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Experimental Strategy May Overcome Resistance to Breast Cancer Drug

Posted Mar 24 2011 9:15pm

U.S. Cancer Survivors Increase to Nearly 12 Million

The number of U.S. cancer survivors increased from 9.8 million in 2001 to 11.7 million in 2007, according to an analysis of new cancer cases and follow-up data from NCI’s Surveillance, Epidemiology, and End Results (SEER) program. The findings appeared in the March 11 Morbidity and Mortality Weekly Report.

According to the report, breast , prostate , and colorectal cancers were the most common types of cancer among survivors, accounting for 51 percent of diagnoses. Among all cancer survivors, 54.3 percent were female, 45.7 percent were male, nearly 7 million were 65 years of age or older, and 4.7 million received their diagnosis 10 or more years earlier.

The number of survivors has risen markedly since 1971, when an estimated 3 million people were living with cancer. The increase seen over the past 4 decades is attributable to a variety of factors, including an aging U.S. population, earlier detection, and more sophisticated treatments that allow individuals to live longer following initial diagnosis.

Because of the considerable growth in the number of cancer survivors, health care and public health professionals should become familiar with their unique medical and psychosocial issues, stressed Dr. Arica White of the CDC’s Division of Cancer Prevention and Control in a news release announcing the findings.

“For many cancer survivors and those around them, the effect of cancer does not end with the last treatment,” said Dr. Julia H. Rowland, director of NCI’s Office of Cancer Survivorship . “Research has allowed us to better understand some of the long-term health risks and quality of life concerns among this population.”

The analysis by NCI and CDC scientists underscores the need for continued research and coordinated efforts to develop and implement best practices for ensuring optimal post-treatment care and support for all cancer survivors, she explained.

Thyroid   Cancer Risk Persists in People Exposed to I-131 Radiation as Children

People who were exposed to radioactive iodine (I-131) as children or adolescents after the 1986 Chernobyl nuclear disaster have a long-term increased risk of developing radiation-related thyroid cancer . In a study of more than 12,000 people in three Ukrainian states near the Chernobyl site, researchers found that the risk of radiation-related thyroid cancer doubled for every gray (Gy) of exposure to the thyroid. (A gray is an international measurement used for radiation dose.) This risk did not decrease over 9 years of follow-up during the study.

The findings were published March 14 in Environmental Health Perspectives.

Researchers led by Dr. Alina Brenner of NCI’s Division of Cancer Epidemiology and Genetics , in collaboration with Ukrainian scientists, prospectively studied 12,514 people who were younger than 18 years of age at the time of the accident and were exposed to a wide range of I-131 doses. All participants had direct measurements of thyroid radioactivity taken within 2 months of the accident. Additional data on I-131 exposure included information on diet (the greatest source of exposure was from consumption of contaminated milk) and lifestyle around the time of the accident.

Between the start of the study in 1998 and 2007, all participants underwent screening examinations every 2 years, regardless of their dose. Individuals diagnosed with thyroid cancer during the first examination were excluded from this analysis.

Sixty-five cases of thyroid cancer were discovered during follow-up. Radiation-related risk of thyroid cancer increased with increasing I-131 dose and was greatest for those individuals who were younger at the time of exposure. Risk appeared similar for men and women.

“Our results suggest that thyroid cancers attributable to I-131 exposure continue to occur two decades after exposure,” concluded the authors. In addition, they wrote, the risk per Gy of exposure does not appear to diminish with time, at least not in the amount of time that this cohort has been followed. Since radiation-related cancer risks are known to persist for many decades, the participants will need to be followed for a longer period of time to determine if an eventual decline in risk occurs.

Incidence   Rate of Second Cancer in the Opposite Breast Has Declined in U.S.

Among women who survive breast cancer , the most frequent new cancer occurs in the opposite, or contralateral, breast. Since 1985, a new study reports, the incidence rate of contralateral breast cancer has declined steadily—at a pace of more than 3 percent per year. Although the causes of this trend are not known, the decline occurred as drugs such as tamoxifen were coming into widespread use to help prevent a recurrence of the disease, researchers reported online in the Journal of Clinical Oncology on March 14.

To assess the incidence rate of contralateral breast cancer over time, Dr. Amy Berrington de González of NCI’s Division of Cancer Epidemiology and Genetics  (DCEG) and her colleagues analyzed statistics from the SEER  database for the years 1975 to 2006.

The downward trend they observed was driven by declining rates of contralateral breast cancer among women whose first breast cancer tested positive for the estrogen receptor (ER). No clear decrease was seen among women with ER-negative tumors. Although the details of hormone treatments were not available in SEER, the annual declines of more than 3 percent after ER-positive first cancers “suggest an important role for the widespread usage of adjuvant therapies, especially hormone treatments,” the study authors noted.

“We know from randomized trials that drugs like tamoxifen significantly reduce the risk of a contralateral breast cancer, by about 40 percent,” said Dr. Berrington de González. The combination of the trial results, the timing of the decline, and the restriction to cancers following ER-positive first breast cancers all point to adjuvant hormonal therapy as a key factor in the decline, she added. 

Tamoxifen was widely adopted in the United States after the results of the Nolvadex Adjuvant Trial were published in 1983. In addition to adjuvant hormone therapies, other factors such as the increased use of chemotherapy may also have contributed to the decline, the study noted. “Newer hormonal therapies like aromatase inhibitors may be even more effective than tamoxifen at reducing contralateral breast cancer rates, and so we would hope to see further reductions in the future,” said Dr. Berrington de González.

Although the decline represents “a notable success,” the study authors cautioned that overall rates of contralateral breast cancer remain high, especially among women whose first breast cancer is ER-negative. “We still need new strategies for reducing risks after an ER-negative cancer, because rates can be as high as 1 percent per year for these women,” said Dr. Berrington de González.

Eribulin   Improves Survival of Women with Metastatic Breast Cancer

Treatment with eribulin (Halaven) improved overall survival in women with metastatic breast cancer whose disease progressed despite multiple rounds of prior chemotherapy, according to the results of a phase III clinical trial called EMBRACE. Based on these findings, the FDA approved eribulin last November for women with metastatic disease who have already undergone at least two previous chemotherapy regimens.

The study results were published online March 2 in The Lancet.

The improvement in overall survival makes the findings “clinically meaningful,” wrote the study’s lead author, Dr. Javier Cortes of the Vall d'Hebron Institute of Oncology in Barcelona, Spain, and his colleagues. “To our knowledge, EMBRACE is the first major single-agent study of a cytotoxic or biological agent to show significantly increased survival in patients with such heavily pretreated metastatic breast cancer.”

Eribulin is a laboratory-made form of halichondrin B, a substance derived from a sea sponge. Similar to some other chemotherapy drugs, it targets the protein tubulin in cells, although it binds to tubulin in a different way, interfering with cancer cell division and growth.

In the trial—funded by Eisai Co., Ltd., which manufactures eribulin—762 patients were randomly assigned to receive either eribulin or the treating physicians’ choice of therapy. Prior to enrolling, trial participants had received, on average, four previous chemotherapy regimens. Because there is no standard of care for women with progressive metastatic breast cancer, the treatments eribulin was compared with “[reflect] real-life choices made by oncologists and their patients,” the researchers wrote.

Women who received eribulin, on average, lived 2.5 months longer than those treated with their physician’s choice (13.1 months versus 10.6 months). Progression-free survival was similar between the groups. Overall, serious side effects were roughly equal in women in both trial arms, although women treated with eribulin had more serious cases of neutropenia , leukopenia , and peripheral neuropathy .

“EMBRACE provides much needed, high-level evidence for chemotherapy use in patients with heavily pretreated breast cancer,” wrote Drs. Nancy Lin and Harold Burstein, of Dana-Farber Cancer Institute, in an accompanying editorial . But a number of important questions remain about the use of eribulin in this group of patients, they noted, including whether there is a subgroup that is more likely to respond to the drug.

“The clinical gains from EMBRACE are sufficiently narrow,” the study authors continued, “that a better understanding of the relation between treatment, symptom control, and quality of life in study participants remains crucial.”

Experimental   Strategy May Overcome Resistance to Breast Cancer Drug

Researchers have identified a protein that may play a critical role in preventing some tumors from responding to the breast cancer drug trastuzumab (Herceptin). The researchers also showed, in preclinical experiments, that it may be possible to overcome this resistance by combining trastuzumab with a drug to inhibit the protein, c-SRC. The findings appeared online in Nature Medicine on March 13.

Multiple mechanisms of resistance associated with trastuzumab have been identified, but there are no effective methods for overcoming this resistance. To address this problem, Dr. Dihua Yu, an NCI-supported investigator from the University of Texas M. D. Anderson Cancer Center, and her colleagues studied signaling pathways that are activated in resistant cancer cells. They found that cellular signals from multiple resistance pathways converged at c-SRC, which is known to play a role in some cancers.

When activated, c-SRC may be a critical component of multiple resistance pathways. Rather than targeting several different signaling pathways individually in resistant cells, it may be possible to inhibit a central component common to all these pathways to overcome resistance, the researchers suggested.

To test this idea, resistant cells were exposed to a combination of trastuzumab plus a c-SRC inhibitor called saracatinib . In the cells and animal models, this combination of drugs made resistant cells more sensitive to trastuzumab, and tumors shrank. Using data from women treated with trastuzumab, the researchers were also able to confirm the association between c-SRC activation and trastuzumab resistance in patients.

“By targeting c-SRC, we reversed its activation in several model systems,” said Dr. Yu. “We consider this to be a powerful strategy for overcoming resistance.” The next steps would be to evaluate clinically applicable c-SRC inhibitors, including dasatinib , and develop a clinical trial to test the approach in patients, she noted.

Also in the Journals: New Clue to Triple-Negative Breast Cancer

A protein that normally helps suppress cell proliferation and tumor formation is mutated or missing in some cases of triple-negative breast cancer , and these alterations may play a role in the development of this disease. The discovery, reported in the March 4 Cell, provides new insights into this aggressive form of breast cancer, which is both poorly understood and difficult to treat.

In normal cells, the protein PTPN12 appears to block growth-promoting signals from proteins called tyrosine kinases. But, in triple-negative breast cancer, PTPN12 activity may be lost. Without this protein acting as a tumor suppressor, cells may produce a range of abnormal growth signals, the researchers found.

The results suggest that it may be possible to treat some triple-negative breast cancers with combinations of available drugs called tyrosine kinase inhibitors .

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