New Drugs, New Direction

Lately, it’s hard to keep pace with breast cancer advances. Innovative drugs—targeted agents, monoclonal antibodies, kinase inhibitors, cancer vaccines, hormone modulators and novel versions of old chemotherapies—are emerging so rapidly that patients, and even some doctors, may not be fully aware of new treatment options. For patients facing critical decisions, it’s worth knowing what’s out there and what’s headed to market.

For the women in the U.S. with metastatic breast cancer, some promising treatments include Halaven (eribulin), a newly approved synthetic substance that incapacitates dividing cells, and poly (ADP-ribose) polymerase (PARP) inhibitors, a group of drugs that block repair of single-strand DNA breaks.

While these drugs are being tested in a variety of tumor types, in the case of PARP inhibitors, some of the immediate benefit—and buzz—applies to their apparent activity in some women with metastatic, triple-negative breast cancer (TNBC).

Stephanie Robin of Boca Raton, Florida, is an energetic mother and fundraiser who has been living with breast cancer since she was diagnosed in 2004 at age 36.

After undergoing bilateral mastectomy with reconstruction and months of chemotherapy, her cancer came back in multiple lung spots in 2007. She received additional treatment cycles to no avail. A genetic counselor, who had determined that Robin harbors a BRCA mutation, encouraged her to enroll in a clinical trial with a PARP inhibitor.

The study explores how PARP inhibitors work in women with advanced breast cancer who have an underlying BRCA deficiency, says Mark Robson, MD, an oncologist and director of the Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center in New York City. He’s taken care of Robin since November 2007, when she began taking the investigational PARP inhibitor, olaparib.

People who inherit mutations in the BRCA gene are prone to malignancies because that protein, when present, repairs double-strand DNA breaks. In normal cells, PARP handles single-stranded DNA nicks. The theory is this: together, these non-overlapping repair systems protect cells with damaged genetic material from dividing. If either mechanism is out-of-whack, chromosomal damage can be propagated and progressive, leading to malignancy. If both enzymes are knocked out, the DNA-damaged cells can’t replicate, and they die—exactly what you’d want to happen to cancerous cells. But normal cells would not be affected since they have normal BRCA function.

“There are two general ways we might use the PARP inhibitors,” Robson suggests. First, they can enhance the effects of other agents. “A lot of drugs cause double-strand DNA breaks,” he explains. PARP inhibitors increase the burden of those breaks by neutralizing the ability of chemotherapy-exposed cells to repair genetic damage. This chemo-sensitizing effect may apply to many tumors; it might also be effective regardless of BRCA status.

The second mechanism applies to patients, such as Robin, who carry BRCA mutations, he says. “For this reason, PARP inhibitors are unlikely to work as single agents except in BRCA-deficient cases,” he says.

Robin is continuing treatment and says she feels fine. She flies to New York City periodically for CT scans and other evaluations for the experimental protocol. Still, she’s aware that many patients on the study, which is restricted to women with BRCA mutations, haven’t fared so well.

Kathy Miller, MD, a breast cancer specialist at Indiana University School of Medicine, has considered this question from an oncologist’s perspective. “What the experience has already made clear is that, while many of these drugs will be profoundly successful, they’ll probably be beneficial to just a small subset of patients,” she says.

In TNBC, typically tough to treat, the tumor cells lack estrogen receptors, progesterone receptors and HER2 overexpression, rendering them insensitive to hormonal treatments and drugs targeting HER2, such as Herceptin (trastuzumab).

TNBC cases account for approximately 15 percent of breast cancers and up to 20 percent for black women and younger, premenopausal women. As things stand, patients with metastatic TNBC have few treatment options apart from chemotherapy.

It’s for this reason that some trials of PARP inhibitors and the chemotherapy drug Halaven, reported at this past June’s meeting of the American Society of Clinical Oncology (ASCO), drew so much attention.

During the meeting, researchers reported on the intravenous PARP inhibitor iniparib and the results of a randomized trial of 116 patients with metastatic TNBC. In the study, women received a commonly used chemotherapy combination regimen, gemcitabine and carboplatin, either alone or in combination with iniparib.

The clear results have since been updated to show that, for women with metastatic TNBC, the addition of iniparib bumped the response rate from 21 to 62 percent and lengthened overall survival from 7.7 months to 12.2 months on average.

The original iniparib trial looked very promising, Miller says. It generated lots of interest in PARP inhibitors, especially for women with triple-negative disease. But she cautions that it was a small study, and other trials so far have not yielded such positive results.

Everybody's been so fixated on the triple-negative breast cancer, but the benefits may be broader.

Some researchers have suggested that PARP inhibitors, because they impede a DNA repair pro- cess, might enhance the risks of secondary cancers from treatment. “We haven’t seen that,” Miller says. “But that theoretical risk might matter more as we use these drugs in the adjuvant setting as opposed to in patients with advanced disease.”

Patients with HER2-positive, metastatic breast cancer have some reason for hope that there may be another treatment with low toxicity because of a drug being studied called T-DM1.

While the data on T-DM1 are preliminary, results of a phase 2 trial released in October at the European Society for Medical Oncology generated enthusiasm among researchers there. At a six-month follow-up, the T-DM1 arm of the study had an overall response rate of 48 percent comparedto 41 percent in the trastuzumab (Herceptin) and docetaxel (Taxotere) arm of the trial. In addition, three of 67 women treated with T-DM1 had complete responses, compared to one of 70 given trastuzumab and docetaxel.

For those women with advanced, refractory breast cancer, the other up-and-coming agent that gained attention with a major ASCO presentation is Halaven. This intravenous drug, derived from the natural marine sponge product halichondrin B, works by crippling microtubules, which are essential to the intracellular scaffolding required for chromosome separation during division.

What’s interesting, says Christopher Twelves, MD, professor at the Leeds Institute of Molecular Medicine and St. James’s Institute of Oncology in the U.K., is that other cancer drugs, such as Taxol (paclitaxel), also bind to tubulin but in a different way. “In the laboratory, cancer cells that are not sensitive to Taxol can still be sensitive to eribulin [Halaven],” he says.

These drugs require us to think differently of breast cancer—as a group of related but very different diseases that happen to occur in the breast.

Twelves presented the clinical findings from a phase 3 open-label study of 762 patients with heavily pretreated, metastatic breast cancer.

In that EMBRACE trial, median overall survival was 13.1 months for patients who received eribulin and 10.6 months for those who didn’t. The drug extends life, on average, by 2.5 months.

Some critics are puzzled by the hype, but Twelves is enthusiastic about the findings thus far.

“Eribulin [Halaven] is more effective compared to other ‘real life’ choices for chemotherapy in terms of likelihood of shrinking the cancer, delaying its progression and also prolonging survival,” he says, adding that it’s the first drug to significantly prolong survival in women with such heavily pretreated disease.

In addition, he says, side effects, such as tiredness and a fall in blood counts, are generally no more troublesome than with other agents.

Miller, in Indiana, is cautiously optimistic about the PARP inhibitors and the growing understanding of breast cancer biology.

“These drugs require us to think differently of breast cancer—as a group of related but very different diseases that happen to occur in the breast.”

According to Miller, distinct breast tumors may need to be treated, diagnosed and even prevented differently. In this context, it’s understandable that some patients, physicians and researchers are encouraged by large studies that demonstrate small benefits. Survival statistics don’t tell the whole story. For a small but significant fraction of patients, such as Robin, who is particularly sensitive to PARP inhibitors, and perhaps other outliers who respond to drugs for reasons unknown, the difference could be a matter of years.