Breast Cancer Update 2

You are here: Home: BCU 2 | 2008: Roundtable Discussion

Roundtable Discussion

Tracks 1-18

Track 1	Updated results of the EBCTCG Overview
Track 2	EBCTCG: Declining rates of mortality associated with breast cancer
Track 3	EBCTCG: Influence of ER status on the efficacy of adjuvant chemotherapy
Track 4	Retrospective analysis of SWOG-8814 tumor blocks using Oncotype DX
Track 5	Clinical indications for Oncotype DX in patients with early node-positive breast cancer
Track 6	Meta-analysis of adjuvant trials with high-dose chemotherapy
Track 7	Adjuvant TC versus AC: Updated results of the US Oncology clinical trial
Track 8	Role of adjuvant anthracyclines according to HER2 status
Track 9	Adjuvant chemotherapy selection for patients with node-positive breast cancer

Track 10	ECOG-E2100: VEGF genetic polymorphisms and clinical outcomes
Track 11	Cardiac safety of adjuvant bevacizumab with dose-dense ACnab paclitaxel
Track 12	Lack of need for steroid premedication with nab paclitaxel
Track 13	Efficacy associated with nab paclitaxel compared to paclitaxel and docetaxel
Track 14	ECOG-E2104: A Phase II adjuvant trial of bevacizumab and dose-dense ACpaclitaxel in women with node-positive breast cancer
Track 15	ECOG-E5103: Adjuvant ACpaclitaxel with or without bevacizumab
Track 16	ATLAS trial: Five versus 10 years of adjuvant tamoxifen
Track 17	Continuation of adjuvant tamoxifen beyond five years in premenopausal women
Track 18	Continuation of an adjuvant aromatase inhibitor beyond five years in postmenopausal women

Select Excerpts from the Interview

Track 10

DR LOVE: Kathy, would you comment on the analysis of ECOG-E2100 with regard to VEGF genetic polymorphisms and the effects of bevacizumab?

DR MILLER: We have been struggling with how to identify patients most likely to benefit from bevacizumab — or any other anti-VEGF therapy. We realized that five polymorphisms are in the VEGF ligand, the VEGF-A gene, that somehow decrease VEGF signaling.

Eleven polymorphisms of the VEGF receptor 2 gene are unstudied, but at least one of them, according to computer modeling, affects the ATP binding domain, so one would expect it to have a significant impact on function.

When tumor blocks collected in the E2100 study were examined, two polymorphisms of the VEGF ligand were identified that seem to clearly influence the risk of toxicity, particularly hypertension (Schneider 2007). Patients who had neither polymorphism and who were homozygous for wild-type VEGF had a low rate of hypertension — in the single digits — whereas patients who were homozygous for one or both of those polymorphisms bore a risk of 40 percent or more.

DR LOVE: Is there a relationship between hypertension and tumor response?

DR MILLER: We haven’t found a relationship between hypertension and response. A different VEGF polymorphism in the E2100 data, however, effects or predicts improved overall survival in the bevacizumab-treated group.

It’s not purely a prognostic factor — it had no influence on overall survival in the paclitaxel-alone group, but it strongly predicted improved overall survival in the combination-therapy group, with a nice demonstration of a gene-dose effect.

We believe these polymorphisms are important and may help us predict which patients will have better outcomes with bevacizumab, and perhaps other VEGF-targeted therapies, and which patients may bear a greater risk of toxicity. We are still examining more samples and other polymorphisms, but we are sufficiently encouraged to include collecting genomic DNA in the adjuvant trial for this type of analysis.

DR HUDIS: I find these data exciting. Although they don’t predict the benefits of bevacizumab, being prepared to manage toxicities with this agent — and maybe even the class of tyrosine kinase inhibitors (TKIs) — will be important.

We have data on 75 patients treated with dose-dense AC followed by nab paclitaxel, all combined with bevacizumab in the adjuvant setting. I’m tempted to apply this analysis to that data set.

DR LOVE: What have you seen so far in this adjuvant trial?

DR HUDIS: It’s a safety study, and the data are still maturing because some patients are still completing the year of bevacizumab. At this point, we have seen reasonable tolerance of this regimen, with a modest incidence of hypertension and proteinuria (McArthur 2007; [4.1]).

The detailed cardiac safety analysis is forthcoming. At this moment, it appears to be no more toxic than one would expect of an anthracycline-based regimen.

Tracks 12-13

DR LOVE: Cliff, in your experience using paclitaxel and nab paclitaxel, how much difference does it make to patients not to receive premedication with steroids?

4.1

DR HUDIS: Patients like not receiving the steroids. They sleep better and experience less aggravation. However, I don’t believe nab paclitaxel is globally less toxic than conventional paclitaxel.

DR LOVE: How does the efficacy of nab paclitaxel compare to docetaxel or paclitaxel?

DR HUDIS: Bill Gradishar reported on a randomized Phase II trial comparing three different schedules of nab paclitaxel to docetaxel (Gradishar 2006; [4.2]). This was a regimen-finding study, and it’s my understanding that they will pick the winner to compare to docetaxel in a Phase III study.

Andrew Seidman is conducting a randomized Phase II trial with three different regimens of nab paclitaxel — the standard regimen administered every three weeks versus a dose-dense, full dose administered every two weeks versus a weekly schedule. Those data are forthcoming and may be reported at ASCO in 2008.

4.2

I don’t expect a different formulation of a taxane will represent a dramatic change in outcomes for patients with breast cancer. We spent many years comparing docetaxel and paclitaxel, but the randomized clinical trials in the adjuvant setting, for example, don’t show much difference. I imagine the nab paclitaxel story will play out similarly.

Track 14

DR LOVE: Kathy, would you discuss the ECOG-E2104 study of bevacizumab in the adjuvant setting?

DR MILLER: This trial was designed to ensure that no prohibitive toxicity was associated with adding bevacizumab to an anthracycline-and taxane-based adjuvant regimen. We were particularly interested in cardiotoxicity. Although few data exist on the concurrent use of bevacizumab and anthracyclines, the data that are available raise the question of whether such use might increase the risk of cardiomyopathy and congestive heart failure.

The E2104 trial compares our preferred option of administering the bevacizumab concurrently with all of the chemotherapy to the sequential option, in which patients receive AC followed by bevacizumab with paclitaxel. Patients are enrolled sequentially — not randomly assigned — so we can’t directly compare the two arms.

4.3

However, if you examine the points in time for which we have relatively similar amounts of follow-up and data, the results appear similar between these two groups, and we have seen no prohibitive toxicities (Miller 2007; [4.3]).

Track 15

DR LOVE: Can you discuss the design of ECOG-E5103?

DR MILLER: Although this trial appears complicated, the simple version is AC followed by weekly paclitaxel versus that same chemotherapy with bevacizumab versus the same chemotherapy with bevacizumab followed by an additional six months of bevacizumab as maintenance (4.4).

The trial allows the patient and her physician to choose whether to receive AC in a dose-dense or an every three-week fashion. Also, a placebo was mandated, so patients who are not receiving bevacizumab will receive a placebo during the chemotherapy in a double-blinded fashion. When patients complete chemotherapy, they’ll all be unblinded and either be finished with treatment or, if they are in the third arm, they’ll be asked to continue the bevacizumab for another six months.

I’m excited about this study. To make it more palatable to patients and their physicians, it’s a one-to-two-to-two randomization. Thus, patients have a four-out-of-five likelihood of receiving bevacizumab for at least some duration.

4.4