Also in the News Researchers funded by the National Institute of Allergy and Infectious Diseases report that pre-existing immunoglobulin E antibodies are the cause of severe adverse reactions experienced by some patients given cetuximab - an immune-based therapy commonly used to treat cancers of the head and neck and colorectal cancers. The findings are reported in the March 13 New England Journal of Medicine.

Nonprotruding Colorectal Growths May Harbor Cancer

Most colorectal cancers are thought to arise from polypoid adenomas - growths that protrude from the mucous membrane in the colon or rectum. A study from the Veterans Affairs (VA) Health Care System in Palo Alto, CA, published in the March 5 Journal of the American Medical Association adds to a growing body of evidence that nonpolypoid colorectal neoplasms (NP-CRNs) - abnormalities that can appear either flat or depressed relative to the surrounding membrane - can also contain precancerous or cancerous cells. Previous studies established the existence of NP-CRNs in Japan, but their prevalence and importance in other parts of the world has remained unclear.

In the VA study, gastroenterologists and pathologists who were trained in a special exchange program with Japanese cancer centers examined 1,819 patients at the Palo Alto VA hospital undergoing colonoscopy for screening, surveillance (for people at high risk of colorectal cancer), or symptoms of colorectal neoplasms. Patients underwent biopsy, removal of polyps or NP-CRNs, or surgery as needed.

The investigators found NP-CRNs in 170 patients (9.35 percent of those examined). Although these lesions were less common than colorectal polyps, they were more likely to contain precancerous or cancerous cells, accounting for only about 15 percent of identified neoplasms but 54 percent of superficial carcinomas. "Nonpolypoid morphology was strongly associated with findings of in situ or submucosal invasive carcinoma," stated the authors.

NP-CRNs missed during colonoscopy may help explain the occurrence of interval colorectal cancers - cancers that arise between scheduled screening colonoscopies in patients who appear not to have any precancerous polyps - explains Dr. David Lieberman from Oregon Health and Science University in an accompanying editorial.

The existence of NP-CRNs will have important implications for colorectal cancer screening in the United States, continued Dr. Lieberman. "The finding that NP-CRNs have high rates of serious pathology suggests that effective screening programs will need to accurately identify patients who harbor these lesions."

Delayed Letrozole Therapy After Tamoxifen Reduces Breast Cancer Recurrence

An analysis of data from a phase III clinical trial that was unblinded 5 years ago indicates that in some breast cancer patients, use of the aromatase inhibitor letrozole (Femara) after 5 years of adjuvant therapy with tamoxifen has survival benefits even if begun several years after completing tamoxifen.

Conducted by the National Cancer Institute of Canada Clinical Trials Group, the trial, known as MA.17, was unblinded in 2003 after an interim analysis demonstrated that letrozole, begun within 3 months after 5 years of tamoxifen, reduced breast cancer recurrence risk compared to placebo. Participants in the placebo arm of MA.17 were then offered the opportunity to begin 5 years of adjuvant treatment with letrozole. MA.17 participants were post-menopausal women with early-stage, ER-positive disease.

This new analysis from MA.17, released online on March 10 by the Journal of Clinical Oncology (JCO), compared the 1,579 women in the placebo arm who began using letrozole after the trial was unblinded with the 804 women who chose not to. The analysis revealed that letrozole improved disease-free survival by 63 percent and distant (or metastatic) disease-free survival by 61 percent. The median time of letrozole initiation after tamoxifen completion was 2.8 years, with a range from 1 to 7 years.

Questions about the optimal approach to adjuvant therapy in this patient population linger, the study's lead author, Dr. Paul Goss from Harvard Medical School, and colleagues noted, because even after 5 years of adjuvant tamoxifen, there continues to be a significant risk of late recurrence and death from breast cancer.

Although interpretation of the findings is "made difficult because this therapeutic intervention was self-selected, not randomly allocated," they continued, the women who took letrozole had disease characteristics that put them at higher recurrence risk than those who did not, suggesting letrozole was responsible for the beneficial effects.

Letrozole use was also associated with an increased risk of bone fractures and osteoporosis (5.2 and 5.3 percent, respectively) compared with those on placebo (3.1 and 1.6 percent). In a related editorial in JCO, Drs. Nancy U. Lin and Eric P. Winer from Dana-Farber Cancer Institute noted that there is a chance that the findings could be understating those comorbid effects. There is a subset of patients treated with aromatase inhibitors "who experience life-altering arthralgias or other adverse effects, leading to difficult discussions weighing [quality of life] against recurrence risk," they wrote.

Everolimus Extends Progression-Free Survival in Advanced Kidney Cancer

A 400-patient, international phase III trial testing the drug everolimus in patients with advanced kidney cancer has been stopped after meeting its primary endpoint, the drug's manufacturer, Novartis, reported February 28.

The trial's Independent Data Monitoring Committee recommended that the trial be halted and patients in the placebo arm of the study be offered everolimus after an interim analysis showed a significant improvement in progression-free survival in patients given everolimus.

Everolimus, also known as RAD001, inhibits mTOR, a protein that regulates tumor cell division and angiogenesis.

Patients in this cancer trial had advanced, progressive disease despite treatment with other recently approved agents for advanced kidney cancer, including sorafenib (Nexavar) and sunitinib (Sutent). Trial participants may also have been treated with bevacizumab (Avastin) and interferon.

Complete interim results from the trial, dubbed RECORD-1, will be presented in May at the American Society of Clinical Oncology annual meeting in Chicago, Novartis explained.

Protein May Control Spread of Breast Cancer

A single protein may trigger the spread of breast cancer cells to other parts of the body by altering the behavior of large numbers of genes. The protein, SATB1, could potentially be used to identify women at risk of metastasis and may be a therapeutic target, Dr. Terumi Kohwi-Shigematsu of the Lawrence Berkeley National Laboratory and her colleagues report in the March 13 Nature.

They describe the protein as a "genome organizer." It coordinates the activity of genes from different chromosome regions by changing how DNA is packaged in the cell nucleus. For cells to acquire new functions, such as invading other tissues, they may need to induce global changes in gene activity.

In breast cancer cells, SATB1 activity may be necessary for and sufficient to induce metastasis. Blocking the protein in an aggressive breast cancer cell line altered the activity of more than a thousand genes and caused the cells to stop tumor growth and metastasis. Conversely, expressing the protein in a non-aggressive cell line fueled growth and metastasis.

The researchers say that SATB1 activity in breast cancer cells could identify women with early-stage disease who are at risk of metastasis. The primary prognostic indicator of metastasis has been the involvement of the lymph nodes, but additional markers are needed.

"Once this protein is expressed in breast cancer cells there is a very high propensity for metastasis," said Dr. Kohwi-Shigematsu. "And it may be possible to predict poor prognosis based on SATB1 expression independently from lymph node status."

SATB1 activity has also been found in colon and lung tumors, and the researchers are investigating how the protein is activated.

In a step toward therapies, the researchers are investigating ways to deliver SATB1 inhibitors directly into breast cancer cells. This is necessary to avoid disrupting the protein's critical role in the development of certain immune cells.

Methylation Markers Suggest Recurrence Risk in Lung Cancer

The switching on and off of a specific set of genes, or methylation, in patients with stage I non-small-cell lung cancer (NSCLC) appears to increase the risk of recurrence following surgery, researchers are reporting. In fact, when two of these genes were methylated (or switched off) in tissue samples from the tumor and mediastinal lymph nodes, the recurrence risk increased as much as 25-fold.

In a small, single institution, nested case-control study published in the March 13 New England Journal of Medicine, Dr. Malcolm Brock, an associate professor of surgery at Johns Hopkins' Sidney Kimmel Comprehensive Cancer Center, and colleagues analyzed the methylation status of seven genes in tumor and lymph node samples from patients who had undergone surgery for stage I NSCLC. Previous research has suggested that these genes may be associated with NSCLC recurrence.

As many as 40 percent of patients with stage I NSCLC treated with surgery will die of recurrent disease, and approximately 80 percent of patients will experience recurrence within 40 months.

Samples from 51 patients whose disease had recurred within 40 months (cases) were compared with samples from 116 patients whose cancers had not recurred (controls). The findings were tested against a small validation cohort of 11 cases and 9 controls.

The methylation status of four of the seven genes - p16, CDH13, RASSF1A, and APC - in tumor and/or lymph node samples were associated with varying levels of increased recurrence risk. The most lethal gene methylation combination was p16 and CDH13. In the original cohort, the 5-year recurrence-free survival rate was 14.3 percent in patients with methylation-induced silencing of both genes in the tumor and mediastinal lymph nodes (in the center of the chest, between the lungs), compared to 63.1 percent in patients without methylation of either gene.

"The DNA evidence we see for many of the recurring cases suggests it may be wise, if our work is confirmed, to reclassify such cancers as advanced disease instead of early stage," Dr. Brock said.

Elderly Medicaid Patients Less Likely to Receive Chemotherapy for Colorectal Cancer

A study using data from the Michigan Tumor Registry and the Centers for Medicare and Medicaid Services showed that elderly Medicaid-insured patients in the state are less likely to initiate or complete chemotherapy for colorectal cancer compared with Medicare-insured patients. The results were published in the March 10 Archives of Internal Medicine. Previous studies have shown that Medicaid-insured patients have worse survival rates for colorectal cancer, but it had not been known if they receive less treatment than patients with other forms of insurance.

The investigators collected data from 4,765 patients aged 65 or older who were diagnosed with colorectal cancer between January 1997 and December 2000 and insured through Medicaid, Medicare, or both. In addition to data on chemotherapy initiation and completion, the investigators compared whether patients were evaluated by an oncologist, subsequently hospitalized, and experienced comorbidities; demographic variables including age, race, sex, household income, and whether patients lived in a metropolitan, urban, or rural area were also studied.

Patients insured through Medicaid were more likely to be African American or of another minority race, female, and to live in a low-income area. For all patients, those with Medicaid insurance were less likely to initiate or complete chemotherapy and less likely to be evaluated by a medical oncologist. Older patients in general were also less likely to initiate chemotherapy, even though studies have shown that these patients benefit from adjuvant treatment.

"The main finding of this study is that Medicaid insurance is associated with a low likelihood of chemotherapy initiation and completion," concluded the authors. "As long as these substantially large groups of patients…have disparate treatment uptake and compliance, the nation as a whole will have difficulty reaching its goals for reduced cancer mortality."