Just a few weeks after the presentation of the early ATAC trial results, anastrozole was rapidly incorporated into the adjuvant setting. In some clinical situations, almost half of oncologists surveyed state that they are utilizing adjuvant anastrozole. While some physicians may propose letrozole or exemestane, the vast majority employing an adjuvant aromatase inhibitor prefer anastrozole.

Also note that while almost all of these women with ER-positive disease receive some form of endocrine therapy, a significant minority of oncologists would not prescribe endocrine therapy for elderly, low-risk women.

Pharmacokinetics of anastrozole and tamoxifen alone and in combination during adjuvant endocrine therapy for early breast cancer in postmenopausal women: A sub-protocol of the “Arimidex® and Tamoxifen Alone or in Combination” (ATAC) trial. Br J Cancer 2001;85(3):317-324. Abstract

Baum M. The ATAC (Arimidex, Tamoxifen, Alone or in Combination) adjuvant breast cancer trial in post-menopausal women. Breast Cancer Res Treat 2001;69(3): Abstract 8.

Buzdar AU. Anastrozole (Arimidex) —- an aromatase inhibitor for the adjuvant setting? Br J Cancer 2001;85(2 suppl):6-10. Abstract

Goss PE. Preliminary data from ongoing adjuvant aromatase inhibitor trials. Clin Cancer Res 2001;7(12 suppl):4397s-4401s. Abstract

Almost two-thirds of the Miami Breast Cancer Conference attendees believe that in 2002, anastrozole will be utilized a great deal as adjuvant endocrine therapy for postmenopausal breast cancer patients. Faculty members Drs Richard Margolese and Patrick Borgen concur with this belief. Of note, nearly 20% believe anastrozole will almost completely replace tamoxifen in these patients this year.

This viewpoint was confirmed in physicians’ predictions for clinical practice thre e years from now, with nearly three-quarters stating that anastrozole will be the most commonly utilized adjuvant endocrine therapy. Interestingly, there is a lack of support of the other aromatase inhibitors as adjuvant therapy. This is likely to continue until compelling, randomized clinical trial data become available for these agents.

Nicholls H. Aromatase inhibitors continue their ATAC on tamoxifen. Trends Mol Med 2002; 8 (4):S12-3. Abstract

With the increased use of chemotherapy in women with invasive breast cancer, many surgeons routinely refer patients for evaluation by a medical oncologist. However, it is also a common practice for surgeons to initiate adjuvant endocrine therapy with tamoxifen. The patterns of care survey demonstrates that this practice is also likely to occur with adjuvant aromatase inhibitors in postmenopausal patients. Surgeons are more likely to initiate adjuvant endocrine therapy in lower-risk patients, who are less likely to receive adjuvant chemotherapy. Almost one-third of Surgeons would manage an older patient with a small, node-negative tumor without referral to a medical oncologist.

Baum M. The ATAC (Arimidex, Tamoxifen, Alone or in Combination) adjuvant breast cancer trial in post-menopausal women. Breast Cancer Res Treat 2001;69(3): Abstract 8.

Buzdar AU. Anastrozole (Arimidex) — an aromatase inhibitor for the adjuvant setting?
Br J Cancer 2001;85(2 suppl):6-10. Abstract.

Nearly all physicians would recommend some form of adjuvant endocrine therapy for premenopausal women with ER-positive cancers, and tamoxifen remains the common choice. Only a small fraction of physicians utilize LHRH agonists or surgical oophorectomy despite findings from an international meta-analysis demonstrating a significant survival advantage for this intervention. A small fraction of oncologists recommend aromatase inhibitors for premenopausal women; however, these agents are only indicated for postmenopausal women. The encouraging early results of the ATAC trial in postmenopausal patients has led to the development of new randomized clinical studies evaluating LHRH agonists plus aromatase inhibitors in premenopausal patients with ER-positive tumors. Until results from these studies a re available, most clinical researchers generally do not advocate the nonprotocol use of this combined approach .

Ovarian ablation for early breast cancer. Early Breast Cancer Trialists’Collaborative Group. Cochrane Database Syst Rev. 2000:CD000485. Abstract

Davidson NE. Ovarian ablation as adjuvant therapy for breast cancer. J Natl Cancer Inst Monogr 2001;30:67-71. Full Text

A widely quoted study by Harvey et al found that even those breast cancer patients with 1-2% of cells with weak tumor ER staining benefit from adjuvant hormonal therapy. All red has questioned the quality control for the performance of this assay and assay interpretation by clinicians managing breast cancer patients. While half of responding oncologists treat breast cancers as ER-positive if they have any staining on immunohistochemistry, another half utilize a laboratory-defined cut-off for this definition.

A common algorithm for determining HER2 status, which is supported by the NCCN, accepts an immunohistochemistry score of 3+ as positive, but recommends FISH testing in tumors with an IHC score of 2+. This approach is reflected in data from the oncologists’ survey. Only 35% commonly obtain FISH testing in their patients.

Harvey JM et al. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 1999;17:1474-81. Abstract

Perez EA et al. HER2 testing in patients with breast cancer: Poor correlation between weak positivity by immunohistochemistry and gene amplification by fluorescence in situ hybridization. Mayo Clin Proc 2002;77(2):148-54. Abstract

Choice of Adjuvant Chemotherapy

Miami meeting attendees: Do you think six cycles of FAC is more effective than four cycles of AC? Oncologists: Which adjuvant chemotherapy regimen would you use in the following 43-year-old women with ER-negative, HER2-negative breast cancer?

There was considerable discussion at the 2000 NIH Consensus Conference on the benefits of 4 cycles of AC chemotherapy compared to a longer duration. Dr Gabriel Hortobagyi argued that indirect evidence supported the use of a longer duration, but the Consensus statement reflected that there was inadequate data to make this a standard recommendation.

Although a large proportion of physicians (including Drs Miller and Mamounas) believe that 6 cycles of FAC is more effective than 4 cycles of AC, the addition of a taxane to the AC regimen was a more common treatment choice. Clearly, in the higher-risk patient, the vast majority of physicians believed AC chemotherapy to be inadequate treatment.

National Institutes of Health Consensus Development Conference statement: Adjuvant therapy for breast cancer, November 1-3, 2000. J Natl Cancer Inst Monogr 2001;(30):5-15. Abstract

Aapro MS. Adjuvant therapy of primary breast cancer: A review of key findings from the 7th international conference, St. Gallen, February 2001. Oncologist 2001;6(4):376-85. Abstract

Hortobagyi GN. Progress in systemic chemotherapy of primary breast cancer: An overview. J Natl Cancer Inst Monogr 2001;(30):72-9. Abstract

Shulman LN. What is the ideal duration of adjuvant therapy for primary breast cancer: Are four cycles of cyclophosphamide and doxorubicin enough? Curr Oncol Rep 2001;3(6):523-8. Abstract

Although the 2000 NIH Consensus Conference on adjuvant therapy of early breast cancer did not reach a consensus on the issue of adjuvant taxanes, community practitioners use adjuvant taxanes frequently, especially in women with high-risk tumors. The impact of age appears to be greatest in the women with intermediate risk, with 60% of oncologists treating a 43-year-old woman with a 2.2 cm tumor and 2+ nodes with taxanes, while only 35% would treat the 65-year-old with similar risk. The impact of ER status appears negligible, despite an unplanned re t rospective subset analysis in a large Interg roup trial demonstrating less benefit of paclitaxel in women with ER-positive than ER-negative tumors.

Mamounas EP, Sledge GW Jr. Combined anthracycline-taxane regimens in the adjuvant setting. Semin Oncol 2001;28(4 Suppl 12):24-31. Abstract

Nabholtz JM, Riva A. The choice of adjuvant combination therapies with taxanes: Rationale and issues addressed in ongoing studies. Clin Breast Cancer 2001;2 Suppl 1:S7-S14. Abstract

Norton L. Theoretical concepts and the emerging role of taxanes in adjuvant therapy. Oncologist 2001;6 Suppl 3:30-5. Abstract

Piccart MJ et al. Taxanes in the adjuvant treatment of breast cancer: Why not yet? J Natl Cancer Inst Monogr 2001;(30):88-95. Abstract

Sparano JA. Taxanes for breast cancer: An evidence-based review of randomized phase II and phase III trials. Clin Breast Cancer 2000:32-40. Abstract

Most physicians state that they do not believe that decisions regarding whether to use adjuvant chemotherapy or endocrine therapy should be influenced by HER2 status of the patient’s tumor. However, there is a significant tendency for oncologists to choose less aggressive or no cytotoxic therapy in patients who have HER2-negative as opposed to HER2-positive tumors. Anthracycline-based chemotherapy is routinely utilized in women with both HER2-positive and HER2-negative cancers as adjuvant therapy. Choice of endocrine therapy, particularly tamoxifen, is not influenced by HER2 status, which is consistent with the lack of conclusive evidence on this question in a variety of clinical trials.

Piccart M et al. The predictive value of HER2 in breast cancer. Oncology 2001;61 Suppl 2:73-82. Abstract

Ravdin PM. Is her2 of value in identifying patients who particularly benefit from anthracyclines during adjuvant therapy? A qualified yes. J Natl Cancer Inst Monogr 2001;30:80-4. Abstract

Sledge GW Jr. Is HER-2/neu a predictor of anthracycline utility? No. J Natl Cancer Inst Monogr 2001;30:85-7. Abstract

The risks and benefits of adjuvant trastuzumab are currently under investigation in several large, randomized clinical trials. Most breast cancer research leaders believe that this intervention should only be utilized in a research setting. However, when presented with a young patient at high risk for recurrence because of multiple positive nodes, about half of physicians would use adjuvant trastuzumab if the tumor were HER2-positive. This practice seems to apply to patients with both ER-positive and ER-negative tumors. A small but significant number of physicians would also utilize trastuzumab in lower-risk women.

Leyland-Jones B, Smith I. Role of Herceptin in primary breast cancer: Views from North America and Europe. Oncology 2001;61 Suppl 2:83-91. Abstract

Nabholtz JM, Slamon D. New adjuvant strategies for breast cancer: Meeting the challenge of integrating chemotherapy and trastuzumab (Herceptin). Semin Oncol 2001;28(1 Suppl 3):1-12. Abstract

Slamon D, Pegram M. Rationale for trastuzumab (Herceptin) in adjuvant breast cancer trials. Semin Oncol 2001;28(1 Suppl 3):13-9. Abstract

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