Tracks 1-20

Track 1 Efficacy and side effects of the HER2 antibody-cytotoxic drug conjugate T-DM1 Track 2 Case discussion: A patient with trastuzumab-refractory, HER2- positive mBC who experienced a durable, near-complete remission with T-DM1 Track 3 Rationale for continuation of biologic therapies upon metastatic disease progression Track 4 Forecast role of T-DM1 in the clinical algorithm for HER2- positive mBC Track 5 Pertuzumab: A first-in-class HER dimerization inhibitor Track 6 Tolerability and side effects of orally administered TKIs Track 7 Pilot study of adjuvant AC paclitaxel/sorafenib in patients with high-risk BC Track 8 Clinical trial experience with weekly and every three-week T-DM1 Track 9 Lack of cardiac toxicity associated with adding bevacizumab to three docetaxel-based adjuvant regimens: TCH, AC docetaxel and TAC Track 10 Cardiac monitoring of patients receiving adjuvant chemotherapy/ trastuzumab Track 11 Typhlitis associated with anthracycline/taxane regimens in combination with bevacizumab Track 12 Role of adjuvant docetaxel/ cyclophosphamide (TC) for early BC Track 13 Use of Oncotype DX for patients with node-positive, ER/PR-positive early BC Track 14 Pathologic CR rate and SPARC tumor correlatives from a Phase II neoadjuvant trial of gemcitabine, epirubicin and nanoparticle albumin-bound (nab) paclitaxel Track 15 Lack of steroid premedication and hypersensitivity reactions with nab paclitaxel Track 16 Mechanism of action of the epothilone analog ixabepilone Track 17 Rationale for TITAN: A Phase III trial of adjuvant AC followed by ixabepilone versus paclitaxel for triple-negative BC Track 18 Potential role for bevacizumab in the treatment of triple-negative BC Track 19 Capecitabine with or without ixabepilone in triple-negative BC: Pooled analysis of two Phase III trials Track 20 Paclitaxel/bevacizumab as first-line therapy for patients with mBC

Select Excerpts from the Interview

Tracks 1, 4

DR LOVE: You are coauthor of a study presented at San Antonio on trastuzumab-DM1 (T-DM1). Can you comment?

DR BURRIS: I was a skeptic about the idea that a cytotoxic agent could be linked to an antibody, retained with the antibody and then delivered to the cancer cells. We have tried this a few times through the years without success. In T-DM1 the cytotoxic agent is mertansine. Maytansine was the parent compound, and this is a derivative. We knew that the maytansine compounds were extremely active but too toxic. With T-DM1, we did not see pancytopenia, hair loss or other classic toxicities associated with maytansine. However, we did observe transient changes in platelet counts, which were probably an immunologic effect.

In the Phase II trial, the median time on prior trastuzumab was approximately 76 weeks, and the response rates to T-DM1 were 30 to 40 percent among patients with previously treated, HER2-positive metastatic disease (Vukelja 2008).

DR LOVE: Where do you see T-DM1 heading?

DR BURRIS: T-DM1 is moving forward, and I believe that in a year it will be utilized as second-line therapy. The data from this study are so promising that a randomized trial (NCT00679341) has recently been initiated comparing T-DM1 to trastuzumab/docetaxel as first-line therapy for HER2-positive metastatic disease.

Track 9

DR LOVE: Would you discuss your group’s study headed by Denise Yardley evaluating the addition of bevacizumab to three different docetaxel-containing adjuvant regimens?

DR BURRIS: The idea was to take the docetaxel-containing regimens that were becoming standards — such as TCH (docetaxel/carboplatin/trastuzumab) — and add the VEGF inhibitor bevacizumab. The goal of our trial was to provide safety data for the BETH study and other trials.

We presented preliminary results at ASCO 2008 (Hart 2008), and the report at San Antonio was a follow-up confirmation. We treated 75 patients with bevacizumab in combination with the following regimens: TCH, AC docetaxel or TAC (docetaxel/doxorubicin/cyclophosphamide; Yardley 2008a; [3.1]). With TCH and bevacizumab, the main concern was cardiac toxicity. We didn’t have any problems — only two of 75 patients showed declines in their ejection fractions (Yardley 2008a).

As we proceed into adjuvant trials with bevacizumab, the results improve with regard to cardiac toxicity because nurses and doctors are becoming internists and are treating hypertension. We no longer have hypertension problems with bevacizumab because we administer ACE inhibitors and diuretics earlier.

Tracks 14-15

DR LOVE: Would you discuss your neoadjuvant study presented at the 2008 SABCS meeting?

DR BURRIS: The neoadjuvant trial involved an aggressive regimen of gemcitabine in combination with epirubicin and nanoparticle albumin-bound (nab) paclitaxel administered as a dose-dense, every other-week approach.

Our pathologic complete response (CR) rate in the breast and lymph nodes was 18 percent. These were patients with initially unresectable or difficult to resect tumors (Yardley 2008b). This was an interesting result. We used pegfilgrastim support, and the toxicity was manageable. We also evaluated the patients’ SPARC status, and a trend toward a higher pathologic CR rate was recorded among the patients with SPARC-positive disease (Yardley 2008b).

DR LOVE: What benefits do you believe nab paclitaxel provides?

DR BURRIS: Not having to use steroids is attractive, particularly for patients with diabetes or other preexisting conditions. The second benefit is being able to administer the drug without fear of a hypersensitivity reaction. They’re uncommon, but in a busy clinic such as ours, we see one every few weeks.

DR LOVE: What about the potential for increased efficacy?

DR BURRIS: In the trial comparing it to paclitaxel in metastatic disease, the response rate and time to progression were better (Gradishar 2005). In Bill Gradishar’s follow-up randomized Phase II study, weekly nab paclitaxel appears to carry a preferential advantage compared to docetaxel (Gradishar 2007; [3.2]).

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EDITOR
Neil Love, MD

INTERVIEWS

Harold J Burstein, MD, PhD
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Jack Cuzick, PhD
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Howard A Burris III, MD
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Mark D Pegram, MD
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