Spotlight

Abstract

Gronwald et al., pp. 2281–2284 Mutations in BRCA1 or BRCA2 greatly increase a woman's chance of developing breast cancer. About a third of women diagnosed with cancer in one breast will develop cancer in the other breast within 10 years of first diagnosis. Treatment with tamoxifen reduces this risk, as can removal of the ovaries. In their current report, Gronwald and colleagues asked whether tamoxifen helps prevent contralateral breast cancer in patients who have previously had their ovaries removed. Though tamoxifen exerted a strong protective effect in women who had gone through natural menopause, the drug did not protect those who had had their ovaries surgically removed. In previous work, the authors compared women with bilateral breast cancer with controls whose cancer had struck only one side. They noted that tamoxifen treatment markedly reduced the risk of contralateral cancer, but they could draw that conclusion only for patients with BRCA1 mutations. Having approximately doubled their number of subjects in the 5 years since that study appeared, the authors can investigate the question with a higher level of precision. Now, they show that tamoxifen administered after initial diagnosis prevents cancer in the opposite breast for both BRCA1 and BRCA2 carriers. Also, no effect of tamoxifen was observed among women whose ovaries had been removed, although that subgroup of women was small. On the basis of their analysis, the authors recommend tamoxifen to prevent contralateral breast cancer in BRCA carriers with intact ovaries. Kreimer et al., pp. 2293–2297 The main risk factors for oral cancer, tobacco use and alcohol consumption, account for over 90% of oral and oropharyngeal squamous cell carcinomas. Poor diet has also been related to increased oral cancer, but because people who use tobacco and alcohol heavily also typically consume a diet low in fruits and vegetables, it has been difficult to rule out the confounding effects of these risk factors. In their current article, Kreimer and colleagues report finding a strong association between a poor diet, low in fruits and vegetables, and oral cancers. The authors combined data from a number of case-control studies conducted in 9 countries to isolate the role of several food groups and body mass index (BMI) on risk of oral cancer. Their analysis confirms previous reports showing an association between low BMI and oral cancer, even among subjects who had never used tobacco or alcohol. Because the questionnaire included information about height and weight covering the 2-year period prior to diagnosis, weight loss due to the disease was less likely to be the cause of the low BMI. Rather, the indicator would seem to point to long-term nutritional deficiencies among oral cancer patients. The study also confirmed that fruit and vegetable consumption protects against oral cancer, although it could not pinpoint which anticarcinogenic agents in the foods reduced the cancer risk. Consumption of fish, red meat, and cured meats also appeared to reduce risk. From this large international study, poor diet emerges as one important risk factor for oral cancer, besides tobacco and alcohol use. Ito et al., pp. 2337–2343 A diagnosis of pancreatic cancer carries little hope of recovery; resistant to most chemotherapy and radiation regimens, this disease claims the lives of 9 out 10 patients within 5 years of diagnosis. One agent, gemcitabine, seems to work against advanced pancreatic cancer, but even with the drug, the response rate remains less than 20%. Although mechanisms have been proposed, there has been no compelling evidence to explain this high level of treatment failure. In the current study, Ito and colleagues investigate the role of mTOR, a molecule that plays a central role in cell survival and proliferation, in pancreatic cancer and show that an mTOR inhibitor stifles the cancer's growth in vitro. Previous investigations have reported activation of Akt in pancreatic cancer; mTOR, which lies downstream of the PI3K/Akt signaling pathway, therefore stands out as a potential target. Recent studies also have revealed that CCI-779, a synthetic rapamycinester that inhibits mTOR, has shown antitumor activity against certain cancers, making it a good candidate for treatment of pancreatic cancer as well. The authors showed that the Akt/mTOR signaling pathway was activated in all 6 pancreatic cancer cell lines examined, suggesting that the pathway might be important for the cancer's development. When tested on the cell lines, combined therapy with CCI-779 and gemcitabine showed no synergistic effect. In mice that had been injected with pancreatic cancer cells, however, combined therapy delayed tumor growth and increased survival compared with single agent therapy. These in vivo results raise the hope that combining CCI-779 with gemcitabine could improve clinical outcomes as well.