While smoking and lung cancer have always been closely linked, recent advances in research have begun to unravel the genetic code behind the disease. Pfizer is revolutionizing treatment for lung cancer patients by targeting the genetic mutations that cause a rare form of this disease called non—small cell lung cancer (NSCLC).

	Xalkori (crizotinib), an oral medication used to treat ALK-positive patients with late-stage NSCLC, was approved by the FDA on Friday. In a teleconference on Tuesday, a team of Pfizer’s researchers and lung cancer specialists explained that even though the drug treats a limited number of lung cancer patients, the drug will only go to the patients who stand to benefit from the drug, thereby maximizing its efficiency by eliminating mass use of the drug in populations where it is not effective.

	Estimates vary on exactly how many NSCLC patients exhibit the ALK mutation. Data presented at the American Society of Clinical Oncologists meeting earlier this year placed the estimate somewhere around 8%, while Pfizer’s estimates put that number closer to 3% to 5%. At the teleconference, Mark G. Kris, MD, chief of the Thoracic Oncology Service at Memorial Sloan-Kettering Cancer Center in New York City, said that between 6000 and 11,000 patients in the United States with the ALK mutation are diagnosed annually.

	To identify which patients are best served by Xalkori, patients are required to undergo a genetic test. The Vysis ALK Break Apart FISH Probe Kit, developed by Abbott Laboratories, is the first test of its kind to identify patients with an abnormal ALK gene. The test will cost about $250 to administer to each patient, roughly in line with similar genetic testing kits, according to Garry Nicholson, President and General Manager of the Pfizer Oncology Business Unit.

	Despite being able to only help a minority of lung cancer patients, the specialists at the conference suggested widespread testing. “I would caution against any kind of patient profiling,” Kris said. “I think, in general, you need to test everyone [with lung cancer].”

Representatives from Pfizer estimated that each month of therapy will cost a patient $9600. Patients take Xalkori orally twice daily. A maximum dosage has not been determined, but some patients who started taking Xalkori during clinical trials have been taking the drug for more than a year.

	The drug’s approval was based on a number of encouraging studies. Earlier this year, the drug showed marked antitumor activity in a study presented at the 14th World Conference on Lung Cancer in Amsterdam. In early phase II results from the single-arm, open-label PROFILE 1005 trial, 51% of 133 patients who had undergone prior chemotherapy who were treated with crizotinib exhibited an overall response, including 1 patient who experienced a complete response. At 12 weeks into the trial, the disease control rate was 74%, indicating that a proportion of participants achieved stable disease, or partial or complete responses.

	Further studies confirmed crizotinib’s effectiveness in treating patients with NSCLC. Two multicenter trials enrolling 255 patients with late-stage ALK-positive NSCLC demonstrated 50% and 61% median objective response rates and mediation duration of response of 42 and 48 weeks, respectively.

	However, no one from Pfizer could provide any estimates on how Xalkori affects a patient’s overall survival. Mace Rothenberg, MD, Senior Vice President of Clinical Development, and Medical Affairs in the Oncology Business Unit at Pfizer, said studies to assess how the drug affects overall survival and progression-free survival are currently underway, but no data are available yet, as the trials are currently ongoing.

Articles

While smoking and lung cancer have always been closely linked, recent advances in research have begun to unravel the genetic code behind the disease.

Xalkori: A Revolution in Lung Cancer Treatment

On Friday, the FDA approved crizotinib (Xalkori) to treat ALK-positive patients with late-stage non—small cell lung cancer (NSCLC).

A diagnostic test used in tandem with the drug was also approved by the FDA. The Vysis ALK Break Apart FISH Probe Kit is the first test of its kind to identify patients with an abnormal 

Crizotinib is an oral compound that blocks signaling in cell pathways by inhibiting kinases, including the protein produced by the abnormal 

 gene. The drug is taken twice a day as a single-agent therapy.

Earlier this year, the drug showed marked antitumor activity in a study presented at the 14th World Conference on Lung Cancer in Amsterdam. In early phase II results from the single-arm, open-label PROFILE 1005 trial, 51% of 133 patients who had undergone prior chemotherapy who were treated with crizotinib exhibited an overall response, including 1 patient who experienced a complete response. At 12 weeks into the trial, the disease control rate was 74%, meaning that a proportion of participants achieved stable disease, or partial or complete responses.

Further studies confirmed crizotinib’s effectiveness in treating patients with NSCLC. A total of 255 patients with late-stage 

&shy;&shy;&shy;positive NSCLC were studied in 2 multicenter, single-arm trials.

In one study, the objective response rate was 50%, with a median response duration of 42 weeks. In another, the objective response rate was 61%, with a median response duration of 48 weeks.

The FDA approved crizotinib under its accelerated approval program because of its ability to treat a serious disease based on clinical data showing that the drug is likely to create a clinical benefit in patients.

The diagnostic test that accompanies crizotinib is a major part of the approval. It is the second targeted therapy to have such a test approved by the FDA this year.

“The approval of Xalkori with a specific test allows the selection of patients who are more likely to respond to the drug,” said Richard Pazdur, MD, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, in a statement released on Friday. “Targeted therapies such as Xalkori are important options for treating patients with this disease and may ultimately result in fewer side effects.”

On Friday, August 26, 2011, the FDA approved crizotinib (Xalkori) to treat ALK-positive patients with late-stage nonâ€“small cell lung cancer (NSCLC).

FDA Approves Crizotinib for Late-Stage Non-Small Cell Lung Cancer

	On Friday, the FDA announced that brentuximab vedotin (Adcetris) has been approved for the treatment of Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL). In July, the drug had been unanimously recommended for accelerated approval by the FDA’s Oncologic Drug Advisory Committee.

Brentuximab vedotin is an antidrug conjugate containing an anti-CD30 monoclonal antibody. The drug selectively targets CD30, an important genetic marker in classic lymphoma and anaplastic large cell lymphoma, while sparing nearby normal cells that do not express the marker. It has been approved to treat HL in patients who have relapsed after receiving autologous stem cell transplant therapy and in patients with sALCL who have relapsed after undergoing at least 1 prior chemotherapy treatment.

It is the first new FDA-approved treatment for HL since 1977 and the first approved specifically for the treatment of ALCL.

	“Early clinical data suggest that patients who received Adcetris for Hodgkin lymphoma and systemic anaplastic lymphoma experienced a significant response to the therapy,” said Richard Pazdur, MD, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, in a statement released on Friday.

A number of prominent studies have confirmed the effectiveness of brentuximab vedotin. Results of a study that involved patients who had previously undergone autologous stem cell transplantation were presented at the American Society of Hematology meeting in 2010. Of the 102 patients enrolled in the study, 75% exhibited some kind of demonstrated response, defined as showing tumor shrinkage of 50% or more. Complete remission was achieved by 34% of patients in the study. Overall, 94% of patients experienced some form of tumor regression.

Another study was presented at the European Hematology Association meeting in June 2011. The phase II study found that 14 of the 15 patients (93%) achieved complete remission of their cutaneous lesions, a side effect of lymphoma, after a median of 14.9 weeks of treatment with brentuximab vedotin. An independent central review further revealed that all 15 patients achieved the objective response to their systemic disease, and 13 of the 15 patients achieved complete remission. The remaining 2 patients achieved partial remission.

Some side effects experienced by the patients in the studies included peripheral sensory neuropathy, fatigue, nausea, upper respiratory tract infection, and diarrhea. The most common adverse events of at least grade 3 were neutropenia, peripheral sensory neuropathy, thrombocytopenia, and anemia. In the study presented at ASH, 20% of patients discontinued brentuximab vedotin because of treatment-related adverse affects. The study authors reported that none of the deaths of patients enrolled in the study were attributable to brentuximab vedotin.

According to the American Cancer Society, of the approximately 8800 cases of Hodgkin lymphoma projected to be diagnosed in 2011, 30% of those patients are expected to be relapsed or refractory Hodgkin lymphoma. 

The FDA announced that brentuximab vedotin has been approved for the treatment of Hodgkin lymphoma and systemic anaplastic large cell lymphoma.

FDA Approves Brentuximab Vedotin for 2 Types of Lymphoma

	On July, 29, 2011, a US appeals court sided with Myriad Genetics, Inc’s patents on the BRCA1 and BRCA2 genes. The court ruled 2-to-1 in favor of Myriad, citing that genes in isolation are not naturally occurring and are therefore allowed to be patented. Many researchers believe that any part of the human genome is naturally occurring and should not be patented.

	The ruling overturned a decision made by a US district court in New York City in March 2010. In that case, Judge Robert W. Street and the court concluded that isolated DNA is a discovery, not an invention, because an isolated portion of DNA differs little from non-isolated DNA since it leaves the nucleotide sequence intact.

	In this current decision, Judge Alan D. Lourie wrote that the appeals court reversed the district court’s decision “that Myriad’s composition claims to ‘isolated’ DNA molecules cover patent-ineligible products of nature…since the molecules as claimed do not exist in nature.”

	With this decision, Myriad’s existing patents, along with thousands of other gene patents, are protected for the moment. Lourie wrote that “…the mere fact that the larger chromosomal polymer includes the same sequence of nucleotides as the smaller isolated DNA is not enough to make it per se a law of nature and remove it from the scope of patentable subject matter…Instead, the claimed isolated DNA molecules, which are truncations (with different ends) of the naturally occurring DNA found as part of the chromosome in nature, are not naturally produced without the intervention of man.”

	The controversial case has divided the scientific research community. Biotechnology companies have been patenting gene sequences for years as a routine part of developing drugs, with more than 4000 genes already patented. The process also creates financial incentives, since companies are able to lay claim to those genes when developing new diagnostic techniques, genetic tests, and novel treatment options. However, many in the research community are of the mind that opportunities for using gene sequences for research are being restricted by the very same process.

	In 2009, the Association for Molecular Pathology (AMP), the American Civil Liberties Union (ACLU), and the Public Patent Foundation filed the lawsuit against the US Patent and Trademark Office and Myriad. They argued that the patents limit patient access to affordable, high-quality testing for BRCA1 and BRCA2mutations, which have been linked to breast cancer, ovarian cancer, and prostate cancer. Myriad not only manufactures the only test available in the United States to detect the patented BRCA mutations, but the company also restricts researchers’ access to the genes. However, those who sequence an entire human genome are not bound by these restrictions.

	The court did make an additional exception for renowned scientist Harry Ostrer, MD, director of the Human Genetics Program at New York University. Because Ostrer, one of the plaintiffs in the case, has demonstrated a capability and desire to begin BCRA testing in his lab, he may challenge Myriad’s patent protection in order to continue his work with the genes. Two other researchers had expressed a desire to begin BCRA testing in their laboratories, but the court ruled that they did not have the same capabilities to perform the research as Ostrer had shown.

	Many legal analysts predict that the case will eventually head to the US Supreme Court to be decided. The plaintiffs intend keep pursuing the case. The Obama Administration filed a friend-of-the-court brief in 2010 siding with the ACLU, one of the plaintiffs in the case. The administration agreed with the ACLU on the basis that isolating something that already exists in nature is not something that should be able to be patented and gain the rights offered by patent protection.

	“Gene patents and exclusive licenses that confine molecular testing to a single provider are detrimental to the public interest by limiting patient access to testing,” said Timothy J. Leary, MD, PhD, president of the AMP, one of other the plaintiffs in this ongoing litigation. “Monopolies on gene testing make it impossible for patients to access alternate tests or get a second opinion about their results. AMP will continue to advocate until a resolution is found either in the courts or in legislation.”

On July, 29, 2011, a US appeals court sided with Myriad Genetics, Inc's patents on the BRCA1 and BRCA2 genes.

Judge Rules BRCA Genes Can Be Patented, Overturning Previous Decision

UV radiation DNA damage. (Illustration by David Herring)

 has been linked to the removal of DNA damage from UVB radiation, a major risk factor in the development of skin cancer. The discovery may help researchers to determine the genetic targets of UVB rays, something that has been historically poorly understood.

By using low suberythermal UVB radiation on 15 genetically altered mice with lower levels of PTEN in their epidermis, researchers were able to show that the mice were predisposed to developing skin cancer. They were compared to mice with normal PTEN levels. The researchers said this supported their conclusion that a 50% reduction in a person’s PTEN level increases their susceptibility to skin tumorigenesis following exposure to UVB radiation.

The study also looked at 69 samples of human skin cells exposed to UVB radiation and subsequently examined the rates of DNA repair. Test samples with lower PTEN levels had slower rates of DNA repair. Research linked the slow rates of DNA repair to a lacking of xeroderma pigmentosum C (XPC), a key DNA repair protein. In this case, XPC was not signaled by PTEN through the AKT/p38 pathway. DNA repair levels increased when XPC was introduced into PTEN-suppressed cells.

The study is scheduled to be published in the August 1, 2011, edition of the journal 

“This was an unexpected finding and definitely provides a new approach for chemoprevention strategies,” said Yu-Ying He, PhD, an associate professor of medicine at the University of Chicago, in a press release. “It’s possible that if we can increase PTEN activity through nutritional supplements or some sort of pharmaceutical intervention, we may be able to prevent this common cancer.”

The authors of the study wrote that PTEN’s role in checkpoint pathways may depend on the type of DNA damage, the efficiency of the repairs on damaged DNA, the waveband-specific signaling pathways between UVB and UVC, or the cell-type-specific response to PTEN inhibition, and that more research must be done to understanding the connection between PTEN and skin cancer at a molecular level.

	Ming M, Feng L, Shea CR, et al. PTEN positively regulates UVB-induced radiation damage repair. 

. 2011;71:5287-5295. doi:10.1158/0008-5472.

The tumor suppressor gene PTEN has been linked to the removal of DNA damage from UVB radiation, a major risk factor in the development of skin cancer. 

Researchers Identify Gene Involved in DNA Repair From UVB Damage

Three new genetic mutations have been identified in patients with Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC). The mutations suggest a previously unknown heritable cause for these esophageal diseases.

A case-control mutation analysis was performed on 255 participants, of which 116 were patients who had been diagnosed with BE, EAC, or both. The analysis was performed as part of a larger BE/EAC study conducted at 16 sites across the United States from 2005 through 2010. Single-SNP, haplotype, and integrative genomic validation identified potentially mutated genes in 116 patients with BE/EAC. Further screening revealed germline mutations of the genes 

 were the most common of the 3 variations, appearing in 8 of the 116 patients (7%; 95% confidence interval, 0.030-0.130, 

< .001). Furthermore, these 3 genetic mutations were not found in the 139 patients in the control group who were not affected by BE or EAC. Proper identification of the 

mutations was replicated in an independent validation series.

The study results will be published in the July 27, 2011 edition of the 

Journal of the American Medical Association

Considered a precursor of EAC, BE occurs in 1% to 10% of the general population, oftentimes in people who already have gastroesophageal reflux disease (GERD), a condition that could affect as much as 35% of Americans. The incidence of EAC in Europe and the United States has increased 350% in the last 30 years, resulting in 14,500 deaths and 16,640 new cases diagnosed in the United States in 2010.

Charis Eng, MD, PhD, chair and founding director of the Genomic Medicine Institute of Lerner Research Institute at Cleveland Clinic, said the study provides valuable insight into the genetic origins of BE/EAC. As genetic markers are identified for these 3 genes, improved risk assessment, early detection, and disease management techniques could be developed, all of which may lead to higher survival rates among patients. 

is associated with inflammation and apoptosis and has also been linked to prostate cancer, while 

have been linked to oncologic and inflammatory pathways.

“We are absolutely thrilled to now know three distinct genes that link to BE/EAC,” Eng said in a press release. “This is essential for improving risk assessment, disease management, and saving lives.”

	Orloff M, Peterson C, He X, et al. Germline mutations in 

 in patients with Barrett esophagus and esophageal adenocarcinoma. 

. 2011;306(4):410-419. doi:10.1001/jama.2011.1029.

Three new genetic mutations have been identified in patients with Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC).

Ben Leach