Therapy Shows Promise in Trials for Hereditary Cancer Patients

Genetics

By Karen Iris Tucker

Published August 11, 2010, issue of August 20, 2010.

An emerging therapy that attacks cancer cells continues to show promise, most recently in two international studies on women who have breast and ovarian cancer and are carriers of cancer-causing mutations particularly prevalent among Ashkenazi Jews.

Two trials tested the experimental capsule olaparib on women whose breast or ovarian cancer had spread to other organs, and who had previously tried at least two other types of chemotherapy. These patients, typically, have built up a stubborn resistance to further treatment. Still, an encouraging percentage responded favorably for a time to the drug.

Both studies featured groups receiving low and high doses of olaparib. Tumors shrank in 11 of 27 women with breast cancer who received the higher dose. The ovarian cancer study experienced similar results, with tumors shrinking in 11 of 33 women receiving the higher dose.

The women in the studies had the added variable of having inherited the BRCA1 or BRCA2 genetic mutations, linked to 5% to 10% of all breast and ovarian cancers. Ashkenazi Jews are at higher risk of carrying these mutations.

Ultimately, the drug ceased its effectiveness for most women, requiring them to seek other treatment options. Yet these were encouraging preliminary results. Olaparib had mild side effects compared to standard chemotherapy, with a much lower incidence of nausea, fatigue and hair loss. It was also taken as a pill — a big deal for cancer patients who endure visits to the infusion suite to get IVs.

“So far I am rather nauseated and sleepy during the day, but it seems to be much easier than the ‘regular’ chemo,” said Ella Lewin, an ovarian cancer patient who just started the therapy, on the higher dosage, at a clinical trial at the University of Pennsylvania. Lewin’s cancer has recurred three times since she was diagnosed six years ago.

Olaparib, made by AstraZeneca, is one of several drugs early in development called “PARP inhibitors.” The poly ADP-ribose polymerase, or PARP, enzyme fixes DNA damage in both healthy and cancer cells. Medicine like Olaparib interfere with, or inhibit, the PARP enzyme, making it even harder for cancer cells with an abnormal BRCA1 or BRCA2 gene to fix DNA damage. These drugs differ from standard chemotherapy in that they don’t appear to harm healthy cells.

“This is one of the ways that modern biology is going to have a greater and greater impact on the cancer problem,” said Dr. Daniel Silver, an assistant professor of medicine at the Dana-Farber Cancer Institute.

Silver, an oncologist who treats breast cancer, said he was excited about the results of the trials, published in The Lancet last month. “Every new tool I have in my toolbox is something else I can use to hold off the progression of the disease longer,” he said.

He referenced the breast cancer study, in which, he said, the average patient responded for a little less than 200 days. “For somebody who, without this, may have been dying very quickly, that’s very significant,” he said. “That’s 200 more days that they have with their family.”

Dr. Mark E. Robson, a co-author of the studies and clinic director of Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center, said the studies benefit from all the genetics research that has been done over the years.

“Without those studies, we wouldn’t have thought to try these drugs in this specific subset of patients,” he said.

This research follows a 2009 study of breast cancer patients involving another PARP inhibitor, iniparib. Half its participants received a combination of iniparib and standard chemotherapy; the other half received the standard treatment alone. The women who got iniparib lived for about 12 months, compared to about eight months for women who did not receive the drug. Iniparib, the first PARP inhibitor to complete phase-three clinical trial, may ultimately be the first to obtain FDA approval.

Dr. Judy Garber, associate professor of medicine at Harvard Medical School and a co-author on the olaparib studies, called the effect of joining a PARP inhibitor with traditional chemotherapy a “double-whammy.”

Of the iniparib data, Garber said, “If you give [PARP inhibitors] with chemotherapy and they work better, maybe this will make chemotherapy more effective for a much broader group of people with cancer that do not have mutations or inheritable forms of cancer. Or, maybe, you give it in the beginning [of treatment] and it’s even more effective than chemo.”

BRCA1 and BRCA2 carriers with a family history of breast or ovarian cancer are asked to consider preventive prophylactic surgery — mastectomy and removal of the ovaries and fallopian tubes. Silver theorized that if the PARP inhibitors are ultimately effective in treating these BRCA tumors, they may even be effective in preventing them.

While cautioning that there is still much research to be done, Silver said, “It may be possible in the future that someone who is a carrier for BRCA1 or 2 might take these drugs for some short period of time — once a year, once a month, on some limited schedule — and that might be enough to substantially decrease their chances of being diagnosed with a malignancy.”

Dr. Harry Ostrer, who is director of the Human Genetics Program at NYU Langone Medical Center and has extensively studied the BRCA mutations in Ashkenazi Jews, called PARP inhibitor research “an interesting new alley.”

Ostrer noted that olaparib clearly had an effect on treating breast and ovarian cancer in both BRCA1 and BRCA2 mutation carriers. While they weren’t cured of their disease, he said, “There was an objective response — their tumors shrunk.”

Robson appears cautiously optimistic about the potential of olaparib. He said that there are a few people in his studies who are continuing to receive the drug and are not seeing progression of their disease.

“It’s another step forward in the targeted therapy arena — defining the unique characteristics of someone’s cancer and going after that specific characteristic to try to get an effective treatment. I think it’s not coming fast enough,” he said, “but it’s coming.”



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