Mammography Plus Breast Ultrasound Yields Mixed Results
First-year screening data from a study comparing ultrasound with or in addition to mammography in women who have increased breast cancer risk indicate that combining the two tests has benefits and drawbacks.
Adding a screening ultrasound to routine mammography revealed 28 percent more cancers than mammography alone. However, the addition of ultrasound to mammography also resulted in a fourfold increase in false-positive findings - that is, screening results leading to a biopsy that revealed no cancer.
The results, published in the May 14 Journal of the American Medical Association, come from a 3-year study of approximately 2,800 women led by the American College of Radiology Imaging Network (ACRIN). The study, ACRIN 6666, was co-funded by NCI and the Avon Foundation, and included participants from 21 different sites.
Of the 40 total cancers diagnosed within 12 months of initial screening, 8 were not detected by either modality alone or the combination of the two, but were discovered later during the 12-month period, for a rate of 3 cancers missed per 1,000 women screened. Overall, mammography alone showed 20 cancers (50 percent of all cancers detected) for a cancer detection rate of 7.6 per 1,000 women screened, while the combination of mammography and ultrasound revealed 31 cancers (78 percent of all cancers detected) for a cancer detection rate of 11.8 cancers per 1,000 women screened.
"Adding a single screening ultra- sound to mammography will yield an additional 1.1 to 7.2 cancers per 1,000 high risk women, but will also substantially increase the number of false positives," wrote the study's principal investigator, Dr. Wendie Berg, and colleagues.
The results raise a number of issues, said Dr. Christiane K. Kuhl, from the University of Bonn in Germany, in an accompanying editorial. They include whether the high false-positive rate associated with adding ultrasound to mammography is worth the benefit of the additional cancers found, and whether MRI may end up being a superior option given the strong results seen with it in a recent study. "Individualized screening schemes tailored to the individual risk and to the personal preferences of a woman may be the way to consider how to screen for breast cancer," Dr. Kuhl concluded.
Follow-up continues in ACRIN 6666 and will include another screening round with mammography and ultrasound at 24 months from study entry, as well as an MRI within 8 weeks of that screening. Reporting of the final results is anticipated in 2009.
Sugar and Signals: EGFR's Dual Role in Cancer
The epidermal growth factor receptor (EGFR), a surface protein found on many cancer cells and an established drug target, is best known for relaying signals into cells that spur their growth. But researchers have now discovered another role for EGFR. The protein helps a cell maintain an adequate supply of the essential nutrient, glucose, according to research in the May 6 Cancer Cell.
Dr. Isaiah Fidler of the University of Texas M.D. Anderson Cancer Center and his colleagues found that EGFR stabilizes another protein on the cell surface, called sodium/glucose cotransporter 1 (SGLT1). This protein channels a constant supply of glucose to cancer cells. A prolonged period without the sugar can cause a cell to destroy itself through a process of self-cannibalization known as autophagy.
The discovery of a second important cellular function of EGFR could help explain why drugs such as erlotinib (Tarceva) and gefitinib (Iressa), which target EGFR signaling, are effective against only a small minority of cancers that express high levels of this protein, the researchers say.
By maintaining proper glucose levels and preventing starvation, EGFR may help tumor cells survive chemotherapy and drugs that inhibit cell signaling. To eradicate these tumor cells, it may be necessary to inhibit both EGFR's glucose-related activities and growth-promoting signals, the researchers conclude.
In an experiment, the researchers blocked the EGFR protein itself, rather than its signals, in prostate cancer cells, and the cells died through autophagy. An accompanying editorial predicts that "this exciting new study" will broaden efforts to target EGFR both as a growth promoter and "as a sweetener."
Two Proteins Interact to Turn Moles Cancerous
Researchers at the Pennsylvania State University College of Medicine have found that two proteins, B-Raf and Akt3, cooperate to change the cell-signal pathways that transform benign moles into melanomas. Their report appears in the May 1 issue of Cancer Research.
Moles (or nevi) are tight clusters of pigment-producing skin cells called melanocytes. These cells are normally distributed evenly between the top two layers of skin, the epidermis and the dermis. The average person has between 10 and 40 moles on their body, usually benign. However, with genetic changes that are still being discovered, nevi can transform into melanoma, which represents fewer than 10 percent of all skin cancers but accounts for 75 percent of skin cancer deaths.
The study team examined a mutation that is found in about 90 percent of moles and approximately 60 percent of melanomas: a single nucleotide change in the B-Raf gene that causes expression of a mutated form of B-Raf protein. Previous research had shown that this mutation alone was insufficient to produce melanoma, so the team tested it in mice with modified levels of another protein, Akt3, that shows deregulated expression in the disease and is known to interact with B-Raf in cell signaling.
They found that the cell-signal pathways associated with Akt3 and normal B-Raf (PI3k and MAPK, respectively) do not inhibit one another in melanocytes, but in melanoma cells where B-Raf is mutated and Akt3 is active, cross-regulation is evident, resulting in decreased MAPK activity and significantly higher activity of PI3k - both signatures of melanoma. Together, the B-Raf mutation and normal Akt3 levels encouraged cells to grow without regard for attachments to surrounding tissues, marking the transformation of melanocytes into melanoma.
When the two proteins were inhibited in melanoma cells, tumor development slowed and apoptosis increased, prompting the researchers to suggest that "therapies for human patients should simultaneously target these signaling pathways for maximal clinical efficacy."
Nutlin-3a Induces Senescence through p53
Although the tumor-suppressor gene p53 is mutated or deleted in about half of all cancers, it remains functional in the other half and could potentially be harnessed to suppress cancer's growth. Recent studies showed that the small molecule nutlin-3a can induce apoptosis in cancer cells by inhibiting the protein MDM2 from binding to and breaking down the p53 protein, but the effects of nutlin-3a on normal cells were not completely understood.
Now, researchers from NCI's Center for Cancer Research (CCR) and their Japanese colleagues report in the May 1 Cancer Research that nutlin-3a induces cell senescence (the inability to grow or divide) in normal cells by the activation of p53 and its associated cell-signaling pathways.
When the researchers treated normal human skin and lung fibroblast (connective tissue) cells with nutlin-3a, almost 100 percent of the cells underwent senescence, but in p53-deficient cell lines, nutlin-3a could neither increase p53 activity nor cause senescence. The investigators confirmed that a set of microRNAs involved in cell senescence were upregulated after the treatment: mir-34a, mir-34b, and mir-34c. In addition, many genes involved in DNA replication, chromatin remodeling, and gene expression, including ING2, were downregulated.
"We need to note the difference in effects of [nutlin-3a] between normal and cancer cells," explained CCR co-author Dr. Izumi Horikawa. "We knew nutlin-3 induced apoptosis in cancer cells. In this research, in normal cells, the major response to nutlin-3a was senescence. Apoptosis is an irreversible death, but cells in senescence are still alive and can be functional." Further preclinical studies are needed to see if nutlin-3a's ability to induce apoptosis in cancer cells and senescence in normal cells is therapeutically relevant and applicable to cancer, he concluded.
Long-Term Smoking Cessation Cuts Cancer, Mortality Risk
New data from the Nurses' Health Study confirm the lethal effect of long-term smoking and indicate that starting smoking at an earlier age increases the risk of death from cancers caused by smoking. However, the study also confirms that the risk of death from diseases caused by smoking, including lung cancer, heart disease, stroke, and respiratory disease, drops dramatically after sustained periods of cessation.
Overall, the analysis, published in the May 7 Journal of the American Medical Association, found that nearly two-thirds of deaths among current smokers were caused by cigarette smoking, compared with only 28 percent among former smokers.
The new data come from more than 20 years of follow up on approximately 104,000 women participating in this long-running observational study. A similar report in 1993 was based on 12 years of follow up. The new report includes an expanded array of disease endpoints. Current smokers had a 63 percent increased risk of colorectal cancer compared with people who had never smoked, but no significant increased risk of ovarian cancer.
"Smoking cessation was beneficial for each cause-specific mortality outcome examined," wrote the study's lead author, Dr. Stacey A. Kenfield, and her colleagues from the Harvard School of Public Health. For example, within 5 years of quitting, the risk of death from lung cancer decreased by 21 percent, while the risk of death from coronary heart disease decreased by 50 percent when compared with people who continued smoking.
Breast Cancer Stem Cells May Resist Chemotherapy
Some breast tumors may contain a subset of cells that not only drive the disease but also resist conventional chemotherapy, new research suggests. These cells, often called cancer stem cells, are defined in part by their ability to self-renew. To eradicate them, it may be necessary to combine chemotherapy with drugs that target pathways involved in self-renewal, according to results in the May 7 JNCI.
One such drug is lapatinib (Tykerb). This drug targets the HER2 and epidermal growth factor receptor proteins, which may contribute to self-renewal. Dr. Jenny Chang of Baylor College of Medicine and her colleagues found that cancer stem cells in breast tumors were unaffected by chemotherapy but may be sensitive to lapatinib.
Previous studies have reported that some breast cancer stem cells express the surface protein CD44 (but little or no CD24 protein), so the researchers examined this population of cells in tumor biopsies before, during, and after treatment. The study included 31 women who received chemotherapy and 21 who received chemotherapy plus lapatinib.
In the chemotherapy group, the proportion of cancer stem cells to other cells in the tumor increased, suggesting that chemotherapy had eradicated the bulk of tumor cells without affecting cancer stem cells. By contrast, in the lapatinib group, the proportion of cancer stem cells to other cells in the tumor remained basically the same. This indicates that the different cell types may have been eradicated with roughly the same frequency.
"The results are encouraging and suggest that inhibition of key regulatory pathways responsible for self-renewal could augment the effects of conventional therapy and improve clinical outcome," the researchers concluded.