New breast cancer drug halts tumor growth better than standard therapy

A new cancer treatment that links chemotherapy with an agent that homes in on specific breast cancer cells was significantly better than the current drug regimen at keeping patients' advanced tumors from progressing, according to results from a Phase III clinical trial led by Kimberly Blackwell, M.D., of the Duke Cancer Institute. Participants with invasive breast cancer who took the investigational drug, called trastuzumab emtansine, or T-DM1, also had fewer and less harsh side effects than study participants who received a standard treatment.

The findings were reported June 3 at the American Society of Clinical Oncology annual meeting in Chicago, and will form the basis for Genentech, the drug's manufacturer, to seek marketing approval from the U.S. Food and Drug Administration. Genentech and its parent company, Roche funded the clinical trial.

"This drug is significantly better than the current approved combination in keeping the cancer under control," said Blackwell, director of the Breast Cancer Clinical Program at Duke and principal investigator of the international study. "This is a drug that brings us another step closer to treating cancer without the side effects of chemotherapy. It's going to be a good option for patients faced with HER-2 positive tumors."

Nearly 1,000 people with advanced breast cancer were enrolled during the three-year study. All the participants had a form of aggressive breast cancer distinguished by elevated levels of a protein known as human epidermal growth factor receptor 2, or HER-2. The protein promotes the growth of cancer cells, and plays a role in about 20 percent of invasive breast cancers.

For many people with HER-2 positive breast cancers, an antibody called trastuzumab has been an effective treatment, binding to the HER-2 protein on the surface of cancer cells and interfering with its ability to fuel tumor growth. Trastuzumab is prescribed alone or as an added treatment along with chemotherapy drugs.

T-DM1 represents one of the first in a new class of cancer-fighting agents called antibody drug conjugates. Linking the antibody trastuzumab directly with chemotherapy, the conjugate works like a sort of smart bomb, homing in on the HER-2 targets in the tumor cells and delivering the added payload of chemotherapy.

Blackwell and colleagues report that the median amount of time people on T-DM1 had no cancer growth was 9.6 months, compared to a median 6.4 months for people receiving the current standard drug regimen of capecitabine and lapatinib.

"These are significant and clinically meaningful improvements against comparative drugs that are highly effective for this group of patients," Blackwell said.

After two years, 65.4 percent of the T-DM1 patients were alive, compared to 47.5 percent of participants on standard treatment. The difference, while a notable trend, failed to meet a statistical benchmark set by its predetermined study design. A later analysis of overall survival is planned.

The new drug also caused fewer side effects. Blackwell said trastuzumab emtansine caused liver injury and a drop in blood platelets in some study participants, but most did not suffer the hair loss, rashes, nausea and diarrhea common to traditional chemotherapies.

"This is a more targeted way of delivering chemotherapy to HER-2 overexpressed cells," Blackwell said. "It delivers the drug directly to the cancer cells, while avoiding cells that don't really need to receive chemotherapy, which keeps patients from getting sick."

As a result, more people were able to stay on the drug without dose reductions, with 16.3 percent of participants on T-DM1 needing to adjust the dosage, compared to 53.4 percent of participants on capecitabine and 27.3 percent for lapatinib.

"As a clinician who takes care of breast cancer patients, it's important to have a treatment that is both effective and well tolerated," Blackwell said. "This drug has very little dose-limiting toxicity. That is in stark contrast to so many of the treatments we have available today. This drug works."

**Source: Duke University Medical Center

Researchers find potential link between drinking alcohol and breast cancer

A research team presented findings that they say may finally explain the link between alcohol consumption and breast cancer. "Cells have different mechanisms to remove toxic substances, such as ethanol, the chemical name for alcohol, that represent a potential risk to them," explains María de Lourdes Rodríguez-Fragoso, professor of pharmacology and toxicology at the Universidad Autonoma del Estado de Morelos in Mexico. "Unfortunately, sometimes these mechanisms produce other toxic substances, including some that are associated with the development of different types of cancer."

Rodríguez-Fragoso presented her group's work at the annual meeting of the American Society for Biochemistry and Molecular Biology, held in conjunction with the Experimental Biology 2012 conference in San Diego on April 23.

Alcohol consumption has long been established as a risk factor for breast cancer. But finding the direct link that makes it so has so far proved elusive. Now, Rodríguez-Fragoso and her collaborators think that they have found the answer, a protein called CYP2E1.

"We knew that CYP2E1 could break down ethanol and that doing so created unstable, highly reactive chemicals known as free radicals," she says. Working with researcher Scott Burchiel and his group at the University of New Mexico, Rodríguez-Fragoso's team had previously found that free radicals were associated with activation of cellular mechanisms that lead to tumor development. "The question then was, does having more CYP2E1 make you more susceptible to ethanol-induced toxicity, thereby increasing your risk of developing cancer?"

CYP2E1 is found in breast cells known as mammary epithelial cells, which are also where most breast cancers originate, suggesting to the researchers that CYP2E1 may be involved in breast cancer development. To test this hypothesis, the researchers administered ethanol to separate cultures of mammary epithelial cells that had varying levels of CYP2E1. Cells that expressed low levels of CYP2E1 were mostly immune to the effects of the ethanol treatment; however, cells with increased amounts of CYP2E1 protein were greatly affected, suggesting that women with higher expression levels of the protein would show similar responses.

Significantly, points out Rodríguez-Fragoso, "our results showed that ethanol-treated human mammary cells had an increase in free radical production, oxidative stress and the activation of cellular mechanisms that cause cells to increase their proliferation rate," all hallmarks of cancer. "So if you are a woman who naturally expresses higher levels of CYP2E1 and you consume alcohol, you would be at a greater risk for developing breast cancer than a woman who expresses lower amounts of CYP2E1," she explains.

A few months ago, the group started investigating CYP2E1 expression levels in breast tissue obtained from healthy women who had undergone mammaplasties. "Preliminary results show that there is great variability in the expression of this enzyme among the analyzed samples," says Rodríguez-Fragoso. "This means that each individual will have a different response to alcohol, and each should take different precautions to minimize their risk of developing breast cancer."

With these results in hand, Rodríguez-Fragoso expressed confidence that her group will be able to develop a method of diagnosis that would focus on the determination of expression levels of CYP2E1 in breast tissue. "If you know the risk probability of certain behaviors on your likelihood of developing cancer, then you can better understand what preventative measures you should be taking," she emphasizes.

The Center for Disease Control and Prevention estimates that breast cancer will be responsible for nearly 40,000 deaths this year alone, with an additional 220,000 diagnoses. "If we can prevent the development of breast cancer associated with alcohol intake by timely diagnoses of markers such as CYP2E1," says Rodríguez-Fragoso, "then the annual numbers of new cases and deaths could be diminished significantly."

**Source: Federation of American Societies for Experimental Biology (FASEB)

Cellular 'glue' resists breast cancer

Early detection and advances in the treatment for breast cancer have improved the chances of survival, however new avenues for treatment are still needed in the battle against this disease. New research published in BioMed Central's open access journal Breast Cancer Researchdemonstrates that the protein Perp, associated with desmosomes (the glue that sticks cells together), is involved in suppressing breast cancer and provides a potential new target for future treatment. Desmosomes attach neighbouring cells together and it is these tiny collections of proteins which are responsible for the mechanical strength of organs and tissues within the body. Desmosomes are also thought to be involved in helping to suppress cancer. Researchers from Stanford University, UC Berkeley, and UC Davis have discovered that the protein Perp is found associated with desmosomes in breast epithelial cells.

Dr Laura Attardi, who led the research, described how loss of Perp affected normal breast tissue function in mice. She said, "Perp deficiency caused defects in desmosomal protein expression in breast epithelial cells. At the same time there was an enhanced inflammatory response in the breast tissue, and tumours tended to develop more quickly. We also found in the lab that breast cancer cells had abnormally low levels of Perp."

These results show that Perp is part of the cellular glue that fastens cells together and has a dual role in the prevention of breast cancer. Inflammatory cells promote cancer and lack of cell adhesion is part of the progression of cancer to metastasis. Perp may well be a new indicator for monitoring breast cancer or a future target for molecular treatment.

**Source: BioMed Central Limited

Eating Cruciferous Vegetables May Improve Breast Cancer Survival

A study by Vanderbilt-Ingram Cancer Center and Shanghai Center for Disease Control and Prevention investigators reveals that breast cancer survivors who eat more cruciferous vegetables may have improved survival. The study of women in China was presented by postdoctoral fellow Sarah J. Nechuta, Ph.D., M.P.H., at the American Association for Cancer Research Annual Meeting in Chicago, Ill.

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"Breast cancer survivors can follow the general nutritional guidelines of eating vegetables daily and may consider increasing intake of cruciferous vegetables, such as greens, cabbage, cauliflower and broccoli, as part of a healthy diet," said Nechuta.
Nechuta, Xiao Ou Shu, M.D., Ph.D., and colleagues investigated the role of cruciferous vegetables in breast cancer survival among women in the Shanghai Breast Cancer Survival Study, a prospective study of 4,886 Chinese breast cancer survivors who were diagnosed with stage 1 to stage 4 breast cancer from 2002 to 2006. Shu, Ingram Professor of Cancer Research, is the principal investigator of the Shanghai Breast Cancer Survival Study.
After adjusting for demographics, clinical characteristics and lifestyle factors, the researchers found cruciferous vegetable intake during the first 36 months after breast cancer diagnosis was associated with a reduced risk for total mortality, breast cancer-specific mortality and disease recurrence.
Survival rates were influenced by vegetable consumption in a dose-response pattern. As women ate more of these vegetables, their risk of death or cancer recurrence decreased.
Women who were in the highest quartiles of intake of vegetables per day had a 62 percent reduced risk of total mortality, 62 percent reduced risk of breast cancer mortality, and 35 percent reduced risk of breast cancer recurrence, compared to women with the lowest quartile of intake."
Nechuta noted that cruciferous vegetable consumption habits differ between China and the United States and suggested this fact be considered when generalizing these results to U.S. breast cancer survivors.
"Commonly consumed cruciferous vegetables in China include turnips, Chinese cabbage/bok choy and greens, while broccoli and Brussels sprouts are the more commonly consumed cruciferous vegetables in the United States and other Western countries," she said. "The amount of intake among Chinese women is also much higher than that of U.S. women."
Cruciferous vegetables contain phytochemicals known as isothiocyanates and indoles which appear to have a protective effect against some types of cancer.
Nechuta said the level of these bioactive compounds, proposed to play a role in the anticancer effects of cruciferous vegetables, depends on both the amount and type of cruciferous vegetables consumed.
She said there is a need for future studies that measure the bioactive compounds in these vegetables and the host factors that may influence the effects of these compounds to improve the understanding of the association between cruciferous vegetable consumption and breast cancer outcomes.

**published in "SCIENCE DAILY"