February 5, 2009

A Good Prognosis Gets Better: Advances in the Treatment of Early-stage Breast Cancer

By Kari Bohlke, ScD

Though a diagnosis of breast cancer will always be a shock, women diagnosed with early-stage breast cancer can be reassured by the fact that because the cancer was caught early, their diagnosis has been delivered when treatment has the best chance of success. Furthermore, recent advances in the treatment of early-stage breast cancer promise greater improvement in patient outcomes.

Early-stage breast cancer refers to cancer that either is confined to the breast or has not spread beyond the axillary (underarm) lymph nodes.[1] These cancers include ductal carcinoma in situ (DCIS) as well as Stage I, Stage II, and some Stage IIIA cancers.

The primary treatment of early-stage breast cancer typically consists of lumpectomy and radiation therapy or mastectomy. These treatments are considered local therapies because they treat cancer in the breast and the surrounding area but not cancer that has spread to other locations in the body. In some cases systemic treatments—such as chemotherapy, hormone therapy, and targeted therapies—which treat cancer that has spread throughout the body—may also be given as adjuvant treatment (treatment after surgery).

Decisions about the need for systemic treatments, and about the most appropriate types, depend on many factors, including tumor size, whether cancer has spread to nearby lymph nodes, hormone receptor status, and HER2 status. Recent advances in the treatment of early-stage breast cancer have involved more-effective and more-individualized approaches to systemic therapy. These advances include targeted therapies that attack cancer cells with specific characteristics, more-effective approaches to hormone therapy and chemotherapy, and the development of tests to predict the risk of cancer recurrence.

HER2 and the Success of Targeted Therapy

Twenty to 30 percent of breast cancers overexpress (make too much of) a protein known as HER2.[2] Overexpression of this protein leads to increased growth of cancer cells and a worse breast cancer prognosis. Fortunately, the development of Herceptin® (trastuzumab)—a treatment that specifically targets HER2-positive cells—has improved the prognosis for women with HER2-positive breast cancer.

Herceptin is a drug that recognizes and binds to HER2-positive cells. The effects of Herceptin are thought to include decreased cell growth and increased cell death.[3] Use of Herceptin was initially evaluated in women with metastatic breast cancer; in these women treatment with chemotherapy plus Herceptin slowed cancer progression and improved survival compared with treatment with chemotherapy alone.[4]

More recently, Herceptin has produced good results in women with early-stage breast cancer. A study known as the Herceptin® Adjuvant (HERA) trial assigned HER2-positive early-stage breast cancer patients to one of three treatment groups following adjuvant chemotherapy: observation, one year of Herceptin, or two years of Herceptin. According to results presented at the 2006 annual meeting of the American Society of Clinical Oncology, women treated with one year of Herceptin had a lower risk of death, a lower risk of local recurrence, and a lower risk of distant metastases compared with women in the observation group. Results for the women assigned to two years of Herceptin are not yet available.[5]

A combined analysis of two other clinical trials evaluated the use of Herceptin given during adjuvant chemotherapy in women with early-stage breast cancer. Compared with women who did not receive Herceptin, those who did had a 52 percent reduction in the risk of recurrence and a 33 percent reduction in the risk of death.[6]

As a result of the success in treating HER2-positive breast cancers, testing for HER2 is now a routine part of the clinical workup for breast cancer.

Beyond Tamoxifen: Aromatase Inhibitors Improve Outcomes in Postmenopausal Women

A majority of breast cancers are estrogen receptor–positive (ER-positive), meaning they are stimulated to grow by the female hormone estrogen. Depriving ER-positive breast cancers of estrogen can slow their growth.

For many years tamoxifen (Nolvadex®) has been a mainstay of hormone therapy for breast cancer. Tamoxifen acts by blocking estrogen receptors. More recently, however, drugs known as aromatase inhibitors have produced superior results to tamoxifen alone in the treatment of ER-positive breast cancer in postmenopausal women.

In premenopausal women the ovaries are the major source of estrogen. After menopause, when ovarian hormone production drops dramatically, some estrogen continues to be produced in tissues outside of the ovaries. In this process androgens produced by the adrenal glands are converted into estrogen. An enzyme called aromatase is required for this conversion.[7] Aromatase inhibitors block the activity of aromatase and stop the conversion of androgens to estrogen. This lowers estrogen levels in postmenopausal women.

When considering how best to use aromatase inhibitors in the treatment of postmenopausal breast cancer, researchers have considered several possibilities: aromatase inhibitors could be used for extended hormone therapy after a woman has completed tamoxifen treatment[8]; women could be switched to aromatase inhibitors after a brief (two- to three-year) period of tamoxifen therapy[9]; or aromatase inhibitors could be used in place of tamoxifen in the initial hormone therapy.[10],[11] Although it’s still uncertain which of these approaches is best, each appears to produce better outcomes than the use of tamoxifen alone. The primary benefit observed thus far is a reduction in the risk of cancer recurrence.

In addition to reducing the risk of recurrence, aromatase inhibitors appear to produce fewer side effects than tamoxifen. Concerns with the use of tamoxifen include an increased risk of uterine cancer and blood clots. Side effects of aromatase inhibitors include decreased bone density and an increased risk of fractures.9,11,[12]

Currently available aromatase inhibitors include Arimidex® (anastrozole), Aromasin® (exemestane), and Femara® (letrozole).

Taxanes Improve Chemotherapy Outcomes

For women with early-stage breast cancer, chemotherapy regimens that include an anthracycline drug such as doxorubicin have been shown to decrease cancer recurrence and improve survival.[13] More recently, the addition of a taxane to these regimens has resulted in further improvements in cancer-free and overall survival in women with node-positive breast cancer.

The taxanes are a class of chemotherapy drugs that include Taxotere® (docetaxel), Taxol® (paclitaxel), and Abraxane® (albumin-bound paclitaxel). In the treatment of early-stage breast cancer, taxanes are commonly given in combination with doxorubicin and cyclophosphamide.

Chemotherapy regimens that include Taxotere or Taxol have been shown to improve survival among women with early-stage, node-positive breast cancer.[14],[15] Abraxane (a new form of paclitaxel) has produced superior results to Taxol in studies of women with metastatic breast cancer[16] and is currently being studied in women with early-stage breast cancer.

As a result of these and other studies, a taxane-containing chemotherapy regimen is now common for women with early-stage, node-positive breast cancer.[17]

Responding to Risk of Recurrence: Test May Influence Treatment Choices

For women with node-negative breast cancer, decisions about the need for chemotherapy require consideration of both the risks and the benefits of treatment. Because an important goal of chemotherapy is to reduce the risk of cancer recurrence, an individualized assessment of recurrence risk may help women and their doctors make treatment choices.

Work in the area of gene expression profiling has contributed to our understanding of recurrence risk and expected response to treatment. Gene expression profiling explores the patterns of genes that are active in tumor cells. Studies suggest that gene expression may provide information about prognosis or likely response to treatment in several types of cancer, including breast cancer.

A gene expression test known as Oncotype DX™ estimates the risk of breast cancer recurrence and also provides information about the expected benefit of chemotherapy. The test evaluates a panel of 21 genes to predict a patient’s 10-year risk of cancer recurrence. The test classifies patients as being at high, intermediate, or low risk of recurrence based on a Recurrence Score.™ The Recurrence Score ranges from zero to 100, with a higher score indicating a greater risk of recurrence.

The link between the Recurrence Score and the response to chemotherapy was demonstrated in a study of 651 node-negative, estrogen receptor–positive breast cancer patients, some of whom had been treated with tamoxifen alone and some with tamoxifen and chemotherapy.[18] Among women with a low Recurrence Score (a low predicted risk of cancer recurrence), the addition of chemotherapy provided minimal benefit. Among women with a high Recurrence Score, the addition of chemotherapy significantly reduced the likelihood of distant cancer recurrence.

To further explore the use of Oncotype DX in guiding chemotherapy decisions, a study known as the TAILORx trial will enroll more than 10,000 breast cancer patients from the United States and Canada.[19] Women in the trial will be assigned to a treatment group based on their Recurrence Score: women with a high Recurrence Score (greater than 25) will receive adjuvant treatment with chemotherapy plus hormone therapy; women with a low Recurrence Score (less than 11) will receive adjuvant treatment with hormone therapy alone; and women with an intermediate Recurrence Score (from 11 to 25) will be randomly assigned to receive adjuvant treatment with either hormone therapy alone or hormone therapy plus chemotherapy. The main focus of the study is the role of the Oncotype DX test in women with an intermediate risk of recurrence. In these women the benefit of chemotherapy remains uncertain.

Not the End of the Story

Recent advances in the treatment of early-stage breast cancer provide more-effective treatment options and also allow for treatments to be better targeted to those women who will benefit the most. For women with HER2-positive tumors, Herceptin (and possibly other targeted therapies currently being studied) can cut the risk of cancer recurrence and improve survival; for postmenopausal women with hormone receptor­–positive breast cancer, the use of aromatase inhibitors at some point in the course of treatment appears to be more effective than tamoxifen alone; for women who are candidates for chemotherapy, a taxane-containing chemotherapy regimen improves outcomes; and for women with node-negative estrogen receptor–positive breast cancer, an estimation of recurrence risk provides prognostic information and may guide treatment choices.

The treatment advances discussed in this article are not the end of the story. Not all women with early-stage breast cancer will benefit from these advances; nor has the risk of cancer recurrence been completely eliminated. But these advances will improve outcomes for a significant proportion of women with early-stage breast cancer, and they also point the way toward additional progress.

[1] Dictionary of Cancer Terms. National Cancer Institute Web site. Available at http://www.cancer.gov/Templates/db_alpha.aspx?CdrID=446564. Accessed September 18, 2006.

[2] National Cancer Institute FactSheet. Herceptin® (Trastuzumab): Questions and Answers. National Cancer Institute Web site. Available at: http://www.cancer.gov/cancertopics/factsheet/therapy/herceptin. Accessed September 18, 2006.

[3] Hobday TJ, Perez EA. Molecularly targeted therapies for breast cancer. Cancer Control. 2005;73-81.

[4] Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. New England Journal of Medicine. 2001;344:783-792.

[5] Smith I, et al. Trastuzumab following adjuvant chemotherapy in HER2-positive early breast cancer (HERA trial): Disease-free and overall survival after 2 year median follow-up. Paper presented at: Annual Meeting of the American Society for Clinical Oncology; June 2-6, 2006; Atlanta, Georgia. Presented at a scientific special session.

[6] Romond E, Perez E, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. New England Journal of Medicine. 2005;353:1673-1684.

[7] Lake DE, Hudis C. Aromatase inhibitors in breast cancer: An update. Cancer Control. 2002;9:490-498.

[8] Goss P, Ingle J, Martino S, et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: Updated findings from NCIC CTG MA.17. Journal of the National Cancer Institute. 2005;97:1262-1271.

[9] Coombes RC, Paridaens R, Jassem J, et al. First mature analysis of the intergroup exemestane study: A randomized trial in disease-free, postmenopausal patients with early breast cancer randomized to continue tamoxifen or to switch to exemestane following an initial 2-3 years of adjuvant tamoxifen. Paper presented at: Annual Meeting of the American Society for Clinical Oncology; June 2-6, 2006; Atlanta, Georgia. Abstract LBA527.

[10] Howell A, Cuzick J, Baum M, et al. Results of the ATAC (Arimidex, tamoxifen, alone or in combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet. 2005;365:60-62.

[11] The Breast International Group (BIG) 1-98 Collaborative Group. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. New England Journal of Medicine. 2005;353:2747-2757.

[12] The Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists’ Group. Comprehensive side-effect profile of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: Long-term safety analysis of the ATAC trial. Lancet Oncology [early online publication]. July 19, 2006.

[13] Early Breast Cancer Trialists Collaborative Group. Polychemotherapy for early breast cancer: An overview of the randomised clinical trials. Lancet. 1998;352:930-942.

[14] Martin M, Pienkowski T, Mackey J, et al. Adjuvant docetaxel for node-positive breast cancer. New England Journal of Medicine. 2005;352:2302-2313.

[15] Henderson I, Berry D, Demetri G, et al. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. Journal of Clinical Oncology. 2003;21:976-983.

[16] Gradishar W, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. Journal of Clinical Oncology. 2005;23:7794-7803.

[17] Cianfrocca M, Gradishar WJ. Controversies in the therapy of early stage breast cancer. Oncologist. 2005;10:766-779.

[18] Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. Journal of Clinical Oncology. 2006;24:3726-3734.

[19] Personalized Treatment Trial for Breast Cancer Launched [press release]. National Cancer Institute Web site. Available at: http://www.cancer.gov/newscenter/pressreleases/TAILORxRelease. Accessed September 18, 2006.

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Tags: Breast Cancer, Uncategorized