MedWire News - Oncology - Polymorphisms may identify sunitinib poor responders

By Laura Dean

24 October 2011

Lancet Oncol 2011; Advance online publication

MedWire News: Polymorphisms in the genes encoding vascular endothelial growth factor receptor 3 (VEGFR3) and cytochrome P450 3A5 (CYP3A5) may partially account for the absence of response and low tolerability to sunitinib observed in some patients with renal-cell carcinoma (RCC), researchers report.

"These data suggest that alternative treatment approaches for patients with these genetic variants should be promoted," write Cristina Rodríguez-Antona (Spanish National Cancer Center, Madrid) and colleagues in The Lancet Oncology.

The researchers explain that sunitinib is a tyrosine kinase inhibitor with proven efficacy in RCC, but around 20% of patients do not respond, while around 32% need dose reductions due to toxicity.

In the present study, Rodríguez-Antona and team aimed to identify polymorphisms as potential markers of sunitinib outcome, focusing on genetic variants that could alter the pharmacokinetics and pharmacodynamics of this drug.

They genotyped 101 RCC patients for 16 single nucleotide polymorphisms (SNPs) in nine genes: VEGFR2, VEGFR3, platelet-derived growth factor receptor α (PDGFR-α), VEGF-A, interleukin 8 (IL-8), CYP3A4, CYP3A5, ATP-binding cassette B1 (ABCB1), and ABCB2.

The researchers then assessed associations between each SNP and efficacy and toxicity of sunitinib using multivariable analyses adjusted for clinical factors associated with survival or toxicity.

After a median follow-up period of 21.2 months, the median progression-free survival (PFS) among 89 patients included the efficacy analysis was 12.3 months.

Objective response was assessed in 78 patients with measurable disease; one (1%) patient had a complete response, 36 (46%) had a partial response, 26 (33%) had stable disease, and 15 (19%) had progressive disease.

The analysis showed that two VEGFR3 missense SNPs, rs307826 and rs307821, were significantly associated with reduced PFS with sunitinib. Indeed, median PFS for people with the wild-type (AA) allele at rs307826 was 13.7 months, compared with 3.6 months for heterozygous (AG) individuals. The corresponding values for the rs307821 wild-type (GG) and heterozygous (GT) alleles were 13.7 months and 6.7 months, respectively.

Although not statistically significant, SNPs in ABCB1, ABCG2, and VEGFR2(rs1128503, rs2231142, and rs1870377) also showed a tendency to have worse response to sunitinib in terms of PFS or overall survival.

In terms of toxicity, the CYP3A5*1 (rs776746) high-metabolizing genotype (AG) was significantly associated with a 3.75-fold increased risk for dose reductions due to toxicity.

The researchers conclude that if their findings are independently validated in further studies, "these genetic variants could provide the basis for individualized renal cancer treatment."

In a related commentary, Brian Rini (Cleveland Clinic Taussig Cancer Institute, Ohio, USA) said: "An ideal predictive biomarker is one that is easily and unambiguously measured and reliably separates patients who will benefit from a specific approach from patients who will benefit from an alternative approach. [The present data] thus represent a small but important step toward truly targeted therapy for patients with renal-cell carcinoma."

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010

Using Gene Therapy to Make Thyroid Tumors More Susceptible to Radioiodine Therapy

Newswise — Falls Church, Virginia. Oct. 27, 2011 – Some forms of differentiated thyroid cancer (DTC) respond to treatment with radioactive iodine, which is taken up by the thyroid gland, destroying the cancerous cells. However patients with two forms of thyroid cancer, radioiodine-refractory DTC and anaplastic thyroid cancer (ATC), do not benefit from radioiodine therapy, and other treatment options are limited.

Christine Spitzweg, MD, and colleagues from Ludwig-Maximilians-University, Munich, Germany, are exploring a novel therapeutic approach intended to modify the genetic make-up of radioiodine-refractory forms of thyroid cancer to make them more susceptible to the anti-cancer effects of radioiodine therapy. Using a non-viral gene delivery system based on nanoparticle vectors, the researchers are able to introduce the gene for the sodium iodide symporter (NIS) into radioiodine-refractory tumor cells, enhancing their uptake of therapeutic radioiodine.

The vectors contain the NIS gene, a protective polymer, and a synthetic peptide that targets the particle to an epidermal growth factor receptor (EGFR) present at varying levels on the surface of thyroid tumor cells. The researchers mixed the thyroid tumor cells with the nanoparticles. In a parallel experiment, the researchers created a similar nanoparticle complex that lacked the EGFR-specific targeting peptide.

According to data presented today at the 81st Annual Meeting of the American Thyroid Association, tumor cell lines containing higher levels of EGFR incorporated more of the nanoparticle complexes. The tumor cell lines that exhibited the most efficient nanoparticle transduction had a 7-10 fold increase in iodide uptake when the nanoparticles contained the EGFR targeting peptide compared to experiments using the complexes lacking the EGFR targeting peptide.

Preliminary tests of this therapeutic approach in mice indicate that a tumor-selective gene delivery strategy can enhance radioiodine uptake by refractory DTC and ATC tumors.

About the ATA Annual Meeting
The 81st Annual Meeting of the American Thyroid Association will be held October 26-30, 2011 at the Renaissance Esmeralda Resort & Spa in Indian Wells (near Palm Springs), California. This four day creative and innovative scientific program, chaired by Drs. Anthony Hollenberg and Martha Zeiger, has carefully balanced clinical and basic science sessions on the latest advances in thyroidology. The ATA meeting is designed to offer continuing education for endocrinologists, internists, surgeons, basic scientists, nuclear medicine scientists, pathologists, endocrine fellows and nurses, physician assistants and other health care professionals. Visit www.thyroid.org for more information.

About the ATA
The American Thyroid Association (ATA) is the leading worldwide organization dedicated to the advancement, understanding, prevention, diagnosis and treatment of thyroid disorders and thyroid cancer. ATA is an international individual membership organization with over 1,400 members from 43 countries around the world. Celebrating its 88th anniversary, ATA delivers its mission through several key endeavors: the publication of highly regarded monthly journals, THYROID, Clinical Thyroidology and Clinical Thyroidology for Patients; annual scientific meetings; biennial clinical and research symposia; research grant programs for young investigators, support of online professional, public and patient educational programs; and the development of guidelines for clinical management of thyroid disease. Visitwww.thyroid.org for more information.

Researchers explore novel therapeutic approach for thyroid cancer

Some forms of differentiated thyroid cancer (DTC) respond to treatment with radioactive iodine, which is taken up by the thyroid gland, destroying the cancerous cells. However patients with two forms of thyroid cancer, radioiodine-refractory DTC and anaplastic thyroid cancer (ATC), do not benefit from radioiodine therapy, and other treatment options are limited.
Christine Spitzweg, MD, and colleagues from Ludwig-Maximilians-University, Munich, Germany, are exploring a novel therapeutic approach intended to modify the genetic make-up of radioiodine-refractory forms of thyroid cancer to make them more susceptible to the anti-cancer effects of radioiodine therapy. Using a non-viral genedelivery system based on nanoparticle vectors, the researchers are able to introduce the gene for the sodium iodide symporter (NIS) into radioiodine-refractory tumor cells, enhancing their uptake of therapeutic radioiodine.
The vectors contain the NIS gene, a protective polymer, and a synthetic peptide that targets the particle to an epidermal growth factor receptor (EGFR) present at varying levels on the surface of thyroid tumor cells. The researchers mixed the thyroid tumor cells with the nanoparticles. In a parallel experiment, the researchers created a similar nanoparticle complex that lacked the EGFR-specific targeting peptide.
According to data presented today at the 81st Annual Meeting of the American Thyroid Association, tumor cell lines containing higher levels of EGFR incorporated more of the nanoparticle complexes. The tumor cell lines that exhibited the most efficient nanoparticle transduction had a 7-10 fold increase in iodide uptake when the nanoparticles contained the EGFR targeting peptide compared to experiments using the complexes lacking the EGFR targeting peptide.
Preliminary tests of this therapeutic approach in mice indicate that a tumor-selective gene delivery strategy can enhance radioiodine uptake by refractory DTC and ATC tumors.
Source: American Thyroid Association

Advanced papillary thyroid cancer patients with BRAFV600E gene mutation at higher risk

Individuals with advanced papillary thyroid cancer (PTC) that are associated with the BRAFV600E gene mutation have a higher risk of recurrent disease and progression to more advanced, poorly differentiated thyroid cancer, according to data presented today at the 81st Annual Meeting of the American Thyroid Association (ATA). An understanding of the biological processes that underlie this progression could lead to the development of more effective therapies.
One approach to studying the role of BRAFV600E in PTC initiation and progression is to create mice in which the gene mutation (BRAFV600E) has been introduced and activated in the thyroid. These transgenic mice develop advanced PTCs that closely resemble human poorly differentiated PTCs. Mabel Ryder, MD, and colleagues from Memorial Sloan-Kettering Cancer Center and the Sloan-Kettering Institute (New York, NY) used BRAFV600E transgenic mice to study the effects of tumor-associatedmacrophages (TAMs), a type of white blood cell, on PTC initiation and progression. In cancers, TAMs are versatile and can either support or inhibit cancer progression. In PTCs, BRAF activation in the thyroid is accompanied by increased levels of colony stimulating factor 1, which stimulates the recruitment of TAMs to the thyroid. Once in the thyroid, TAMs accumulate alongside cancer-associated myofibroblasts (CAMs) to form a dense layer within and around the thyroid. The researchers used genetic techniques to kill the TAMs in PTCs. The result was a significant reduction in PTC size, total tumor cell volume and a more well-differentiated, less advanced PTC. The authors also demonstrated a functional link between TAMs, the recruitment of CAMs and PTC initiation. The researchers observed that when TAMs are depleted during PTC initiation, the density of CAMs is significantly diminished along with an impairment of PTC initiation.
"Many of the new treatments for thyroid cancer, such as kinase inhibitors, aim to block the activity of oncoproteins present within tumor cells. Our data suggests that immune cells in the tumor microenvironment play an important role in the biology of these cancers. This may be clinically relevant since there are new agents in development that can target TAMs, and we believe these should be explored, particularly in patients with advanced forms of the disease," said Dr. Ryder.
Based on these findings, the researchers concluded that TAMs have an important role in the initiation and progression of PTC and may represent a potent therapeutic target for combating advanced thyroid cancers that do not respond to conventional therapies.
Source American Thyroid Association (ATA)

New rapid method for detection of BRAF V600E gene in thyroid tissue

During surgical removal of thyroid tissue suspicious for cancer, fast, reliable, and cost-effective techniques are needed to analyze the resected tissue for biomarkers—including BRAF V600E, is a molecular biomarker for papillary thyroid cancer (PTC)—that can confirm the presence and type of cancer cells. Researchers have developed a new, rapid method for direct detection of the BRAF V600E gene in thyroid tissue without the need to purify DNA from tumor cells—high resolution melting analysis (HRM).
In HRM analysis, a sample of the resected thyroid tissue is homogenized and the DNA-containing portion is collected and washed. Polymerase chain reaction (PCR), a targeted gene detection technique, is then used to identify the presence of the BRAF V600E gene in the tissue sample. This is achieved without having to purify or sequence the DNA.
Jun Hee Park and G. Park from Chosun University Hospital, Republic of Korea, have demonstrated that HRM is at least as effective as alternative methods that rely on purified DNA for intra-operative detection of the BRAF V600E biomarker, according to data presented today at the 81st Annual Meeting of the American Thyroid Association (ATA). Using HRM to analyze cancerous tissue from 96 patients, Park and Park obtained a positive result for BRAF V600E in 58 of 96 samples (60.4%). The same 96 samples were subjected to two other testing methods that both required DNA purification—DNAsequencing and restriction fragment length polymorphism (RFLP) analysis. These analytical methods yielded a positive BRAF V600E result in 46.8% and 61.5% of samples, respectively. In comparison to these two techniques, direct HRM produced comparable results, was economical, and was suitable for intra-operative use with results available within 50 minutes.
Source: American Thyroid Association

Exelixis' thyroid cancer drug may get early approval - Yahoo! News

(Reuters) - Exelixis Inc's drug to treat a rare form of thyroid cancermet the main goal of a late-stage study, prompting the company to look to an accelerated approval process that could bring the drug to market within a year.

Shares of San Francisco-based Exelixis were up 18 percent at $7.09 in heavy trading on Monday on Nasdaq. They had touched a high of $7.53 earlier in the day.

Exelixis said based on the study it was requesting permission to begin a rolling submission of data toward the marketing application of the drug cabozantinib in advanced medullary thyroid cancer(MTC).

"With the positive data, we expect cabozantinib's filing to be completed in first quarter of 2012, with potential approval in the third quarter," Lazard Capital Markets analysts said in a note.

The drug significantly improved median progression-free survival (PFS) in patients suffering from MTC to 11.2 months versus 4 months for those on placebo in a trial called EXAM.

While that was lower than the numbers returned by AstraZeneca Plc's competing Caprelsa, Jefferies analysts said the drugs appeared comparable given that the EXAM trial appears to have enrolled more severe patients.

About 44,600 new thyroid cancer cases were diagnosed in the United States during 2010, and about 1,690 people died from the disease, according to the National Cancer Institute.

Cabozantinib, which is also being tested for metastatic ovarian cancer and castration-resistant prostate cancer (CRPC), is an oral drug designed to limit blood supply to tumors and block two segments of a pathway used by cancer cells to grow and spread.

In June, Exelixis reported data from a clinical trial showing cabozantinib led to significant tumor shrinkage in several different types of solid tumors, including 24 percent of patients with metastatic ovarian cancer, but also caused the deaths of six patients.

The EXAM trial is being conducted under a special protocol assessment (SPA) agreement, which guarantees that the design and analysis of the trial are adequate to support a marketing application submission to the U.S. Food and Drug Administration.

(Reporting by Esha Dey and Kavyanjali Kaushik in Bangalore; Editing by Roshni Menon and Supriya Kurane)

Many cancer survivors struggle with PTSD symptoms - Yahoo! News

NEW YORK (Reuters Health) - A cancer diagnosis can leave lasting psychological scars akin to those inflicted by war, according to a new survey.

More than decade after being told they had the disease, nearly four out of 10 cancer survivors said they were still plagued by symptoms of post-traumatic stress disorder, or PTSD.

Those symptoms include being extra jumpy, having disturbing thoughts about the cancer and its treatment, or feeling emotionally numb toward friends and family.

One in 10 patients also said they avoided thinking about their cancer and one in 20 said they steered clear of situations or activities that reminded them of the disease.

That could amount to a medical problem, in addition to the psychological toll, said lead researcher Sophia Smith from the Duke Cancer Institute in Durham, North Carolina.

"You worry if the patient is avoiding medical care, you worry they might not be getting follow-ups," she told Reuters Health. "We don't have data to support that, but we worry about it."

The survey is based on 566 patients with non-Hodgkin's lymphoma, a relatively common kind of cancer that strikes about 66,000 Americans every year.

Smith's team had surveyed these patients for PTSD symptoms once before, estimating that about one in 12 had full-blown PTSD. The diagnosis involved a trio of symptoms, including avoidance, arousal and flashbacks.

Many more had one or more PTSD symptoms, however. And the new survey, published in the Journal of Clinical Oncology, shows they often persist.

Overall, half of the patients had no PTSD symptoms 13 years after their diagnosis. The problems had disappeared in 12 percent, but had remained or worsened in 37 percent.

"This study found that people seemed to have worse PTSD later on," said Bonnie L. Green, a trauma expert who pioneered the study of PTSD in breast cancer survivors, but was not linked to the new work.

"It's just very stressful for people to be told that they have cancer," Green, of Georgetown University in Washington, D.C., told Reuters Health. "You can't just assume that they feel bad now, but it will go away."

She stressed that it's only a minority of patients who develop full-blown PTSD, but added that depression is common after a cancer diagnosis.

The new survey shows that low-income people are extra vulnerable to the psychological impact of living with cancer.

"I am particularly concerned about the patients who are poor or have less resources," said Smith.

She said doctors have to be better at recognizing distress in patients and improving patients' experience when they get the diagnosis.

"Each time they come in you are asking not only if they're having pain, but also if they are having stress," Smith said. "There are wonderful therapies out there."

Those treatments include trauma counseling and talk therapy, which have been proved effective in several studies. Smith recommended the website http://www.ptsd.va.gov/ for people interested in more information about PTSD.

SOURCE: http://bit.ly/n1pJMg Journal of Clinical Oncology, online October 11, 2011.

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How do people cope emotionally if the cancer recurs?

How do people cope emotionally if the cancer recurs?

Ongoing Cancer: Understanding Cancer that Doesn't Go Away

For some people, cancer is a one-time event. They go through treatment and recovery, and the disease does not return. For others, cancer may not ever fully disappear. Their cancer may respond to treatment and then come back, or treatment may simply keep it from growing and spreading. For people living with cancer, it's important to understand what it means when cancer doesn't go away – and how remission and recurrence may be part of your cancer journey.

Facing the same cancer more than once can be a frustrating and exhausting experience. Learn how you can better cope with the effects of recurring cancer here.

When cancer is not growing or changing but is still present in your body, over time, it is sometimes referred to as a "chronic" (meaning ongoing) disease. The cancer may be responding to treatment well enough that it is not growing, spreading, or causing new issues, but the signs and symptoms of the cancer remain. In cases like these, cancer can sometimes be managed with ongoing care, much like other chronic diseases such as heart disease or diabetes. In other cases, the cancer may mean that signs and symptoms of the cancer go away partially or completely thanks to treatment, but the cancer is still in the body. When the signs and symptoms of cancer aren't present for at least a month, doctors refer to this period as remission. Some remissions can last months or years, but since the cancer may not be totally gone, a remission is not considered a "cure." The cancer could come back, and you may need additional treatments to try to control it once more.

When a cancer comes back after treatment, it is known as cancer recurrence. The cancer sometimes returns at the same spot (known as local recurrence) or it may show up in parts of the body that were not previously affected. Some types of cancers, such as ovarian cancer, are more likely to return than others. People with recurring cancer may need multiple rounds of treatment or they may need to change the type of treatment they receive.

Remember that even when a cure is not possible, treatment may help keep cancer at bay. If you have cancer that does not go away, talk to your doctor about what options may be right for you.