Treating Metastatic Breast Cancer: New breeds, old dogs and new tricks

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There has never been a more fruitful or hopeful time in breast cancer research, particularly in the arena of drug development. In their 2009 report (this link opens to a PDF), the Pharmaceutical Research and Manufacturers of America, the professional organization of the pharmaceutical industry, lists more than 800 cancer medicines currently in clinical trials, with 106 in breast cancer alone. Many more treatments are in a translational phase of development, moving up from basic or laboratory science and tests in animal models (usually mice or rats) to testing in women with metastatic breast cancer. Below I discuss just a few of the many  abstracts and oral presentations that presented data on targeted agents in clinical development here at the San Antonio Breast Cancer Symposium in Texas.

Denosumab
Three quarters of women with metastatic breast cancer develop bone metastases, which can cause pain, fractures and other miseries. In recent years, high-potency intravenous bisphosphonates, like zoledronic acid (Zometa) and pamidronate (Aredia), have made a big  difference in the quality of life of women with bone metastases by slowing the growth of their tumors, preventing fractures and reducing pain. (These drugs are close cousins to the bisphosphonates used to treat osteoporosis.)

Today we heard a presentation about denosumab, a new monoclonal antibody that targets RANKL inhibition, a mediator of osteoclast formation. Osteoclasts are cells that are involved in destroying bone so it can be replaced by new bone. A study comparing denosumab with standard Zometa treatment in women with metastatic disease found a meaningful reduction in bone fractures, pain and time before these women needed radiation to control pain. Because denosumab is a more targeted drug, there were fewer side effects in the patients who received it than in who received Zometa. Unfortunately, denosumab was not able reduce the incidence of osteonecrosis of the jaw. This particularly troublesome side effect occurred in about 2 percent of the patients who were on either drug.

Moving drugs into the breast cancer arena
Some presentations discussed drugs used  in other diseases that are now being studied as breast cancer treatments. One such drug is metformin, which is used to treat diabetes. Cancer researchers became interested in metformin after doctors reported observing a lowered incidence of breast cancer in diabetics receiving metformin compared with those not receiving this drug. Their observation led to laboratory investigations aimed at identifying possible mechanisms of action, and, now, clinical trials will soon begin investigating their effectiveness.

When hearing about promising population studies, or laboratory findings, I’ve learned through long experience not to get too excited. After all, other drugs in common use have been similarly investigated, and many, like the COX-2 inhibitors and the statins, have not withstood the careful scrutiny of clinical trials. As a result, I watch closely to see if any real benefit is seen in a phase II or III clinical trial. If and when that happens, I allow myself to get excited, as I did last summer, when researchers reported findings from a new class of drugs called PARP inhibitors that may prove to be the first targeted therapy for women with breast cancer who have a BRCA mutation or who have triple-negative disease.

New approach to HER2
We don’t always have to wait the dozen or more years that it takes for a new drug to be developed and tested to find a successful new treatment. Sometimes, combinations of already approved therapies can provide impressive results beyond those achievable with either drug alone.

It is common for women with HER2-positive metastatic disease to receive multiple lines of treatments that include the monoclonal antibody trastuzumab (Herceptin). Lapatinib (Tykerb) is a tyrosine kinase inhibitor that is approved by the U.S. Food and Drug Administration for use in combination with the oral chemotherapy drug Xeloda after Herceptin plus a chemotherapy drug has failed. Some years ago, researchers wondered if creating a “total blockade” of the HER2 pathway by using both Herceptin and Tykerb might be more effective than using lapatinib alone.

Kimberly Blackwell, a medical oncologist at Duke University Medical Center, in Durham, N.C.,  presented results from a trial that enrolled 296 women with HER2-positive metastatic breast cancer that tested this idea. All of the women had received on average three prior Herceptin plus chemotherapy regimens. In this trial, these “heavily pretreated” patients were randomized to receive either the combination of Herceptin and Tykerb or Tykerb alone. Blackwell reported that the addition of Herceptin to Tykerb  improved overall survival from nine months to 14.5 months—an impressive finding. (Remember, the increase of five and a half months only describes the average.)

If treatment failure ordinarily would be evidence of resistance, and a signal that it’s time to move on to another treatment, why would Herceptin continue to be beneficial? Many oncologists believed that Herceptin continued to exert continuing control over this aggressive form of breast cancer, even when treatment appeared to fail. However, until now, there was never definitive proof to support the practice of continuing Herceptin past treatment failure. This study not only confirms the continued use of Herceptin after treatment failure, but it offers patients a treatment regimen without chemotherapy—something many women undergoing continuous treatment will certainly appreciate.

Musa Mayer
AdvancedBC.org

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