BreastCancerUpdate.com - Surgeons 1

Tracks 1-19

Track 1	Introduction
Track 2	Overview of adjuvant aromatase inhibitors in postmenopausal patients
Track 3	Efficacy of aromatase inhibitors versus tamoxifen
Track 4	Survival benefit of aromatase inhibitors versus tamoxifen
Track 5	Endometrial changes associated with tamoxifen
Track 6	Impact of aromatase inhibitors on bone density
Track 7	Vasomotor symptoms and vascular toxicities associated with tamoxifen
Track 8	Arthralgias associated with aromatase inhibitors
Track 9	Clinical implications of the adjuvant aromatase inhibitor trials
Track 10	Aromatase inhibitors combined with LHRH agonists for premenopausal patients

Track 11	Oncotype DX assay and benefits of adjuvant chemotherapy
Track 12	Use of the Oncotype DX assay in clinical practice
Track 13	Clinical trials of adjuvant trastuzumab for HER2-positive breast cancer
Track 14	BCIRG 006: Adjuvant trial of docetaxel/carboplatin/ trastuzumab
Track 15	TOPO II assay in patients with HER2-positive disease
Track 16	Delayed adjuvant trastuzumab for patients with HER2-positive disease
Track 17	Combining trastuzumab with dose-dense chemotherapy
Track 18	Adjuvant trastuzumab for patients with node-negative breast cancer
Track 19	Single-agent trastuzumab as adjuvant therapy for elderly patients

Select Excerpts from the Interview

Track 3

DR LOVE: Could you discuss the efficacy findings of the aromatase inhibitors compared to tamoxifen?

DR MACKEY: We’re excited to see all of the adjuvant aromatase inhibitor trials are showing that disease-free survival is improved (Howell 2005; Jonat 2005). Roughly one in five to one in three recurrences are prevented by the use of an aromatase inhibitor rather than a standard tamoxifen regimen for five years.

DR LOVE: Of course, that’s also with tamoxifen lowering the relapse rate significantly compared to no endocrine therapy.

DR MACKEY: Exactly. Tamoxifen is actually a very effective drug. It reduces the risk of recurrence by about 50 percent. The aromatase inhibitors are providing a benefit in addition to that one half improvement in risk.

Track 4

DR LOVE: What’s been seen in terms of the overall survival of women on aromatase inhibitors versus tamoxifen in the adjuvant setting?

DR MACKEY: With long-term follow-up of the women on these aromatase inhibitor trials, we’re starting to obtain a hint that survival might also be improved. It’s beginning to look as though the trend is there in a couple of trials and one meta-analysis ( Jonat 2005; [3.1]).

Track 11

DR LOVE: Would you talk about the Oncotype DX assay and how it can be integrated into the management plan for a patient with an ER-positive tumor?

DR MACKEY: The Oncotype DX assay is the best example we have of taking our understanding of the biology of breast cancer and trying to make predictions about the behavior of that tumor in the future. It falls into the class of tests we call predictive assays. Whereas a prognostic assay would tell a health-care provider or a patient the odds of having a negative outcome, a predictive assay helps in deciding how to manage a person’s disease.

A predictive assay tells you, although your prognosis may be such, if we treat with a specific therapy, we can change that prognosis, and this specific therapy is the right therapy for you. Hence, predictive assays are extremely valuable, and prognostic assays are “a dime a dozen.”

If you have a woman for whom you’re trying to make a treatment decision and you’re not clear whether she warrants chemotherapy or whether hormone therapy is enough with an estrogen receptor-positive tumor, you can take the woman’s tumor block and send it away for a central laboratory analysis. They analyze the levels of several different genes and send you back an Oncotype DX score.

The score you receive reflects the spectrum of possible biologic behaviors of the breast cancer, whether it will be highly endocrine sensitive or less sensitive to endocrine manipulation, in which case you might strongly consider chemotherapy. The Oncotype DX assay is a state-of-the-art technique, and you can determine from the assay results those women who would benefit from chemotherapy in addition to tamoxifen. Although I’m hopeful that we can fully validate this assay and perhaps even improve on it, and I do think it’s a major step forward, I would like to see a little bit more validation and a comparison with good quantitative estrogen receptor and HER2 assessment.

Track 13

DR LOVE: Can you review the key findings of recent trials evaluating adjuvant trastuzumab?

DR MACKEY: This is the most exciting story that has happened in my career of treating breast cancer. Trastuzumab is an antibody treatment directed at the HER2 protein, which is found on the surface of breast cancer cells. HER2-overexpressing breast cancers are seen in about one out of five breast cancers.

Trastuzumab for advanced breast cancer was a big breakthrough in 1998. Now we have five studies reporting that if you administer adjuvant trastuzumab to a woman who has a HER2-driven breast cancer, her chances of having a recurrence are markedly reduced (Romond 2005; Piccart-Gebhart 2005; Slamon 2005).

In general, if we put them all together and average the effects, a 50 percent reduction in the risk of recurrence exists in any given year.

From the results of the HERA trial, which was conducted primarily in Europe, we know that utilizing adjuvant trastuzumab for one year after chemotherapy reduces the risk of recurrence by about half (Piccart-Gebhart 2005).

The American trials took advantage of what we knew from the metastatic setting, which was that trastuzumab worked best if you administered it with chemotherapy; therefore, the North American trials combined trastuzumab with a taxane-based chemotherapy regimen.

The NSABP and the NCCTG trials administered AC for four cycles followed by paclitaxel, and patients were randomly assigned to receive paclitaxel with or without trastuzumab. AC followed by a taxane with trastuzumab outperformed AC followed by a taxane.

The effect was remarkably robust, a 50 percent reduction in recurrence and, in addition, a hint of improved overall survival, even though the median follow up of those trials is only about two years (Romond 2005).

The Breast Cancer International Research Group (BCIRG) ran another adjuvant trastuzumab trial (BCIRG 006) with 3,200 patients. We knew from the metastatic setting there was a potential for heart damage when you administered doxorubicin or epirubicin with trastuzumab. There was concern that if we administered AC and then followed it with trastuzumab, we would run into cardiac problems. In the NSABP-B-31 and NCCTG-N9831 trials, the heart failure rate was about 2.5 to 4.1 percent.

The design of BCIRG 006 included AC followed by docetaxel for four cycles as the standard arm. The second arm was AC followed by docetaxel with trastuzumab, and the third arm was actually the most interesting and novel — it discarded the anthracycline entirely and relied purely on docetaxel/carboplatin and trastuzumab (TCH), all given from day one of chemotherapy.

At the 2005 San Antonio Breast Cancer Symposium, Dennis Slamon, who designed this study, presented its first results. We saw, in the second arm, a 50 percent reduction in recurrence. So ACTH with docetaxel instead of paclitaxel was a very effective regimen. In the third arm, we found about a 40 percent reduction in the risk of recurrence with TCH. The interesting thing was we had virtually no congestive heart failure in the third arm (Slamon 2005).

Select publications