2009 Turning Point

Targeted therapy takes aim at breast and ovarian cancers
by Pat McCaffrey

Fermina Hanson, at home here in New Hampshire, has been taking a new, targeted therapy to treat her breast cancer. Below is her Dana-Farber oncologist, Harold Burstein, MD, PhD. 

When Fermina Hanson needed to have chemotherapy and radiation for her breast cancer, one side effect really got her down. It wasn't the nausea or fatigue, although both were debilitating. The thing she remembers most was the psychological impact of losing her long, dark hair. "It was traumatic, and a real struggle," Hanson recalls.

Back on therapy for a recurrence of her cancer, the 54-year old Hanson is having a different experience this time. For the last eight months, she has been taking an experimental drug called a PARP inhibitor. [PARP stands for poly (ADP-ribose) polymerase.] A PARP inhibitor is a new, targeted therapy for breast and ovarian cancer that is being tested at Dana-Farber. Her treatment consists of eight pills, twice a day. Her tumor has receded. Her hair looks great.

Targeted therapies, such as PARP inhibitors, are designed to zero in on the exact genetic changes that make cancer cells so deadly, and leave normal cells alone. That lets the treatment effectively kill tumors and spare patients from the severe side effects that often come with chemotherapy.

Harold Burstein, MD, PhD 

For Hanson, whose cancer is caused by a mutation in one of the two most common breast cancer genes (BRCA1 and BRCA2), the PARP inhibitors offer the first potential treatment aimed at hereditary breast cancer. That is good news for the approximately five percent of breast and ovarian cancer patients with BRCA mutations. For other women, new research points to a similar defect even in tumors without BRCA mutations, and opens the door to the possibility that PARP inhibitors could be effective against a wider range of both ovarian and breast cancers.

Six ways to fix DNA

Research into BRCA function over the past decade, including key work by scientists in Dana-Farber's Women's Cancers Program, elucidated the role of BRCA proteins involved in DNA repair. Researchers have identified six different repair mechanisms (or pathways), each made up of dozens of proteins that work together to mend breaks and correct genetic mistakes. This process is critical to cell life; without it, cells quickly accumulate a lethal load of genetic damage.

In breast and ovarian cancers with BRCA mutations, one of the six repair pathways loses function. To survive, the cells compensate by increasing the activity of an alternative repair pathway. The PARP enzyme is a key protein in the back-up pathway, and the tumors soon become dependent on PARP activity for their survival.

Once the biology of PARP in BRCA-deficient cells became clear, clinical translation quickly followed. PARP-inhibiting compounds were already sitting on the shelf at several pharmaceutical companies, the product of earlier investigations for other disease treatments. So far, the results from clinical trials in cancer patients have been encouraging.

In the Gynecologic Medical Oncology Program, Director Ursula Matulonis, MD, and her team have completed a first study of the PARP inhibitor AZD2281. All of the women who took part had recurrent ovarian cancer and the BRCA1 or BRCA2 mutations; they all received the PARP inhibitor, and though the study was small, the doctors saw some "remarkable" responses. "PARP inhibitors are definitely active drugs in these patients," Dr. Matulonis said.

Doctors are now recruiting for a follow-on study comparing the same PARP inhibitor to a standard treatment regimen in women with advanced ovarian cancer whose cancer progressed in spite of prior chemotherapy.

Fermina Hanson had her first bout with breast cancer in 1997. When the tumor reappeared in 2004, she came to see Harold Burstein, MD, PhD, at Dana-Farber's Breast Oncology Center. She received a standard course of radiation and chemotherapy for her BRCA2-positive tumor. Two years later, after another local recurrence, Dr. Burstein suggested a clinical trial. The first experimental treatment she tried had no effect, but she then enrolled in a multi-center study of PARP inhibitors and she's seen her tumor shrink.

When she was undergoing chemotherapy and radiation, Hanson traveled to Dana-Farber at least weekly from her home in Brookline, New Hampshire, and had to take a leave from her job as a medical secretary when the side effects became too severe. With the PARP inhibitor, she takes her pills in the morning and evening, feels a little tired and sometimes nauseous, but she says, "I go to work, I do everything I want to do. To have a drug with so few side effects and that is effective, is wonderful."

"This is a very new drug, and I know there aren't that many people on it worldwide. But my background matched it, and now I'm having positive results," Hanson said. "A big reason I chose to go to Dana-Farber is because they have these opportunities for study drugs. I feel blessed to have this chance."

Not for BRCA cells only?

Women's Cancers Program physician/scientists Ursula Matulonis, MD, (left) and Dan Silver, MD, PhD, see promise in the use of PARP inhibitors for some breast and ovarian cancer patients. 

Only a fraction of women with breast and ovarian cancer have BRCA mutations, but many tumors have defects in DNA repair. In ovarian cancer, up to 70 percent of tumors are deficient in some part of the the BRCA DNA repair pathway, even though their BRCA genes may be normal. The problem could lie in regulation of BRCA gene expression or in trouble with other proteins in the same pathway. Whatever the cause, if the cells are relying on the PARP pathway to take up the slack, the inhibitor might work for these tumors, too.

To test that idea, Dr. Matulonis is planning a trial to evaluate the compound AZD2281 in women with recurrent ovarian cancer that is still responsive to platinum, whether their tumors have BRCA mutations or not.

In breast cancer, a similar opportunity may exist to treat an aggressive and stubborn class of tumors known as triple negatives. These cancers lack three clinical cancer markers, estrogen receptors, progesterone receptors, and the growth-promoting protein HER2. Because of this, the cells do not respond to anti-estrogen therapy, or to the HER2-targeted therapy trastuzumab.

Dan Silver, MD, PhD, then a research fellow with David Livingston, MD, found that triple negative breast cancers share features of BRCA-mutated tumors, including defects in DNA repair and an accompanying sensitivity to the DNA-damaging drug cisplatin. Could this parallel extend to sensitivity to PARP inhibitors?

Dr. Silver, now an assistant professor in the Women's Cancers Program, believes so. He has found that some of the tumors are very sensitive to PARP inhibitors when grown in the lab. This work is being translated in a clinical trial in collaboration with Judy Garber, MD, MPH, the director of the Friends of Dana-Farber Cancer Risk and Prevention Clinic. Building on the program's recent success using cisplatin chemotherapy to treat triple-negative breast cancers, the researchers plan to combine a PARP inhibitor with cisplatin, and treat women with newly diagnosed triple-negative tumors, with or without BRCA mutations.

Hitting the target

Alan D'Andrea, MD, has spent the last 15 years uncovering the genes and proteins involved in all six DNA repair pathways, and he thinks there may be more tumors with the right profile for PARP inhibitor treatment.

"Any cell that has become dependent on the PARP pathway for survival is fair game," says Dr. D'Andrea, the chief of the Division of Radiation and Cancer Biology.

To sort out the cancers that qualify, Dr. D'Andrea and colleagues are working out a series of laboratory tests to determine, in tumor samples, which DNA repair pathways are active. Having that information up front will allow doctors to figure out which patients are the best candidates for PARP inhibitor treatment. "This is a really good opportunity for personalized medicine," Dr. D'Andrea says. "Our challenge is to find the perfect patients for the PARP inhibitors."

Many questions remain about the new approach. Which PARP inhibitors of several in the pipeline will emerge as the best? Should the inhibitors be combined with chemotherapy? Should they be used early in treatment, or later? Resistance to PARP inhibitors can emerge when cells find a way to reactivate the BRCA-dependent repair pathway – will that limit their use?

It will take time to get the answers, but Dr. Matulonis sees PARP inhibitors as just the beginning of a whole new class of therapies. "As time goes on we are going to see more and more drugs targeting DNA repair," she says. "For women with ovarian cancer who don't have the BRCA mutation, this is going to be an area of new drug therapies and active research. This is an exciting time."

2009 Turning Point