Fresh use of targeted therapy advances treatment of early HER2-positive breast cancer

Researcher-clinician offers advice for navigating the new world of molecular treatment

JACKSONVILLE, Fla. -- The news that the world's first targeted therapy, trastuzumab (Herceptin), is now available for many women with early-stage HER2-positive breast cancer "highlights a truly significant advance in the management of breast cancer," says Edith Perez, M.D., director of Mayo Clinic's Breast Clinic in Jacksonville, Fla.

Dr. Perez, who led one of the four pivotal studies that proved the drug's benefit in early-stage disease, says the approval of trastuzumab by the Food and Drug Administration (FDA) on Nov. 16 for this new use now allows physicians to manage an aggressive type of breast cancer much more effectively than just a few years ago.

It also signifies the importance for women who are newly diagnosed with breast cancer to ensure the care they will receive is the best possible, says Dr. Perez. "Women have helped lead a revolution in the care of breast cancer, and now I think all patients should know all that they can do to help direct their care," she says.

"We know that a million people are diagnosed with breast cancer in this world every year, and many are diagnosed with early disease that is potentially curable," Dr. Perez says. "This advance, and all the research continuing on novel therapies based on molecular markers in cancer, provides a brighter future for these patients."

Between 25 percent and 30 percent of breast cancer is HER2-positive, meaning that growth-promoting HER2 proteins are overly abundant on the outside of the cancer cells, promoting an aggressive disease.

Trastuzumab was landmark drug

Apart from skin cancer, breast cancer is the most common cancer in American women, and due to screening, more and more women are being diagnosed with the disease. But in the last decade, breast cancer's death toll has been steadily dropping--the average survival rate five years after treatment is now more than 88 percent, according to American Cancer Society. This can be attributed to improved understanding of the disease that has led to more effective treatments. HER2 pushes a cell to divide, and while a little on a cell is normal, a lot is not. No one knows why, in these so-called "HER2-positive" tumors, these proteins are over-expressed. But when this happens, cancer becomes aggressive. Trastuzumab is a specific type of biologic therapy, a monoclonal antibody, designed to shut down activity of these HER2 proteins by sticking to and "smothering" them, halting the pro-growth molecular instructions that these proteins relay into the body of the cancer cells. When approved by the FDA in 1998, trastuzumab helped usher in the era of targeted therapy because it specifically attacks a molecular defect on a cancer cell.

The first use of trastuzumab, however, was in women whose cancer was the most difficult to treat, because it had spread beyond the breast. Still, when used with chemotherapy, trastuzumab reduced tumor size by more than 50 percent, and extended survival, according to investigators who conducted these clinical studies. The best response to trastuzumab was seen in patients with the highest levels of HER2 protein in their tumors, proving the therapy was truly zeroing in on the right molecular target.

Extending benefit to early disease

The clear benefit of adding trastuzumab to chemotherapy for patients with advanced breast cancer, considering its overall tolerability, led several investigators (including Dr. Perez) to develop studies in the late 1990s. Researchers sought to test how the drug would treat HER2-positive cancer before it had a chance to spread. They believed that if the drug could help women with the poorest prognoses, the benefit it could offer women with the earliest stages of invasive, HER2-positive breast cancer might be dramatic.

What they found was almost the proverbial magic bullet. In one of four major national studies that examined early use of trastuzumab, they discovered that the drug could change the natural history of the disease. Trastuzumab cut cancer recurrence--the return of the disease by 52 percent, compared to standard therapy, Dr. Perez reported late last year. "That's the largest improvement we've seen in more than 30 years, and perhaps ever in the treatment of breast cancer," she noted at the time results were announced.

Conducted with the help of researchers nationwide and "the gracious patients" who participated, the study has since led to a change in treatment of women whose early-stage breast cancer is HER2-positive, Dr. Perez says.

It appears the hard work paid off. This change in treatment is now available outside the parameters of a clinical study. Today it's FDA-approved.

"Our ultimate goal is to prevent cancer from returning," Dr. Perez says, "and this drug takes us closer to reaching the era when breast cancer will no longer be a lethal disease."

Empowering patients

Although this new era of molecular medicine may seem complicated, there is a lot that patients can do to help chart their own treatment course, Dr. Perez says.

  • Make sure your tumor biopsy is tested for biological markers. The standard of care today is that all women with invasive breast cancer should have tumor tissue marker tests to look for presence and quantity of the HER2 protein or HER2 gene. Other important tests need also to examine whether tumor growth is being driven by estrogen, and so they measure the abundance of estrogen receptor (ER) or progesterone receptor (PR) proteins. Women who already had a biopsy or tumor removal and know that it wasn't tested for one of the tissue tumor markers can ask their physician to contact the laboratory where the sample was analyzed and request a new test on the stored tissue.

  • Ask what kind of laboratory your biopsy samples will be sent to for testing. Dr. Perez recently published a study that found 12 percent to 18 percent of positive HER2 tests done in local labs are actually negative when tested at a central or reference laboratory that is experienced in finding the HER2 gene. That false positive means a significant number of patients could have been given therapies that could not possibly help them, while excluding them from treatments that could.

  • Discuss the results of this test with your physician. Tumors that are and are not HER2-positive may be positive for ER or PR, and those cancers can be treated with anti-hormonal therapy. Even within this group of hormone-sensitive cancers, tests exist. And, more tests are being developed to help determine which tumors might respond to chemotherapy and which may not need such treatment. Find out if your oncologist has access to these tests.

  • Ask your oncologist if you have the opportunity to participate in other research that is testing newer therapies. For example, the experimental drug lapatinib has been found to be of benefit to advanced HER2-positive cancer when combined with chemotherapy, and also when added to trastuzumab. (This last result is based on preliminary findings from one clinical trial, and the agent is slated for testing in earlier stage HER2-positive cancers in late 2006 and 2007.) Newer anti-hormonal treatments also are being investigated for ER-positive breast cancers.

  • If you are diagnosed with HER2-positive breast cancer, make sure your treatment center will provide cardiac assessment tests before and during treatment. Dr. Perez says that cardiac toxicity has been seen in patients who have used trastuzumab, but that the problems are usually reversible with treatment, or just by stopping trastuzumab for a period of time. Still, baseline cardiac assessments and periodic checks are a must and ready access to a cardiologist is preferred.


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Last reviewed: By John M. Grohol, Psy.D. on 30 Apr 2016
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