In diffuse large B-cell lymphoma (DLBCL), researchers have identified three patterns of gene activity in and around tumors that may determine survival following therapy. These patterns, or gene signatures, were associated with survival in three independent populations of patients treated with standard therapies for the disease.
The results suggest that DLBCL, like other cancers, is not a single disease but rather consists of multiple, biologically distinct subtypes. In addition, the study highlights the importance of the tumor microenvironment - the nonmalignant host cells adjacent to tumors - in some forms of the disease.
Dr. Louis M. Staudt of NCI's Center for Cancer Research (CCR) and his colleagues in the Lymphoma/Leukemia Molecular Profiling Project published their findings in the November 27 New England Journal of Medicine.
"Interestingly, we found that it's not just the characteristics of the malignant cells that influence patient survival, but also features of the tumor microenvironment in the lymph node," said Dr. Georg Lenz of CCR, the study's first author.
The team analyzed 414 pretreatment biopsy specimens from two groups of patients and linked the results to clinical outcomes. This revealed a previously unknown gene signature and confirmed two signatures identified in an earlier study. One of these signatures, called germinal-center B-cell, is based on gene activity in malignant lymphoma cells; it distinguishes two forms of the disease, known as germinal-center B-cell-like and activated B-cell-like DLBCL.
All three signatures were validated in a third patient population; each was also found to predict survival after treatment with combination chemotherapy called CHOP or CHOP plus rituximab (Rituxan).
The researchers suggest that their results have implications for clinical trials. Some patients have a better prognosis regardless of the therapy, and this could make a drug seem better than it actually is. "When you are enrolling patients on clinical trials, you need to know which kind of DLBCL is being treated so that the results can be assessed accurately and compared across trials," said Dr. Staudt.
For instance, patients with a tumor-microenvironment signature called stromal 1 tended to respond to treatment. But those with a microenvironment signature called stromal 2 had an inferior prognosis.
The stromal 2 signature includes genes linked to angiogenesis, the growth of tumor blood vessels. Based on this finding, the researchers propose that these patients may benefit from antiangiogenic drugs, such as bevacizumab (Avastin), while other patients may see little benefit from these agents.
"One wonders whether an antiangiogenic agent should be added to the treatment of patients with a lymphoma containing the stromal 2 signature," writes Dr. Charis Eng of the Genomic Medicine Institute at the Cleveland Clinic in an accompanying editorial.
Dr. Eng praised the study, noting that the results are consistent with recent studies showing a connection between the tumor microenvironment and clinical outcomes in other cancers.
"These findings give us a completely new way of thinking about this lymphoma," said Dr. Staudt. Researchers may now shift some attention away from malignant cells and toward developing a better understanding of tumor microenvironment, he added.
After Menopause, Weight Affects Breast Cancer Rates More than Mammography Use
Women who are overweight or obese after menopause face an increased risk of breast cancer, but a large prospective cohort study indicates that the frequency of mammography use and screening accuracy are not the primary explanations for higher rates of breast cancer in these women. The same is true of large, invasive breast cancer tumors and advanced stage disease; risk increases with weight, but higher rates are not explained by the frequency or accuracy of screening mammography before breast cancer was diagnosed. The study appears in the December 3 Journal of the National Cancer Institute.
Dr. Karla Kerlikowske of the San Francisco Veterans Affairs Medical Center and colleagues gathered data on 287,115 postmenopausal women who were registered in the Breast Cancer Surveillance Consortium database. Reflecting a trend in the U.S. population, 58 percent of the women in the study were overweight or obese. The women were not using postmenopausal hormone therapy when they received their mammograms between 1996 and 2005; 4,446 of them were diagnosed with breast cancer within a year of getting a mammogram.
Compared to women with a normal body mass index (BMI 18.5-24.9), risk for the first year after a mammogram was about 12 percent higher in overweight women (BMI between 25-29.9), 20 percent higher with a BMI between 30-34.9, and 30 percent higher when their BMI was higher still. Similar but independent patterns were found for high-grade, advanced-stage, estrogen receptor-positive, and large invasive disease. Factoring in the frequency of the women's previous mammogram use did not change these results.
Though under-using mammography did not entirely account for the higher rate, the authors cite its value as "the only secondary prevention measure that has been proven to decrease breast cancer mortality" by detecting disease at an earlier, more treatable stage. And though the link found here between higher BMI and advanced stage disease was moderate, it was also conclusive. "Our results suggest that postmenopausal women who are overweight or obese…should be encouraged to lose weight and to undergo routine screening mammography, two factors that may decrease the number of women who are diagnosed with advanced disease," the authors wrote.
Breast Cancer Family History Boosts Risk, Even without BRCA Mutations
Women who test positive for gene mutations associated with breast cancer often take steps to prevent the disease. But little is known about what steps, if any, women should take if they have a family history of breast cancer but lack BRCA1 or BRCA2 gene mutations. Now, a new study suggests that the risk among these women may be high enough that they should discuss prevention options with their physicians, such as screening with breast MRI and chemoprevention with tamoxifen or raloxifene, according to the study's author.
Women with a significant family history of breast cancer have an approximately fourfold increased risk of developing breast cancer compared with the general population, even if they do not carry the high-risk mutations, the study found. A significant family history is defined as two or more close relatives with the disease under age 50, or three close relatives with the disease at any age.
Dr. Steven Narod of the University of Toronto presented the findings last month at the Frontiers in Cancer Prevention Research conference near Washington, D.C. He urged physicians to discuss prevention with the thousands of women who test negative but have a significant family history of breast cancer. "We've been doing this testing since 1995, and there is a huge population of women out there whose risk is very high. And yet they have not been targeted for prevention," he said at a press briefing.
"We don't need to wait for the future," Dr. Narod added. "We should be able to implement this now."
His team followed 1,492 women who tested negative for BRCA1 and BRCA2 mutations from 365 families for at least 5 years. Based on the number of breast cancers in the group versus the number expected in the general population, the researchers calculated that a significant family history was associated with a 30 to 40 percent lifetime risk. By comparison, carriers of BRCA mutations have a lifetime risk of the disease as high as 85 percent.