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Advances in Breast Cancer Treatment 2008
By Kari Bohlke, ScDThe 31st San Antonio Breast Cancer Symposium (SABCS), held December 10 to 14, 2008, brought together thousands of scientists, physicians, and advocates to discussthe latest research on breast cancer prevention, screening, treatment, and survivorship. Important studies presented at this year’s conference addressed HER2-positivebreast 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 cancercells 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 thebehavior of these small cancers, researchers evaluated the records of 965 women with small cancers that had not been treated with HER2-targeted therapy orchemotherapy.[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 therapymay 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 assessthe 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 functionabnormally 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 IIIclinical 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 monthsamong 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 ofHerceptin 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, locallyadvanced 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 ofwomen treated with neoadjuvant chemotherapy alone. This study suggests that the addition of Herceptin to neoadjuvant chemotherapy improves outcomes in women withlocally 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 ofestrogen 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 ofthe 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 anaromatase 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 thanwomen 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 reportedto 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 toeffectively process tamoxifen. Some people, however, have versions of this gene that are less effective at processing tamoxifen, and these people may derive little benefitfrom 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, womenwere 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 likelyto develop a cancer recurrence than those who were extensive metabolizers. This higher risk of recurrence among women who were poor metabolizers suggests thattamoxifen 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. Womenwith higher breast density are at increased risk of developing breast cancer. Breast density can be assessed by mammography.
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In a study of tamoxifen for breast cancer prevention, researchers reported that women who experienced reductions in breast density while on tamoxifen appeared to havethe 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 wassimilar 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 mayprovide 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 patientswith 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 21genes 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 agreater 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 inCombination (ATAC) study.[8]The study enrolled postmenopausal women with early, hormone receptor–positive breast cancer and compared two different hormonaltherapies: 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 ortamoxifen, 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 increasesthe risk of breast cancer. In results presented at SABCS, researchers used updated information from the WHI clinical trials as well as information from another componentof the WHI—the WHI Observational Study—to further explore the relationship between estrogen plus progestin and risk of breast cancer.[9]The results confirmed thatusers of estrogen plus progestin were more likely than nonusers to develop breast cancer. This increased risk declined markedly and fairly rapidly, however, once womenstopped 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 usingpostmenopausal 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 usedestrogen 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 ofestrogen plus progestin have a tendency to be less deadly than breast cancers that develop in women who have never used postmenopausal hormones. It must beremembered, 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, andthese 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 4,000women with benign breast disease.[11]Two percent had been diagnosed with atypical hyperplasia, 26 percent had been diagnosed with proliferative disease withoutatypia, 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 proliferativedisease without atypia. Compared with women in the general population, risk of breast cancer was more than six times higher among women with atypical hyperplasia andtwo times higher among women with proliferative disease without atypia. Risk of breast cancer among women with non-proliferative disease was only slightly higher thanamong 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 bonemetastases 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 neoadjuvantchemotherapy 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 receivedZometa. 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 withthe 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 fractureoccurred).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 amongwomen treated with delayed Zometa. Disease-free survival (survival without cancer recurrence or a new cancer) was also better among women treated with immediateZometa. Fracture risk was similar in the two groups. The researchers concluded that among women treated with Femara, immediate treatment with Zometa improved bonedensity 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 treatedwith 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 ofdenosumab 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 thepatients had previously been treated with a bisphosphonate drug (another class of bone drugs). Patients were assigned to continue with bisphosphonate treatment or toswitch 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
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Advances in Breast Cancer Treatment 2008
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