Making real progress against breast cancer

 (This article was first printed in the October 2005 issue of the Harvard Women's Health Watch. For more information or to order, please go to www.health.harvard.edu/womens.)

Talk to any breast cancer specialist who attended the May 2005 American Society of Clinical Oncology (ASCO) meeting — the largest annual gathering of cancer researchers and clinicians in the world — and you’re likely to detect excitement in their voices. This was a year when they heard results that could markedly change the way they take care of their patients. The buzz was about targeted therapy, that is, treatment aimed directly at gene products (proteins) and other factors responsible for cancerous cell growth.

Fundamental to this approach is an understanding that not all breast cancers are alike. Although researchers have long known that breast cancer doesn’t behave the same way in everyone — after all, some women do well with traditional treatments and others don’t — they’ve only recently begun to penetrate the disease at a molecular level and appreciate that it’s actually many diseases. This new knowledge is beginning to make it possible to match the right therapy with the right patient.

Perhaps just as exciting is the prospect that advances are likely to come more quickly now that certain developments and tools are in place. Getting a breast cancer diagnosis will no doubt always be scary, but it’s becoming possible to envision a time when finding a lump or hearing the words “You have breast cancer” won’t evoke the terror it did in years past.

Taking aim at the troublemakers

Much of the excitement at the 2005 ASCO meeting centered on trastuzumab — better known as Herceptin — a drug designed to act against breast cancer cells that are genetically programmed to make too much of a protein called HER2 (human epidermal growth factor receptor 2). Women whose breast cancers overproduce HER2 are said to be HER2 positive, and they generally have a poor prognosis, even with chemotherapy. About 25% of all breast cancers overexpress HER2.

Herceptin was approved in 1998 for HER2 positive women whose breast cancer has spread (metastasized). The drug doesn’t work for everyone, but when it does, the results can be astounding; in some cases, breast tumors have disappeared. This led to trials of Herceptin in newly diagnosed women whose breast cancers are HER2 positive. Results from two such trials were presented at a 2005 ASCO session described by some as “transformational” and “practice-changing.” According to breast cancer clinician and researcher Dr. Harold Burstein, at Boston’s Dana Farber Cancer Institute, “It’s the kind of thing where you look at the data…and you immediately say, Yes, that’s obvious. People should get this.”

The data showed that adding Herceptin to standard chemotherapy cut the rate of breast cancer recurrence by 52%, compared to chemotherapy alone. Researchers still don’t know whether Herceptin works better when given with chemotherapy or after it. But there’s no question that it should now be a first-line therapy — not just a treatment for metastatic disease. One unanswered question is how to manage heart problems, which affect 3%–4% of women who take Herceptin with the chemotherapy drug Adriamycin. It may be that a different chemotherapy regimen can work as well without affecting the heart. A trial testing this idea is underway as of late summer 2005.

Earlier in 2005, researchers involved in another Herceptin study reported that women with early-stage HER2 positive breast cancer did so much better if they received Herceptin plus chemotherapy before surgery that the trial was stopped and revised so that all participants could take advantage of the combined treatment.

Other encouraging news from the ASCO meeting involved Avastin (bevacizumab), a drug that targets VEGF (vascular endothelial growth factor), a substance that may be present in large amounts in some aggressive cancers. VEGF stimulates the growth of blood vessels, which cancers use to feed themselves. Avastin blocks that activity. (This approach, called anti-angiogenesis, is based on discoveries made by Harvard Medical School researcher Dr. Judah Folkman.) In a trial involving 700 women whose breast cancer had spread to other organs (and who were not HER2 positive), paclitaxel (Taxol) plus Avastin nearly doubled the length of survival time without the disease getting worse, compared with Taxol alone.

The success of Herceptin and other targeted therapies has helped speed the pace of research on the biological features of breast cancer and therapies to address them. According to Dr. Paul E. Goss, director of breast cancer research at Massachusetts General Hospital in Boston, “Every time there’s a new discovery, the excitement about it is not just that it’s going to benefit women with breast cancer, but that breathing down its neck is the competitor or the addition that’s going to further improve the outcome for women.”

Determining who needs chemotherapy

Another implication of Herceptin’s success is the importance of getting good information about a breast cancer’s specific characteristics, so that women can be offered the best treatment for their particular situation.

Therapy decisions have traditionally been guided by pathology reports, which describe the results of tests on tumor tissue and include information about the tumor’s size, the extent of lymph node involvement, whether the cancer has spread to other areas of the body, its estrogen receptor (ER) status — positive or negative — and now, HER2 status. Tissue is also examined for cellular signs of so-called aggressiveness.

We know that women with early-stage, ER-positive, node-negative breast cancer — the majority of all breast cancers — should be given hormonal therapy, such as tamoxifen, after initial treatment. Most of these women do well, but cancer progresses in about 25% of them. Past studies have found that adding chemotherapy to tamoxifen further reduces recurrence risk by about 25%. The problem is, 25% is just an average. No one knows which women will benefit from the added chemotherapy and which won’t. As a result, many who are at very low risk for a recurrence are getting chemotherapy — treatment they don’t need that causes hair loss, nausea, extreme fatigue, and sometimes cognitive problems.

Enter Oncotype DX, a diagnostic test that may help fine-tune treatment for early-stage breast cancer in this particular group of women. Oncotype DX extracts genetic information from a tumor sample and analyzes it for the presence of 16 genes that are strongly linked to breast cancer recurrence. Results are converted to a score between 0 and 100 that’s correlated with the chance of recurrence within 10 years of diagnosis. Women with low scores are likely to get little, if any, benefit from chemotherapy, while the cancers of high scorers may be particularly responsive to it. Several studies on the technology were presented at the ASCO meeting.

It’s too early to know whether using the test actually improves outcomes. But oncologists agree that a tool that helps read the molecular signature of a woman’s breast cancer should add more certainty to treatment decisions and is likely to help spare more women from chemotherapy.

For now, a complete and accurate pathology report remains the foundation of treatment planning. That’s one reason it’s important, whenever possible, to get breast cancer care at a major cancer center, such as those designated by the National Cancer Institute (for a list of locations, phone numbers, and Web sites, see www3.cancer.gov/cancercenters).

Update on aromatase inhibitors

Hormonal therapy is standard for ER-positive breast cancer. For 20 years, that’s meant tamoxifen, which is also used to prevent breast cancer in high-risk women. But tamoxifen loses its effectiveness after five years. It also increases the risk of endometrial cancer, stroke, and blood clots. These concerns prompted scientists to investigate aromatase inhibitors, a newer class of drugs that interfere with estrogen production in the body. (Tamoxifen blocks estrogen by a different mechanism.)

Three aromatase inhibitors — anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) — are approved for treating breast cancer that has spread. They’re also now being used for early-stage breast cancer. Studies have shown they do a better job than tamoxifen in preventing recurrence and the development of new cancer in the other breast in postmenopausal women. Consequently, tamoxifen for five years is no longer the gold standard, though it may still be a first choice for some women. Aromatase inhibitors can cause bone loss and musculoskeletal pain (although less so with Aromasin), and some oncologists worry that this may increase the likelihood of fractures. Aromatase inhibitors are not used in premenopausal women because they don’t effectively inhibit estrogen production in the ovaries.

A large number of studies — some reported in 2004 and 2005 and at ASCO — are investigating the best use of both tamoxifen and aromatase inhibitors. It appears that women do better taking tamoxifen for two to three years, then switching over to an aromatase inhibitor, although for how long is unclear. According to Dr. Goss, there’s some evidence that the two drugs are synergistic; it may be that tamoxifen primes the cancer cells and the activity of the aromatase inhibitor finishes them off. Several studies are under way to investigate different doses of aromatase inhibitors and durations of therapy.

A new trial, the ExCel study, will test Aromasin to see if it can prevent breast cancer in women at high risk for the disease. The study is being conducted in the United States, Canada, and Spain and coordinated by the National Cancer Institute of Canada Trials Group. For more information, visit http://www.excelstudy.com/, or call 800-422-6237 (toll free) or, in Canada, 888-939-3333 (toll free).

 (This article was first printed in the October 2005 issue of the Harvard Women's Health Watch. For more information or to order, please go to www.health.harvard.edu/womens.)

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