstract

Background

During early clinical development, prospective identification of a predictive biomarker and validation of an assay method may not always be feasible. Dichotomizing a continuous biomarker measure to classify responders also leads to challenges. We present a case study of a prospective–retrospective approach for a continuous biomarker identified after patient enrollment but defined prospectively before the unblinding of data. An analysis of the strengths and weaknesses of this approach and the challenges encountered in its practical application are also provided.

Methods

HERALD (NCT02134015) was a double-blind, phase 2 study in patients with non-small cell lung cancer (NSCLC) randomized to erlotinib with placebo or with high or low doses of patritumab, a monoclonal antibody targeted against human epidermal growth factor receptor 3 (HER3). While the primary objective was to assess safety and progression-free survival (PFS), a secondary objective was to determine a single predictive biomarker hypothesis to identify subjects most likely to benefit from the addition of patritumab. Although not identified as the primary biomarker in the study protocol, on the basis of preclinical results from 2 independent laboratories, expression levels of the HER3 ligand heregulin (HRG) were prospectively declared the predictive biomarker before data unblinding but after subject enrollment. An assay to measure HRG mRNA was developed and validated. Other biomarkers, such as epidermal growth factor receptor (EGFR) mutation status, were also evaluated in an exploratory fashion. The cutoff value for high vs. low HRG mRNA levels was set at the median delta threshold cycle. A maximum likelihood analysis was performed to evaluate the provisional cutoff. The relationship of HRG values to PFS hazard ratios (HRs) was assessed as a measure of internal validation. Additional NSCLC samples were analyzed to characterize HRG mRNA distribution.

Results

The subgroup of patients with high HRG mRNA levels (“HRG-high”) demonstrated clinical benefit from patritumab treatment with HRs of 0.37 (P = 0.0283) and 0.29 (P = 0.0027) in the high- and low-dose patritumab arms, respectively. However, only 102 of the 215 randomized patients (47.4%) had sufficient tumor samples for HRG mRNA measurement. Maximum likelihood analysis showed that the provisional cutoff was within the optimal range. In the placebo arm, the HRG-high subgroup demonstrated worse prognosis compared with HRG-low. A continuous relationship was observed between increased HRG mRNA levels and lower HR. Additional NSCLC samples (N = 300) demonstrated a similar unimodal distribution to that observed in this study, suggesting that the defined cutoff may be applicable to future NSCLC studies.

Conclusions

The prospective–retrospective approach was successful in clinically validating a probable predictive biomarker. Post hoc in vitro studies and statistical analyses permitted further testing of the underlying assumptions. However, limitations of this analysis include the incomplete collection of adequate tumor tissue and a lack of stratification. In a phase 3 study, findings are being confirmed, and the HRG cutoff value is being further refined.

Source:http://www.ebiomedicine.com

Building the Evidence Base of Blood-Based Biomarkers for Early Detection of Cancer: A Rapid Systematic Mapping Review


 There are a large number of biomarkers with potential utility for early cancer detection from blood samples

Few biomarkers have been studied sufficiently with clinical validation to allow their use in combination for screening in the general population.

We used an iterative mapping review of 20,000 references, retrieving 3,990 relevant papers, and identified 788 markers in blood of potential use

Screening for cancer can save lives, but it is difficult to justify individual screening programmes for many cancer types. However, cancers of different types share many attributes, and markers of cancer biology found in the blood. We surveyed the literature to identify known biomarkers using a new mapping approach. With nearly 20,000 papers on the subject, we retrieved 3990 papers, and identified 788 markers in blood of potential use. Most have not been studied enough to justify their use in clinical practice. This evidence based approach should help us to develop a blood-based cancer screening test in the general population.

Abstract

Background

The Early Cancer Detection Consortium is developing a blood-test to screen the general population for early identification of cancer, and has therefore conducted a systematic mapping review to identify blood-based biomarkers that could be used for early identification of cancer.

Methods

A mapping review with a systematic approach was performed to identify biomarkers and establish their state of development. Comprehensive searches of electronic databases Medline, Embase, CINAHL, the Cochrane library and Biosis were conducted in May 2014 to obtain relevant literature on blood-based biomarkers for cancer detection in humans. Screening of retrieved titles and abstracts was performed using an iterative sifting process known as “data mining”. All blood based biomarkers, their relevant properties and characteristics, and their corresponding references were entered into an inclusive database for further scrutiny by the Consortium, and subsequent selection of biomarkers for rapid review. This systematic review is registered with PROSPERO (no. CRD42014010827).

Findings

The searches retrieved 19,724 records after duplicate removal. The data mining approach retrieved 3990 records (i.e. 20% of the original 19,724), which were considered for inclusion. A list of 814 potential blood-based biomarkers was generated from included studies. Clinical experts scrutinised the list to identify miss-classified and duplicate markers, also volunteering the names of biomarkers that may have been missed: no new markers were identified as a result. This resulted in a final list of 788 biomarkers.

Interpretation

This study is the first to systematically and comprehensively map blood biomarkers for early detection of cancer. Use of this rapid systematic mapping approach found a broad range of relevant biomarkers allowing an evidence-based approach to identification of promising biomarkers for development of a blood-based cancer screening test in the general population.

Source:http://www.ebiomedicine.com

Two thirds of cancer mutations result from completely random DNA mistakes


An increased focus on early detection will be needed to effectively treat the disease

a yellow breast cancer cell on a red background

A breast cancer cell, photographed by a scanning electron microscope, which produces a 3-dimensional images.

Humans have forever questioned what causes human cancer. And we’ve come a long way: Early theories proposed by Hippocrates in the middle ages suggested the disease arose from supposed “black bile” accumulating in the body. This and other subsequent theories—like cancer cells themselves as infectious, contagious agents—have been debunked by modern research. Scientists now understand cancer arises from mutations created in our DNA when cells replicate and three factors cause those mutations: Environmental, hereditary, and random ones. However, the influence of one of those factors over another is still largely unknown.

Now, a group of researchers at The Johns Hopkins University used new statistical models to figure this out. After analyzing 32 common cancer types, the researchers estimate that 66 percent of cancer mutations are from random ones that occur when cells divide, 29 percent from environmental factors, and 5 are inherited. This means that for people with these cancers, about two thirds of all mutations that eventually result in cancer happen not because of factors in their environment or what they inherit from their parents, but rather as a direct result of how healthy cells grow and divide. The geneticists say researchers should use this new understanding to focus more efforts to detect and treat cancer as early as possible.

 Cell division, in which one cell breaks apart into two cells in an effort to create new, needed healthy ones, is a natural process. But as this occurs, random mutations happen to the DNA within the cells. Other factors can cause these mutations, too. Environmental ones like smoking or eating a diet low in fiber increase the rate that these errors occur. When enough of these mutations accumulate—no matter what their cause—that’s when the cells begin dividing uncontrollably. That uncontrolled division is what we call cancer.

The researchers wanted to know how much of an influence each mutation-causing factor had on the occurrence of cancer. For 32 cancer types, they pulled together medical information from patients around the world, including those patients’ DNA sequences, information about their lifestyle, and what type of cancer they had. They combined these data sets to understand the influence of each mutation factor. Here’s how one analysis, for lung cancer, would go: Researchers already know the average number of random mutations that happen to an otherwise healthy person who eats well and never smokes. Say that number is 100. From those data sets, and from previous research, they found smokers have cell mutation rates that are three times higher than healthy, non-smokers. So you would expect to find 300 mutations in smokers. So, probabilistically, you can attribute that extra 200 to smoking. They did a similar analysis for 31 other cancers by comparing the mean number of mutations from healthy individuals to mutations attributed to known environmental and heritable causes of those cancers.

 Comparing the 32 types of cancers further demonstrated the effect random mutations have. Cancer is more common in tissues that divide often. For example, cells in the colon divide much more frequently than cells in the brain, which is why colon cancer is much more common in the population than brain cancer is. But overall, the numbers they got—66 percent random, 29 percent environmental, and 5 percent inherited—told the researchers that a majority of cancers occur from random, unpredictable “mistakes” that can’t be predicted.

causes of cancer in the body

DNA mutations, which ultimately cause cancer, result from three causes: they’re inherited, they happen randomly as cells divide, or they occur due to environmental factors like smoking. Researchers found that the cause is different for each organ, charted above. Lung cancer, for example, has a larger percentage of environmental mutations because of smoking whereas brain cancer is almost entirely a result of random errors stated in the graph as “Replicative”.

It offers comfort to the millions of patients who have developed cancer but have led near perfect lives, says Bert Vogelstein, a co-author of the study and professor of pathology and oncology at Johns Hopkins. “We want it to help people avoid feeling guilty about their cancers. These cancers would have occurred not matter what they did.” The researchers say the results could also help guide future research: Understanding how to recognize cancer early on, when its first developing, could offer a better chance at successfully treating it.

So is there anything we can do to slow down, or even completely eliminate these random mutations? Right now, the researchers say most are unavoidable, but it may be possible that some of them could become avoidable in the future. There are four ways that cells randomly mutate during cell division. One of them, called reactive oxygen species or “free radicals” could theoretically be reduced by exposing cells to special antioxidants. Vogelstein says a better understanding of these mutations could open up areas of research to develop these kinds of antioxidant preventative therapies. “It’s similar to our understanding of cholesterol,” Vogelstein says. “Before we knew about cholesterol, we didn’t know we could try to lower it to prevent cardiovascular disease.”

And perhaps this type of research couldn’t come soon enough. The researchers think that in the future, as populations continue to age, the percent of cancer cases attributable to random mutations is only going to increase. As bodies get older, their cells will have experienced more division, which increases the chances of mutations and cancer. Vogelstein says the way we are going to keep up with this increase is finding better ways to detect cancer in its early stage.

Source:http://www.rawstory.com

Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study.


Summary

Background

Although trastuzumab plus chemotherapy is the standard of care for first-line treatment of HER2-positive advanced gastric cancer, there is no established therapy in the second-line setting. In GATSBY, we examined the efficacy and tolerability of trastuzumab emtansine in patients previously treated for HER2-positive advanced gastric cancer (unresectable, locally advanced, or metastatic gastric cancer, including adenocarcinoma of the gastro-oesophageal junction).

Methods

This is the final analysis from GATSBY, a randomised, open-label, adaptive, phase 2/3 study, done at 107 centres (28 countries worldwide). Eligible patients had HER2-positive advanced gastric cancer and progressed during or after first-line therapy. In stage one of the trial, patients were randomly assigned to treatment groups (2:2:1) to receive intravenous trastuzumab emtansine (3·6 mg/kg every 3 weeks or 2·4 mg/kg weekly) or physician’s choice of a taxane (intravenous docetaxel 75 mg/m2every 3 weeks or intravenous paclitaxel 80 mg/m2 weekly). In stage two, patients were randomly assigned to treatment groups (2:1) to receive the independent data monitoring committee (IDMC)-selected dose of trastuzumab emtansine (2·4 mg/kg weekly) or a taxane (same regimen as above). We used permuted block randomisation, stratified by world region, previous HER2-targeted therapy, and previous gastrectomy. The primary endpoint (overall survival) was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01641939.

Findings

Between Sept 3, 2012, and Oct 14, 2013, 70 patients were assigned to receive trastuzumab emtansine 3·6 mg/kg every 3 weeks, 75 to receive trastuzumab emtansine 2·4 mg/kg weekly, and 37 to receive a taxane in the stage 1 part of the trial. At the pre-planned interim analysis (Oct 14, 2013), the IDMC selected trastuzumab emtansine 2·4 mg/kg weekly as the dose to proceed to stage 2. By Feb 9, 2015, a further 153 patients had been randomly assigned to receive trastuzumab emtansine 2·4 mg/kg weekly and a further 80 to receive a taxane. At data cutoff, median follow-up was 17·5 months (IQR 12·1–23·0) for the trastuzumab emtansine 2·4 mg/kg weekly group and 15·4 months (9·2–18·1) in the taxane group. Median overall survival was 7·9 months (95% CI 6·7–9·5) with trastuzumab emtansine 2·4 mg/kg weekly and 8·6 months (7·1–11·2) with taxane treatment (hazard ratio 1·15, 95% CI 0·87–1·51, one-sided p=0·86). The trastuzumab emtansine 2·4 mg/kg group had lower incidences of grade 3 or more adverse events (134 [60%] of 224 patients treated with trastuzumab emtansine vs 78 [70%] of 111 patients treated with a taxane), and similar incidences of adverse events leading to death (eight [4%] vs four [4%]), serious adverse events (65 [29%] vs 31 [28%]), and adverse events leading to treatment discontinuation (31 [14%] vs 15 [14%]) than did taxane treatment. The most common grade 3 or more adverse events in the trastuzumab emtansine 2·4 mg/kg weekly group were anaemia (59 [26%]) and thrombocytopenia (25 [11%]) compared with neutropenia (43 [39%]), and anaemia (20 [18%]), in the taxane group. The most common serious adverse events were anaemia (eight [4%]), upper gastrointestinal haemorrhage (eight [4%]), pneumonia (seven [3%]), gastric haemorrhage (six [3%]), and gastrointestinal haemorrhage (five [2%]) in the trastuzumab emtansine 2·4 mg/kg weekly group compared with pneumonia (four [4%]), febrile neutropenia (four [4%]), anaemia (three [3%]), and neutropenia (three [3%]) in the taxane group.

Interpretation

Trastuzumab emtansine was not superior to taxane in patients with previously treated, HER2-positive advanced gastric cancer. There is still an unmet need in this patient group and therapeutic options remain limited.

Source:http://www.thelancet.com