Genetic Testing in New NSCLC: Worth the Effort?


“If you build it, they will come,” the saying goes, but has that been the case with genetic/genomic testing in patients with newly diagnosed non-small cell lung cancer (NSCLC)? After all, research has shown that about 40% of patients with NSCLC have one of these molecular alterations in their tumor, and using these tests can help sort out those who have KRAS-mutated disease, versus epidermal growth factor receptor (EGFR) mutations, versus ALK, ROS1, or RET translocations, guiding patients to the most effective targeted therapy.

A recent international survey of oncologists revealed that while the use of genetic/genomic is on the rise, many clinicians are either bypassing testing altogether, or if the patient did undergo testing, the results were not used to make treatment decisions.

 Overall, genetic testing can help clinicians get a better handle on the subtype of NSCLC they are contending with, based on specific molecular alterations. This improved disease description will give patients a better chance of receiving the most effective treatment with the least toxicity and, ideally, at the right price point.

For instance, EGFR mutations are currently the most common genomically classified subgroup of NSCLC. These mutations tend to be more prevalent in tumors with adenocarcinoma histology, in patients who have never smoked tobacco, in patients of East Asian race, and women. Results of genetic/genomic testing can then set patients up for treatment with agents such as gefitinib (Iressa) and erlotinib (Tarceva).

Guidelines established by specialty groups, including the College of American Pathologists and the International Association for the Study of Lung Cancer, recommend testing for EGFR mutations (along with testing for ALK mutations) in patients with advanced-stage disease. Whether early-stage patients should undergo the same is uncertain.

“The question of whether or not to test a diagnostic specimen in early-stage disease is a local decision that must be made in conjunction with each institution’s oncology care team, as insufficient published evidence supports a universal recommendation,” according to 2013 guidelines from the groups mentioned above. “The benefits of testing all early-stage disease patients must be balanced against the cost of performing testing that may not be used to select therapy for the patients who never have relapse.”

But genetic screening in early NSCLC isn’t out of the question, wrote Jean-Charles Soria, MD, PhD, of Gustave Roussy Cancer Center in Villejuif, France, in an email to MedPage Today. He pointed out that there is a debate over the risk of relapse in stage I-II cancer, but even if that risk is over a 5-year period, it “reaches 50%, so I also believe it could help.”

 Even in early-stage NSCLC, molecular testing can serve as a decisive factor in the choice of therapeutic strategies for patients, explained Frédérique Nowak, PhD, of the French National Cancer Institute (INCa) in Boulogne-Billancourt, France in an email to MedPage Today.

For example, early testing can rule out if a patient is simply ineligible for treatment with gefitinib, an EGFR tyrosine kinase inhibitor (TKI). Nowak cited a 2012 study that she and Soria co-authored that found that EGFR testing avoided a median of 8 weeks of administration of gefitinib for EGFR-negative patients.

An added benefit to testing? The potential for a significant reduction in treatment costs. “In France in 2010, about 15,000 of the 16,834 patients with lung cancer who benefited from EGFR screening were EGFR-mutation negative and thus were ineligible for TKI-EGFR treatment,” Nowak stated.

“As 8 weeks of gefitinib treatment costs €4,600 per patient in France [about $5,000], this would mean overall savings of €69 million [about $74 million]. According to the numbers of EGFR tests performed in 2011, the spared costs should be even greater,” she added.

Seven years ago, INCa, along with the French Ministry of Health, launched a campaign to implement molecular testing for all cancer patients across the French national healthcare system. The network is made up of 28 regional molecular genetic centers that perform tests for free for all patients in their regions.

 Nowak reported that the network now “is fully deployed in the country. For lung cancer, the tumors of more than 24,000 patients were screened for EGFR mutation and ALK rearrangement in 2014. It roughly corresponds to all non-epidermoid NSCLC patients at a metastatic stage in France.”

Back to the survey results, which revealed that one of the impediments to implementing genetic testing in newly diagnosed patients may be the wait for the results – the turnaround time for test findings can range from 1 to 2 weeks. About a quarter of U.S.-based survey respondents stating that was too long.

In general, lung cancer takes some time to develop before a diagnosis is made; a few extra days of waiting for test results that can have a major impact on treatment course and patient outcomes shouldn’t be that onerous, noted survey leader James Spicer, PhD, MBBS, of King’s College London.

“Personally — and I think this is a fairly common viewpoint — turnaround within 1 week — 5 working days — would definitely be acceptable; 2 weeks or more becomes a problem,” he said.

While Spicer told MedPage Today that he wasn’t surprised by the survey results, his group also did not find any evidence that clinicians were skeptical about EGFR testing overall. Instead, it may be a matter of continual education to emphasize the benefits of genetic testing in NSCLC patients across the board.

“We should be aiming for every suitable NSCLC patient to be tested, and every patient receiving an appropriate treatment for their type of lung cancer,” Spicer said in a written statement about the survey results. He added that “there is still work to be done in emphasizing the importance of obtaining EGFR test results prior to the initiation of treatment, and using this vital information to select optimum therapy.”

A Small RNA That Promotes Lung Cancer.


Gene expression in both healthy and cancerous tissues is controlled by a wide array of regulatory molecules including a group of small RNA molecules known as microRNAs. New research, performed by Ethan Dmitrovsky and colleagues, at Dartmouth Medical School, Hanover, now provides evidence that the microRNA miR-31 promotes lung cancer by repressing the expression of a number of tumor suppressor genes (i.e., genes that generate proteins that suppress the development of cancer).

The initial series of experiments conducted in the study indicated that miR-136, miR-376a, and miR-31 were all overexpressed in mouse and human malignant lung tissue compared with paired normal tissue. Importantly, knockdown of miR-31 expression repressed the in vitro growth of mouse and human lung cancer cell lines and reduced the in vivo tumorigenicity of mouse lung cancer cell lines.

Further analysis provided a potential mechanism by which modulation of miR-31 expression levels could affect lung cancer cell growth: miR-31 repressed expression of the tumor-suppressor genes LATS2 and PPP2R2A. As miR-31 and these target genes were inversely expressed in human lung cancers, the authors conclude that their data has clinical relevance and that miR-31 promotes lung cancer by repressing expression of specific tumor suppressors.

Source: http://www.sciencedaily.com

 

 

Gene Involved in Lung Tumor Growth Identified.


Lung cancer researchers at St. Joseph’s Hospital and Medical Center in Phoenix, Ariz., in collaboration with researchers at the Translational Genomics Research Institute and other institutions, have identified a gene that plays a role in the growth and spread of non-small cell lung cancer tumors, opening the door for potential new treatment options.

The study, titled “Elevated Expression of Fn14 in Non-Small Cell Lung Cancer Correlates with Activated EGFR and Promotes Tumor Cell Migration and Invasion,” was published in the May 2012 issue of The American Journal of Pathology. Landon J. Inge, PhD, is the lead scientist in the thoracic oncology laboratory at St. Joseph’s Center for Thoracic Disease and Transplantation and was a member of the study’s research team.

Lung cancer is the leading cause of cancer deaths worldwide, and approximately 85 percent of these cancers are non-small cell lung cancers (NSCLC). Patients with NSCLC frequently have tumors with mutations in the epidermal growth factor receptor (EGFR) gene. When activated, this mutated gene leads to tumor development and growth. By studying lung cancer samples from patients who had undergone tumor resection, the researchers discovered that many patients with EGFR mutations also exhibited higher than normal levels of the gene fibroblast growth factor-inducible 14 (Fn14). The researchers believe that activation of EGFR can lead to increased expression and activity of the Fn14 gene.

The research team also discovered that while over-expression of Fn14 enhances lung tumor formation and metastasis, suppression of Fn14 reduces metastasis in NSCLC.

“Our data suggest that Fn14 levels can contribute to NSCLC cell migration and invasion,” says Dr. Inge. “Thus, tumor suppression through the targeting of Fn14 may prove to be a therapeutic intervention in NSCLC and other tumor types.”

The Fn14 gene has been found to be elevated in other types of tumors, as well, including glioblastoma and certain types of breast cancer, suggesting that Fn14 may be a therapeutic target for multiple cancer therapies.

Source: http://www.sciencedaily.com

Marijuana Cuts Lung Cancer Tumor Growth In Half, Study Shows.


The active ingredient in marijuana cuts tumor growth in common lung cancer in half and significantly reduces the ability of the cancer to spread, say researchers at Harvard University who tested the chemical in both lab and mouse studies.

They say this is the first set of experiments to show that the compound, Delta-tetrahydrocannabinol (THC), inhibits EGF-induced growth and migration in epidermal growth factor receptor (EGFR) expressing non-small cell lung cancer cell lines. Lung cancers that over-express EGFR are usually highly aggressive and resistant to chemotherapy.

THC that targets cannabinoid receptors CB1 and CB2 is similar in function to endocannabinoids, which are cannabinoids that are naturally produced in the body and activate these receptors. The researchers suggest that THC or other designer agents that activate these receptors might be used in a targeted fashion to treat lung cancer.

“The beauty of this study is that we are showing that a substance of abuse, if used prudently, may offer a new road to therapy against lung cancer,” said Anju Preet, Ph.D., a researcher in the Division of Experimental Medicine.

Acting through cannabinoid receptors CB1 and CB2, endocannabinoids (as well as THC) are thought to play a role in variety of biological functions, including pain and anxiety control, and inflammation. Although a medical derivative of THC, known as Marinol, has been approved for use as an appetite stimulant for cancer patients, and a small number of U.S. states allow use of medical marijuana to treat the same side effect, few studies have shown that THC might have anti-tumor activity, Preet says. The only clinical trial testing THC as a treatment against cancer growth was a recently completed British pilot study in human glioblastoma.

In the present study, the researchers first demonstrated that two different lung cancer cell lines as well as patient lung tumor samples express CB1 and CB2, and that non-toxic doses of THC inhibited growth and spread in the cell lines. “When the cells are pretreated with THC, they have less EGFR stimulated invasion as measured by various in-vitro assays,” Preet said.

Then, for three weeks, researchers injected standard doses of THC into mice that had been implanted with human lung cancer cells, and found that tumors were reduced in size and weight by about 50 percent in treated animals compared to a control group. There was also about a 60 percent reduction in cancer lesions on the lungs in these mice as well as a significant reduction in protein markers associated with cancer progression, Preet says.

Although the researchers do not know why THC inhibits tumor growth, they say the substance could be activating molecules that arrest the cell cycle. They speculate that THC may also interfere with angiogenesis and vascularization, which promotes cancer growth.

Preet says much work is needed to clarify the pathway by which THC functions, and cautions that some animal studies have shown that THC can stimulate some cancers. “THC offers some promise, but we have a long way to go before we know what its potential is,” she said.

Source: http://www.sciencedaily.com

Harvard Study Shows “Marijuana Cuts Lung Cancer Tumor Growth In Half”.


The active ingredient in marijuana cuts tumor growth in common lung cancer in half and significantly reduces the ability of the cancer to spread, say researchers at Harvard University who tested the chemical in both lab and mouse studies.
They say this is the first set of experiments to show that the compound, Delta-tetrahydrocannabinol (THC), inhibits EGF-induced growth and migration in epidermal growth factor receptor (EGFR) expressing non-small cell lung cancer cell lines. Lung cancers that over-express EGFR are usually highly aggressive and resistant to chemotherapy.smoking_1117THC that targets cannabinoid receptors CB1 and CB2 is similar in function to endocannabinoids, which are cannabinoids that are naturally produced in the body and activate these receptors. The researchers suggest that THC or other designer agents that activate these receptors might be used in a targeted fashion to treat lung cancer.

“The beauty of this study is that we are showing that a substance of abuse, if used prudently, may offer a new road to therapy against lung cancer,” said Anju Preet, Ph.D., a researcher in the Division of Experimental Medicine.

Acting through cannabinoid receptors CB1 and CB2, endocannabinoids (as well as THC) are thought to play a role in variety of biological functions, including pain and anxiety control, and inflammation. Although a medical derivative of THC, known as Marinol, has been approved for use as an appetite stimulant for cancer patients, and a small number of U.S. states allow use of medical marijuana to treat the same side effect, few studies have shown that THC might have anti-tumor activity, Preet says. The only clinical trial testing THC as a treatment against cancer growth was a recently completed British pilot study in human glioblastoma.

In the present study, the researchers first demonstrated that two different lung cancer cell lines as well as patient lung tumor samples express CB1 and CB2, and that non-toxic doses of THC inhibited growth and spread in the cell lines. “When the cells are pretreated with THC, they have less EGFR stimulated invasion as measured by various in-vitro assays,” Preet said.

Then, for three weeks, researchers injected standard doses of THC into mice that had been implanted with human lung cancer cells, and found that tumors were reduced in size and weight by about 50 percent in treated animals compared to a control group. There was also about a 60 percent reduction in cancer lesions on the lungs in these mice as well as a significant reduction in protein markers associated with cancer progression, Preet says.

Source: realfarmacy.com

Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial.


Background

Icotinib, an oral EGFR tyrosine kinase inhibitor, had shown antitumour activity and favourable toxicity in early-phase clinical trials. We aimed to investigate whether icotinib is non-inferior to gefitinib in patients with non-small-cell lung cancer.

Methods

In this randomised, double-blind, phase 3 non-inferiority trial we enrolled patients with advanced non-small-cell lung cancer from 27 sites in China. Eligible patients were those aged 18—75 years who had not responded to one or more platinum-based chemotherapy regimen. Patients were randomly assigned (1:1), using minimisation methods, to receive icotinib (125 mg, three times per day) or gefitinib (250 mg, once per day) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, analysed in the full analysis set. We analysed EGFR status if tissue samples were available. All investigators, clinicians, and participants were masked to patient distribution. The non-inferiority margin was 1·14; non-inferiority would be established if the upper limit of the 95% CI for the hazard ratio (HR) of gefitinib versus icotinib was less than this margin. This study is registered with ClinicalTrials.gov, number NCT01040780, and the Chinese Clinical Trial Registry, number ChiCTR-TRC-09000506.

Findings

400 eligible patients were enrolled between Feb 26, 2009, and Nov 13, 2009; one patient was enrolled by mistake and removed from the study, 200 were assigned to icotinib and 199 to gefitinib. 395 patients were included in the full analysis set (icotinib, n=199; gefitinib, n=196). Icotinib was non-inferior to gefitinib in terms of progression-free survival (HR 0·84, 95% CI 0·67—1·05; median progression-free survival 4·6 months [95% CI 3·5—6·3] vs 3·4 months [2·3—3·8]; p=0·13). The most common adverse events were rash (81 [41%] of 200 patients in the icotinib group vs 98 [49%] of 199 patients in the gefitinib group) and diarrhoea (43 [22%] vs 58 [29%]). Patients given icotinib had less drug-related adverse events than did those given gefitinib (121 [61%] vs 140 [70%]; p=0·046), especially drug-related diarrhoea (37 [19%] vs 55 [28%]; p=0·033).

Interpretation

Icotinib could be a new treatment option for pretreated patients with advanced non-small-cell lung cancer.

Source: Lancet

 

EU Okays Afatinib for NSCLC, Filgrastim and Defibrotide.


The European Committee for Medicinal Products for Human Use (CHMP) has recommended that the targeted agent afatinib (Giotrif, Boehringer Ingelheim) be approved for use in nonsmall-cell lung cancer (NSCLC) that tests positive for EGFRmutations.

Afatinib was recently approved for this indication in the United States under the trade name Gilotrif.

This is the third drug to target EGFR mutations in NSCLC; it joins erlotinib (Tarceva) and gefitinib (Iressa). Both are available in most countries in the world, with one notable exception — gefitinib is not available in the United States.

About 10% to 15% of NSCLC is positive for EGFR mutations in Western populations; in Asian populations, the incidence is higher.

Filgrastim Biosimilar

The CHMP also recommended approval for the growth factor filgrastim (Grastofil, Apotex) for the treatment of neutropenia, which is a biosimilar to Neupogen (Amgen). “Studies have shown Grastofil to have a comparable quality, safety, and efficacy profile to Neupogen,” the committee noted.

Filgrastim is a granulocyte colony-stimulating factor that regulates the production and release of functional neutrophils from the bone marrow. It is used in cancer patients to counteract the myelosuppressive effects of chemotherapy by reducing the duration of neutropenia and the incidence of febrile neutropenia.

Change of Mind on Defibrotide

In addition, in its July meeting, the CHMP recommended the approval of defibrotide (Defitelio, Gentium) for use in the treatment of severe hepatic veno-occlusive disease, also known as sinusoidal obstructive syndrome, related to hematopoietic stem cell transplantation. The product has orphan drug status for this indication.

The CHMP issued a negative opinion on this product in March 2012. But at the request of the company, the committee re-examined its stance. After that re-examination, it issued a positive opinion for the very narrow indication of severe veno-occlusive disease.

The mechanism of action of defibrotide has not been fully elucidated, the committee notes in its summary. The drug increases the breakdown of blood clots, and it might also protect cells lining the blood vessels, it notes. The most common adverse events are hemorrhage, hypotension, and coagulopathy.

Source: Medscape.com

Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial.


Background

Previous trials have shown that anti-EGFR monoclonal antibodies can improve clinical outcomes of patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SCCHN). We assessed the efficacy and safety of panitumumab combined with cisplatin and fluorouracil as first-line treatment for these patients.

Methods

This open-label phase 3 randomised trial was done at 126 sites in 26 countries. Eligible patients were aged at least 18 years; had histologically or cytologically confirmed SCCHN; had distant metastatic or locoregionally recurrent disease, or both, that was deemed to be incurable by surgery or radiotherapy; had an Eastern Cooperative Oncology Group performance status of 1 or less; and had adequate haematological, renal, hepatic, and cardiac function. Patients were randomly assigned according to a computer-generated randomisation sequence (1:1; stratified by previous treatment, primary tumour site, and performance status) to one of two groups. Patients in both groups received up to six 3-week cycles of intravenous cisplatin (100 mg/m2 on day 1 of each cycle) and fluorouracil (1000 mg/m2 on days 1—4 of each cycle); those in the experimental group also received intravenous panitumumab (9 mg/kg on day 1 of each cycle). Patients in the experimental group could choose to continue maintenance panitumumab every 3 weeks. The primary endpoint was overall survival and was analysed by intention to treat. In a prospectively defined retrospective analysis, we assessed tumour human papillomavirus (HPV) status as a potential predictive biomarker of outcomes with a validated p16-INK4A (henceforth, p16) immunohistochemical assay. Patients and investigators were aware of group assignment; study statisticians were masked until primary analysis; and the central laboratory assessing p16 status was masked to identification of patients and treatment. This trial is registered with ClinicalTrials.gov, number NCT00460265.

Findings

Between May 15, 2007, and March 10, 2009, we randomly assigned 657 patients: 327 to the panitumumab group and 330 to the control group. Median overall survival was 11·1 months (95% CI 9·8—12·2) in the panitumumab group and 9·0 months (8·1—11·2) in the control group (hazard ratio [HR] 0·873, 95% CI 0·729—1·046; p=0·1403). Median progression-free survival was 5·8 months (95% CI 5·6—6·6) in the panitumumab group and 4·6 months (4·1—5·4) in the control group (HR 0·780, 95% CI 0·659—0·922; p=0·0036). Several grade 3 or 4 adverse events were more frequent in the panitumumab group than in the control group: skin or eye toxicity (62 [19%] of 325 included in safety analyses vs six [2%] of 325), diarrhoea (15 [5%] vs four [1%]), hypomagnesaemia (40 [12%] vs 12 [4%]), hypokalaemia (33 [10%] vs 23 [7%]), and dehydration (16 [5%] vs seven [2%]). Treatment-related deaths occurred in 14 patients (4%) in the panitumumab group and eight (2%) in the control group. Five (2%) of the fatal adverse events in the panitumumab group were attributed to the experimental agent. We had appropriate samples to assess p16 status for 443 (67%) patients, of whom 99 (22%) were p16 positive. Median overall survival in patients with p16-negative tumours was longer in the panitumumab group than in the control group (11·7 months [95% CI 9·7—13·7] vs8·6 months [6·9—11·1]; HR 0·73 [95% CI 0·58—0·93]; p=0·0115), but this difference was not shown for p16-positive patients (11·0 months [7·3—12·9] vs 12·6 months [7·7—17·4]; 1·00 [0·62—1·61]; p=0·998). In the control group, p16-positive patients had numerically, but not statistically, longer overall survival than did p16-negative patients (HR 0·70 [95% CI 0·47—1·04]).

Interpretation

Although the addition of panitumumab to chemotherapy did not improve overall survival in an unselected population of patients with recurrent or metastatic SCCHN, it improved progression-free survival and had an acceptable toxicity profile. p16 status could be a prognostic and predictive marker in patients treated with panitumumab and chemotherapy. Prospective assessment will be necessary to validate our biomarker findings.

Source: Lancet

Treatment With a Next-Generation ALK Inhibitor Results in High Response Rates Following Crizotinib Failure in Advanced, ALK-Positive NSCLC.


A majority of patients with advanced non-small cell lung cancer (NSCLC) whose tumors harbor mutations in the anaplastic lymphoma kinase (ALK) gene responded to treatment with a novel ALK inhibitor despite progressing on earlier ALK inhibitor therapy, according to new results from a phase I study (Shaw AT et al.). The trial highlights the potential role of second-line ALK-targeted therapy in the treatment of ALK-positive NSCLC.

Approximately 3% to 7% of patients with NSCLC have ALK rearrangements, which occur more commonly in nonsmokers, younger patients, and adenocarcinomas. ALK-mutated tumors become dependent on ALK signaling, and as a result, are highly susceptible to ALK inhibition. Crizotinib, a first-generation ALK inhibitor, can induce response rates of 60% in patients with advanced ALK-positive NSCLC, but most patients develop resistance to crizotinib within one to two years.

In general, ALK rearrangements do not overlap with other oncogenic drivers such as EGFR and KRAS mutations in patients with NSCLC (Gainor JF et al.). New options for ALK-targeted therapy, therefore, expand treatment options for patients who are not candidates for other targeted therapies, and for those who progress on current ALK inhibitor therapy.

Alice T. Shaw, MD, PhD, Assistant Professor at Harvard Medical School in Boston, presented findings from a multicenter, open-label, single-arm study of 122 patients with locally advanced or metastatic ALK-positive NSCLC. Of these, 63% had progressed on prior crizotinib therapy, and 31% were ALK-inhibitor naïve. All patients received LDK378, an oral next-generation ALK inhibitor that has shown 20-fold greater potency against ALK compared with crizotinib.

Response rates to LDK378 400-750 mg once daily were high in 114 evaluable patients, with 75% demonstrating some degree of tumor regression. The complete response rate was 58% for all patients, with no apparent differences between those with crizotinib resistance (57%) and those with no prior exposure to an ALK inhibitor (60%). Responses were durable, with a prolonged median duration of response (8.2 months) and median progression-free survival (8.6 months). Imaging studies also demonstrated the activity of LDK378 against central nervous system (CNS) metastases.

“CNS relapses are a major cause of morbidity and mortality in patients treated with crizotinib, so establishing the CNS activity of LDK378 is extremely important,” Dr. Shaw said.

Treatment with LDK378 was generally well tolerated. The most common adverse events included mild gastrointestinal symptoms in 58%-73% of patients. Grade ≥3 adverse events included elevated ALT (19%), elevated AST (10%), diarrhea (8%), and elevated lipase, hypokalemia, and nausea in 5% of patients. Three patients (2%) discontinued LDK378 due to adverse events. No treatment-related deaths were reported.

The current gold standard for detecting ALK rearrangements is fluorescence in situ hybridization (FISH). Many institutions, however, are exploring the use of immunohistochemistry screening with ALK-specific antibodies, reserving ALK FISH to confirm ALK positivity (Tsao MS et al.Lantuejoul S et al.).

Based on early findings from this trial, the FDA recently designated LDK378 as a breakthrough therapy, a designation intended to expedite the development and review of new therapies for serious or life-threatening conditions. LDK378 is currently under evaluation in phase II and III trials of patients with advanced NSCLC who have received prior chemotherapy and crizotinib and in patients who are crizotinib-naïve.

Another investigational ALK inhibitor, CH5424802, showed antitumor activity in in a phase I/II study of patients with ALK-positive NSCLC and no prior exposure to ALK-inhibitor therapy (Nakagawa K et al.). AP26113, a dual inhibitor of ALK and EGFR, is also under development for the treatment of ALK-positive NSCLC.

Source: The oncologist

 

 

ine-hei�j1.# 0 ground:white’>In females, there was a marked deterioration of glucose tolerance, which may be related to the 2-fold induction of estrogen sulfotransferase and reduced expression of estrogen receptor α (25%) and estrogen target genes (>34%).

 

Because of the very low doses of pollutants used in the mixture, these findings may have strong implications in terms of understanding the potential role of environmental contaminants in food in the development of metabolic diseases.”

Endocrine-Disrupting Chemicals Likely to Cause Harm Even at Low ‘Safe’ Doses

The chemical contaminants used in the study were chosen not only because they’re pervasive in the food supply, but also because they’re known endocrine disruptors. The glands of your endocrine system and the hormones they release influence almost every cell, organ, and function of your body. It is instrumental in regulating mood, growth and development, tissue function, metabolism, as well as sexual function and reproductive processes.

Endocrine disrupters are substances or mixtures that alter the functions of your endocrine system and consequently cause adverse health effects, either in your body or in your offspring. These types of chemicals can exert their effects by:

  • Mimicking the biological activity of your hormones by binding to a cellular receptor. This can initiate your cell’s normal response to the naturally-occurring hormone at the wrong time or to an excessive extent (agonistic effect).
  • Binding to the receptor but not activating it. Instead the presence of the chemical on the receptor prevents binding of the natural hormone (antagonistic effect).
  • Binding to transport proteins in your blood, thus altering the amounts of natural hormones that are present in your blood circulation.
  • Interfering with the metabolic processes in your body, affecting the synthesis or breakdown rates of your natural hormones.

The strongest evidence showing that exposure to these types of environmental chemicals can lead to disruption of endocrine function comes from the bizarre changes seen in a number of wildlife species, such as male fish transforming into females, frogs developing a variety of defects like multiple testes or ovaries, and hermaphrodite bears, just to name a few.

Yet, it’s commonly stated that these chemicals are not dangerous to humans because they exist at such low levels, even as research suggests otherwise. For instance, of 115 published animal studies, 81 percent found significant effects from even low-level exposure to BPA.

And the latest study only adds to this undeniable knowledge:

“With this study, we have succeeded in providing proof-of-concept that low doses of contaminants, even at levels normally considered to be without health impacts in humans, do in fact affect humans when subjected to chronic exposure, and when the contaminants are combined with a high-calorie diet,” the researchers said.2

What Are the Long-Term Health Risks from Exposure to Common Food Contaminants?

A typical American comes in regular contact with some 6,000 chemicals and an untold number of potentially toxic substances on a less frequent basis. There are about 75,000 chemicals regularly manufactured and imported by US industries, so you could be exposed to any number of them. Disturbingly, many of them have never been fully tested for safety, and virtually none have been studied in combination with one another, which is how real-world exposure occurs and where their toxicities can be amplified exponentially.

Upwards of 20 environmental chemicals, most of them endocrine-disrupting chemicals, have been shown to cause weight gain when exposure occurs during fetal and infant development, although some are also linked to adult exposures. Others, including BPA, PCBs, phthalates and agricultural pesticides can lead to health problems including:

Non-descended testes in young males Breast cancer in women Prostate cancer in men
Developmental effects on the nervous system in children Attention deficit hyperactivity in children Thyroid cancer

 

According to a World Health Organization (WHO) and United Nations Environment Program (UNEP) report:3

“The diverse systems affected by endocrine-disrupting chemicals likely include all hormonal systems and range from those controlling development and function of reproductive organs to the tissues and organs regulating metabolism and satiety. Effects on these systems can lead to obesity, infertility or reduced fertility, learning and memory difficulties, adult-onset diabetes or cardiovascular disease, as well as a variety of other diseases.”

Specifically, health problems linked to some of the most common food contaminants include:

  • BPA: Plasticizing chemicals like BPA, found in plastics and canned food linings, disrupt embryonic development and are linked to heart disease and cancer. Beware that many manufacturers of ‘BPA-free’ products have simply replaced BPA with bisphenol-S (BPS), an equally toxic chemical. More recently, research has found that other bisphenols used in the production of consumer products, namely, bisphenols M, AP and P, are actually more toxic to DNA than BPA.4
  • Phthalates: Phthalates dysregulate gene expression and cause genital anomalies, especially in baby boys, that may pass down several generations. Phthalates are found in vinyl flooring, detergents, automotive plastics, soap, shampoo, deodorants, fragrances, hair spray, nail polish, plastic bags, food packaging, garden hoses, inflatable toys, blood-storage bags, and intravenous medical tubing.
  • Dioxins: Dioxins are a byproduct of industrial processes, such as chlorine bleaching of paper products and the manufacturing of some pesticides. Because they are persistent environmental pollutants, they accumulate in the food chain and more than 90 percent of human exposure is through foods like meat, dairy products and fish. According to WHO, “Dioxins are highly toxic and can cause reproductive and developmental problems, damage the immune system, interfere with hormones and also cause cancer.”5
  • PCBs: Like dioxins, PCBs are persistent organic pollutants (POPs) that persist in the environment and resist breaking down, accumulating in the food chain and posing serious risks to human health and the environment. For instance, even though PCBs have been banned in the US for decades, they are still present in your environment. PCBs and other POPs have caused birth defects and other abnormalities among wildlife, along with damage to virtually every human bodily system.

Tips for Finding the Purest Foods Possible

When it comes to staying healthy, avoiding processed foods and replacing them with fresh, whole foods is the “secret” you’ve been looking for. The more steps your food goes through before it reaches your plate, the greater your chances of contamination becomes. If you are able to get your food locally, you eliminate numerous routes that could expose your food to contamination with not only disease-causing pathogens but also with the chemical contaminants noted above, which often exist in food packaging.

It’s also important to choose your fresh foods wisely, as you’ll want to focus on those grown in non-polluted areas using organic farming methods. Whatever food you’re looking to eat, whether organic or locally grown, from either your local supermarket or a farmer’s market, the following are signs of a high-quality, healthy food. Most often, the best place to find these foods is from asustainable agricultural group in your area. You can also review my free nutrition plan to get started on a healthy eating program today:

It’s grown without pesticides and chemical fertilizers (organic foods fit this description, but so do some non-organic foods) It’s not genetically engineered It contains no added growth hormones, antibiotics, or other drugs
It does not contain artificial anything, nor any preservatives It is fresh (if you have to choose between wilted organic produce or fresh conventional produce, the latter may still be the better option as freshness is important for optimal nutrient content) It was not grown in a concentrated animal feeding operation (CAFO)
It is grown with the laws of nature in mind (meaning animals are fed their native diets, not a mix of grains and animal byproducts, and have free-range access to the outdoors) It is grown in a sustainable way (using minimal amounts of water, protecting the soil from burnout, and turning animal wastes into natural fertilizers instead of environmental pollutants)  

 

Source: mercola.com

Panitumumab Fails to Improve Outcome in Esophagogastric Cancer.


Adding panitumumab to chemotherapy resulted in significantly shorter overall survival.

 

For patients with adenocarcinomas of the esophagus and stomach, conventional 5-fluorouracil (5-FU) plus platinum-based chemotherapy achieves an overall survival of only 9 to 11 months. The only targeted therapy approved for this disease is trastuzumab, which improves response and survival when combined with chemotherapy in human epidermal growth factor receptor 2 (HER2)-positive metastatic disease (JW Oncol Hematol Sep 14 2010).

Investigators from the U.K. now report the results of an industry-funded, open-label, multicenter, randomized, phase III trial of the epidermal growth factor receptor (EGFR)-targeted agent panitumumab plus chemotherapy for untreated metastatic esophagogastric cancer. Patients received either EOC: epirubicin (50 mg/m2), oxaliplatin (130 mg/m2), and capecitabine (1250 mg/m2/day for 21 days) cycled every 3 weeks; or modified EOC plus panitumumab: epirubicin (50 mg/m2), oxaliplatin (100 mg/m2), and capecitabine (1000 mg/m2/day for 21 days) plus panitumumab (9 mg/kg) cycled every 3 weeks.

Of 1000 planned patients, only 553 were treated due to early trial closure after an interim analysis showed inferior overall survival with modified EOC plus panitumumab. Most patients treated were male (82%–83%), were age 60 or older (60%–62%), and had performance status 1 (52%) and cancers of the esophagus (38%–40%) or gastroesophageal junction (27%–34%).

Although rates of response were equivalent in the two treatment arms (42%–46%), modified EOC plus panitumumab resulted in inferior overall survival (the primary endpoint; 8.8 vs. 11.3 months; HR 1.37; P=0.013) and a trend toward inferior progression-free survival (6.0 vs. 7.4 months; HR 1.22; P=0.068). Modified EOC plus panitumumab resulted in more grade 3 or 4 diarrhea, mucositis, and skin rash, but less grade 3 or 4 neuropathy and hematologic toxicity, likely due to a shorter duration of therapy.

Comment: This large, randomized trial in unselected patients with advanced esophagogastric cancer indicates that the addition of panitumumab to chemotherapy has a deleterious effect on patient outcomes. These findings are consistent with those simultaneously reported for cetuximab (JW Oncol Hematol May 28 2013).Given these strikingly negative results, interest in further study of potential EGFR-targeted therapies for esophagogastric cancer will likely diminish, and the possibility of discovering a biomarker to identify patients who might benefit from such treatments is unlikely.

 

Source: Journal Watch Oncology and Hematology