Advances in Breast Cancer Treatment 2008

Posted on March 27th, 2009 by

Updates from the 2008 San Antonio Breast Cancer Symposium

By Kari Bohlke, ScD

The 31st San Antonio Breast Cancer Symposium (SABCS), held December 10 to 14, 2008, brought together thousands of scientists, physicians, and advocates to discuss the latest research on breast cancer prevention, screening, treatment, and survivorship. Important studies presented at this year’s conference addressed HER2-positive breast cancer, hormonal therapy, prediction of recurrence risk, breast cancer risk factors, and the potential of bone drugs to improve outcomes.

HER2-positive Breast Cancer

Twenty to 25 percent of breast cancers overexpress (make too much of) a protein known as HER2.[1] Overexpression of this protein leads to increased growth of cancer cells and a worse breast cancer prognosis. Fortunately, the development of drugs that specifically target HER2-positive cells has improved prognosis for women with HER2-positive breast cancer.

Small HER2-positive Cancers

A question that remains uncertain is the need for HER2-targeted therapy among women with small (less than 1 centimeter) HER2-positive breast cancers. To explore the behavior of these small cancers, researchers evaluated the records of 965 women with small cancers that had not been treated with HER2-targeted therapy or chemotherapy.[2]

By the end of five years, 6 percent of women with HER2-negative breast cancer had recurrence compared with 23 percent of women with HER2-positive breast cancer. This study suggests that even small HER2-positive breast cancers have an increased risk of recurrence. Consideration of adjuvant treatment with HER2-targeted therapy may be important for all women with HER2-positive breast cancer regardless of the size of the cancer. It should be noted, however, that this study did not directly assess the effectiveness of HER2-targeted therapy in women with small cancers.

Combination of Tykerb and Femara

Femara® (letrozole) is a type of hormonal therapy known as an aromatase inhibitor. Tykerb® (lapatinib) is a drug that targets two related proteins that often function abnormally in breast cancer cells: HER2 and EGFR.

To evaluate the combination of Tykerb and Femara in the initial treatment of hormone receptor–positive, metastatic breast cancer, researchers conducted a Phase III clinical trial among 1,286 postmenopausal women. Study participants received treatment with Femara alone or Femara plus Tykerb.[3]

In the subset of women who were HER2-positive, progression-free survival was 8.2 months among women treated with Femara plus Tykerb, compared with 3.0 months among women treated with Femara alone. This study suggests that the combination of Tykerb and Femara delays cancer progression among women with HER2-positive, hormone receptor–positive, metastatic breast cancer.

Neoadjuvant Herceptin

Herceptin® (trastuzumab) is a HER2-targeted therapy that has been shown to improve outcomes among women with HER2-positive breast cancer, but the role of Herceptin in neoadjuvant (before surgery) therapy has not been well established.

To evaluate Herceptin in combination with neoadjuvant chemotherapy, researchers conducted a Phase III clinical trial among 228 women with HER2-positive, locally advanced breast cancer.[4] Half the women were given neoadjuvant chemotherapy alone, and half were given neoadjuvant chemotherapy plus Herceptin.

At three years 70.1 percent of women treated with neoadjuvant chemotherapy plus Herceptin were free of cancer recurrence or progression, compared with 53.3 percent of women treated with neoadjuvant chemotherapy alone. This study suggests that the addition of Herceptin to neoadjuvant chemotherapy improves outcomes in women with locally advanced, HER2-positive breast cancer.

Hormonal Therapy

Treatment of hormone receptor–positive breast cancer often involves hormonal therapies that suppress or block the action of estrogen. These therapies include tamoxifen (Nolvadex®) as well as agents known as aromatase inhibitors. Tamoxifen acts by blocking estrogen receptors, whereas aromatase inhibitors suppress the production of estrogen in postmenopausal women.

Aromatase Inhibitors Improve Outcomes

In a combined analysis of previous studies, researchers compared aromatase inhibitors with tamoxifen in the treatment of early, postmenopausal breast cancer.[5] Some of the previous studies compared five years of treatment with an aromatase inhibitor with five years of treatment with tamoxifen; others evaluated the effect of switching to an aromatase inhibitor after two to three years of tamoxifen. In both types of studies, women treated with an aromatase inhibitor had a lower risk of cancer recurrence than women treated with tamoxifen alone.

Gene Influences Tamoxifen Response

Pharmacogenomics refers to the study of how inherited genetic variation influences drug response. In the case of tamoxifen, a gene known as CYP2D6 has been reported to influence response to the drug. CYP2D6 plays a role in activating tamoxifen and many other drugs. Most people have two functional versions of this gene and are able to effectively process tamoxifen. Some people, however, have versions of this gene that are less effective at processing tamoxifen, and these people may derive little benefit from the drug.

The effect of CYP2D6 variants was assessed in a study of postmenopausal women with estrogen receptor–positive breast cancer.[6] Based on CYP2D6 testing, women were classified as “extensive,” “intermediate,” or “poor” metabolizers. Response to tamoxifen was expected to be best among the extensive metabolizers.

Among women who were assigned to five years of adjuvant (post-surgery) treatment with tamoxifen, those who were poor metabolizers were almost four times more likely to develop a cancer recurrence than those who were extensive metabolizers. This higher risk of recurrence among women who were poor metabolizers suggests that tamoxifen was less effective in this group and that other treatment options may need to be considered.

Changes in Breast Density Linked with Tamoxifen Effect

Breast density refers to the extent of glandular and connective tissue in the breast. Breasts with more glandular and connective tissue—and less fat—are denser. Women with higher breast density are at increased risk of developing breast cancer. Breast density can be assessed by mammography.

In a study of tamoxifen for breast cancer prevention, researchers reported that women who experienced reductions in breast density while on tamoxifen appeared to have the greatest reduction in breast cancer risk.[7] Conversely, women who had little reduction in breast density during tamoxifen treatment had a risk of breast cancer that was similar to the risk in women not treated with tamoxifen. The researchers concluded that changes in breast density after 12 to 18 months of treatment with tamoxifen may provide information about which women are benefiting from the drug.

Predicting Risk of Cancer Recurrence

Oncotype DX® is a genomic test that previously has been shown to predict the likelihood of a cancer recurrence, of benefit from chemotherapy, and of survival in patients with newly diagnosed breast cancer that has not spread to their lymph nodes (node-negative) and is estrogen receptor–positive. Oncotype DX evaluates the activity of 21 genes from a sample of the patient’s cancer to determine the patient’s recurrence score. The recurrence score ranges from 0 to 100, with a higher score indicating a greater risk of recurrence. Oncotype DX is covered by several large health insurers and has been added to medical guidelines for early-stage breast cancer.

To evaluate the use of Oncotype DX in a broader group of patients, researchers assessed 1,231 women who participated in the Arimidex, Tamoxifen Alone or in Combination (ATAC) study.[8] The study enrolled postmenopausal women with early, hormone receptor–positive breast cancer and compared two different hormonal therapies: tamoxifen and Arimidex® (anastrozole, an aromatase inhibitor).
Information about distant cancer recurrences was collected over a nine-year period. Among both node-negative and node-positive patients treated with either Arimidex or tamoxifen, higher recurrence scores were linked with a higher risk of distant recurrence. Information about recurrence risk may help guide treatment decisions.

Who Is at Increased Risk of Breast Cancer?

Studies presented at SABCS provided additional information about two breast cancer risk factors: postmenopausal hormone use and benign breast disease.

Estrogen plus Progestin

Previous results from the Women’s Health Initiative (WHI) clinical trials indicated that postmenopausal hormonal therapy with combined estrogen plus progestin increases the risk of breast cancer. In results presented at SABCS, researchers used updated information from the WHI clinical trials as well as information from another component of the WHI—the WHI Observational Study—to further explore the relationship between estrogen plus progestin and risk of breast cancer.[9] The results confirmed that users of estrogen plus progestin were more likely than nonusers to develop breast cancer. This increased risk declined markedly and fairly rapidly, however, once women stopped using hormones.

These analyses support the claim that the recent decreases in breast cancer incidence in the United States may be due to a reduction in the number of women using postmenopausal hormones.

In another study researchers assessed the impact on breast cancer survival of hormone use prior to breast cancer diagnosis.[10] They found that women who used estrogen plus progestin before their breast cancer diagnosis were 47 percent less likely to die of breast cancer. This suggests that breast cancers that develop in users of estrogen plus progestin have a tendency to be less deadly than breast cancers that develop in women who have never used postmenopausal hormones. It must be remembered, however, that breast cancer is also more common in women who use estrogen plus progestin.

Benign Breast Disease

Benign breast disease refers to several types of non-cancerous changes in breast tissue. Three categories of benign breast disease include atypical hyperplasia, proliferative disease without atypia, and non-proliferative disease. In atypical hyperplasia, the number of cells within the ducts or lobules of the breast is increased, and these cells appear abnormal under the microscope. In proliferative disease without atypia, there is also an increase in the number of cells, but the cells appear normal. Finally, in non-proliferative disease, women have fibrocystic changes within the breast but no increase in cell number.

To explore the relationship between benign breast disease and breast cancer among women under the age of 50, researchers evaluated information from more than 4,000 women with benign breast disease.[11] Two percent had been diagnosed with atypical hyperplasia, 26 percent had been diagnosed with proliferative disease without atypia, and 72 percent had been diagnosed with non-proliferative disease.

During 20 years of follow-up, 326 of the women were diagnosed with breast cancer. Atypical hyperplasia carried the greatest risk of breast cancer, followed by proliferative disease without atypia. Compared with women in the general population, risk of breast cancer was more than six times higher among women with atypical hyperplasia and two times higher among women with proliferative disease without atypia. Risk of breast cancer among women with non-proliferative disease was only slightly higher than among women in the general population.

Bone Drugs Continue to Show Benefits

Neoadjuvant Chemotherapy plus Zometa

Zometa® (zoledronic acid) is a bisphosphonate drug that is used for the treatment of cancer-related hypercalcemia (high levels of calcium in the blood) and of bone metastases in patients with advanced cancers. Recent research has focused on the potential anticancer effects of Zometa and the ability of Zometa to prevent treatment-related bone loss among women with early-stage breast cancer.

In a study of women with locally advanced breast cancer, researchers compared neoadjuvant chemotherapy alone to neoadjuvant chemotherapy combined with Zometa.[12] Women who received the combination of neoadjuvant chemotherapy and Zometa experienced more cancer shrinkage than women treated with neoadjuvant chemotherapy alone; median tumor size after treatment was 20.5 mm (millimeters) in the women who received Zometa and 30 mm in the women who did not received Zometa. The researchers concluded that Zometa may have a direct anti-tumor effect on breast cancer when combined with neoadjuvant chemotherapy.

Zometa Prevents Bone Loss in Patients Treated with Femara

Although aromatase inhibitors reduce recurrence risk, they are also linked with bone loss. To evaluate Zometa for the prevention of bone loss among women treated with the aromatase inhibitor Femara, researchers conducted a Phase III clinical trial among postmenopausal women with early, hormone receptor–positive breast cancer.[13] Some women received immediate treatment with Zometa, and others received delayed treatment with Zometa (treatment that began only after bone loss or a fracture occurred).

After three years of follow-up, bone mineral density at the lumbar spine and the hip was increased among women treated with immediate Zometa and decreased among women treated with delayed Zometa. Disease-free survival (survival without cancer recurrence or a new cancer) was also better among women treated with immediate Zometa. Fracture risk was similar in the two groups. The researchers concluded that among women treated with Femara, immediate treatment with Zometa improved bone density and disease-free survival.

Denosumab in Metastatic and Early-stage Breast Cancer

Denosumab is an investigational drug that targets a protein known as the RANK ligand. This protein regulates the activity of osteoclasts (cells that break down bone). Denosumab is being evaluated for the management of bone loss among patients with a variety of conditions, including postmenopausal osteoporosis and cancer treated with certain types of hormonal therapy. The ability of denosumab to delay bone metastases among patients with cancer is also being studied. An application for approval of denosumab has been submitted to the U.S. Food and Drug Administration.

A Phase II clinical trial presented at SABCS evaluated the effect of denosumab among patients with bone metastases and elevated bone resorption levels.[14] All of the patients had previously been treated with a bisphosphonate drug (another class of bone drugs). Patients were assigned to continue with bisphosphonate treatment or to switch to denosumab. In the subset of women with breast cancer (46 patients total), 76 percent of those treated with denosumab achieved a specified reduction in bone resorption, compared with 33 percent of those who continued with bisphosphonate treatment. These results suggest that denosumab has a beneficial effect on bone in breast cancer patients with bone metastases and elevated bone resorption in spite of prior bisphosphonate treatment.

A study of denosumab among women with early-stage breast cancer was also presented at SABCS.[15] The results provide additional evidence that denosumab improves bone density among breast cancer patients treated with an aromatase inhibitor.

References

[1]. Targeted Agents Active Against HER2-positive Breast Cancer: Questions and Answers. National Cancer Institute Web site. Available at: http://www.cancer.gov/newscenter/pressreleases/ALTTOQandA. Accessed December 30, 2008.

[2]. Early Stage, HER2 Positive Breast Cancer Patients at Increased Risk of Recurrence: Largest Study of Its Kind Finds Subset of Women That May Need Additional Therapy [press release]. M. D. Anderson Cancer Center Web site. Available at: http://www.mdanderson.org/departments/newsroom/display.cfm?id=BD7AE450-A5C9-4C64-BD4666C8CA98CE4F&method=displayFull&pn=00c8a30f-c468-11d4-80fb00508b603a14. Accessed December 30, 2008.

[3]. Johnston S, Pegram M, Press M, et al. Lapatinib combined with letrozole vs. letrozole alone for front line postmenopausal hormone receptor positive (HR+) metastatic breast cancer (MBC): First results from the EGF30008 trial. Paper presented at: 31st Annual San Antonio Breast Cancer Symposium; December 10-14, 2008; San Antonio, Texas. Abstract 46.

[4]. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer: Primary efficacy analysis of the NOAH trial. Paper presented at: 31st Annual San Antonio Breast Cancer Symposium; December 10-14, 2008; San Antonio, Texas. Abstract 31.

[5]. Ingle J, Dowsett M, Cuzick J, et al. Aromatase inhibitors versus tamoxifen as adjuvant therapy for postmenopausal women with estrogen receptor positive breast cancer: Meta-analysis of randomized trials of monotherapy and switching strategies. Paper presented at: 31st Annual San Antonio Breast Cancer Symposium; December 10-14, 2008; San Antonio, Texas. Abstract 12.

[6]. Goetz M, Ames M, Gnant M, et al. Pharmacogenetic (CYP2D6) and gene express profiles (HOXB13/IL17BR and molecular grade index) for prediction of adjuvant endocrine therapy benefit in the ABCSG 8 trial. Paper presented at: 31st Annual San Antonio Breast Cancer Symposium; December 10-14, 2008; San Antonio, Texas. Abstract 57.

[7]. Cuzick J, Warwick J, Pinney L, et al. Change in breast density as a biomarker of breast cancer risk reduction: Results from IBIS-1. Paper presented at: 31st Annual San Antonio Breast Cancer Symposium; December 10-14, 2008. Abstract 61.

[8]. Dowsett M, Cuzick J, Wales C. et al. Risk of distant recurrence using Oncotype DX in postmenopausal primary breast cancer patients treated with anastrozole or tamoxifen: A TransATAC study. Paper presented at: 31st Annual San Antonio Breast Cancer Symposium; December 10-14, 2008; San Antonio, Texas. Abstract 53.

[9]. Chlebowski RT, Kuller L, Anderson G. et al. Breast cancer after stopping estrogen plus progestin in the Women’s Health Initiative. Paper presented at: 31st Annual San Antonio Breast Cancer Symposium; December 10-14, 2008; San Antonio, Texas. Abstract 64.

[10]. Marshall SF, Chang E, Clarke CA, et al. Hormone therapy use before diagnosis and breast cancer survival in the California Teachers Study. Paper presented at: 31st Annual San Antonio Breast Cancer Symposium; December 10-14, 2008; San Antonio, Texas. Abstract 65.

[11]. Ghosh K, Pankratz VS, Reynolds CA, et al. Benign breast disease and breast cancer risk in young women. Paper presented at: 31st Annual San Antonio Breast Cancer Symposium; December 10-14, 2008; San Antonio, Texas. Abstract 62.

[12]. Winter MC, Thorpe HC, Burkinshaw R, et al. The addition of zoledronic acid to neoadjuvant chemotherapy may influence pathological response—exploratory evidence for direct anti-tumor activity in breast cancer. Paper presented at: 31st Annual San Antonio Breast Cancer Symposium; December 10-14, 2008; San Antonio, Texas. Abstract 5101.

[13]. Eidtmann H, Bundred NJ, DeBoer R, et al. The effect of zoledronic acid on aromatase inhibitor associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: 36 months follow-up of ZO-FAST. Paper presented at: 31st Annual San Antonio Breast Cancer Symposium; December 10-14, 2008; San Antonio, Texas. Abstract 44.

[14]. Gralow J, Lipton A, Fizazi K, et al. Effects of denosumab treatment in breast cancer patients with bone metastases and elevated bone resorption levels after therapy with intravenous bisphosphonates: Results of a phase 2 randomized trial. Paper presented at: 31st Annual San Antonio Breast Cancer Symposium; December 10-14, 2008; San Antonio, Texas. Abstract 1155.

[15]. Ellis GK, Bone HG, Chlebowski R, et al. A 24-month subgroup analysis of the effect of denosumab on bone mineral density in women with breast cancer undergoing aromatase inhibitor therapy. Paper presented at: 31st Annual San Antonio Breast Cancer Symposium; December 10-14, 2008; San Antonio, Texas. Abstract 2106.

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