You are here: Home: BCU 6 | 2006: Marc E Lippman, MD

Tracks 1-11
Track 1 Introduction
Track 2 Development of therapies targeting apoptotic pathways
Track 3 Identification of predictors of response to chemotherapy and targeted therapies
Track 4 Classification of breast cancer based on molecular profile
Track 5 Utility of the Oncotype DX™ assay and other discriminant models in breast cancer
Track 6 Effectiveness of chemotherapy based on hormone receptor status
Track 7 Topoisomerase II-alpha (TOPO II) gene amplification as a predictor of response to anthracycline-containing chemotherapy in BCIRG 006
Track 8 Effectiveness of trastuzumab in patients coamplifying HER2 and cMYC
Track 9 Potential mechanisms of action of bevacizumab
Track 10 Identification and therapeutic targeting of mutations in cancer
Track 11 Barriers to the continued development of cancer therapeutics and technologies

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Track 2

Arrow DR LOVE: Jenny Chang did some fascinating work with trastuzumab in the neoadjuvant setting showing that apoptosis was a big part of its antitumor effect (Mohsin 2005; [1.1]). Overall, what do we know about how trastuzumab works?

Arrow DR LIPPMAN: Some conflicting data exist on the mechanisms of action of trastuzumab. One thing that seems fairly certain is that it interferes with the signaling of the EGF receptor family on the cell surface.

Trastuzumab is an antibody to HER2. By interfering with that receptor, it blocks the intracellular signaling from that receptor, which is, in effect, a growth factor signal to the cell. Therefore, the cell is unable to continue its normal proliferative process and commonly undergoes apoptotic cell death.

Track 6

Arrow DR LOVE: What are your thoughts on the issue of response to chemotherapy based on estrogen-receptor status?

Arrow DR LIPPMAN: Almost 30 years ago, we published, in The New England Journal of Medicine, that patients with ER-negative disease responded more frequently to chemotherapy (Lippman 1978) than patients with ER-positive disease. Those data have been replicated in the meta-analyses conducted in England by Sir Richard Peto and his collaborators (EBCTCG 2005).

The clue as to why that occurs is obtained if you observe recurrence rates for women with breast cancer as a function of whether their disease is ER-positive or ER-negative. It is commonly said, but that doesn’t necessarily make it the truth, that having ER-positive disease is a good prognostic factor. The data show — and this has now been shown several times — that early on, if your disease is ER-positive, your relapse rates are lower.

Over time, the patients with ER-negative disease who relapse at a higher rate initially stop relapsing, perhaps because most of the ones with bad prognoses have already died, whereas the patients with ER-positive disease continue to relapse, and those lines actually cross. At about 10 to 15 years, you’re worse off having ER-positive than ER-negative disease.

Biologically, that probably means ER-positive tumors are growing more slowly. Therefore, the whole story of why chemotherapy works a little better is probably based on the fact that ER-negative tumors have a slightly higher cycling rate and are faster growing. A wealth of data suggests they’re a little more sensitive to chemotherapy.

Tracks 7, 8

Arrow DR LOVE: What was your impression of Dennis Slamon’s presentation at the 2005 San Antonio Breast Cancer Symposium from the BCIRG 006 trial, specifically the data on TOPO II?

Arrow DR LIPPMAN: These were very exciting data, which I hope are substantiated. It makes biological sense — TOPO II is a target for doxorubicin. That would potentially explain which subsets of patients gained particular advantage from the doxorubicin combinations compared to the platinum combinations (Slamon 2005; [1.2]).

I’m not ready to draw the conclusion that Professor Slamon seemed to want to draw, which is that in those patients who did not overexpress TOPO II, the use of a nondoxorubicin-containing combination was as efficacious (Slamon 2005).

That may be true, but I’m not there yet. I believe we need more analysis. Given the additional cardiac risks of using trastuzumab with doxorubicin, particularly in older women, it would be nice to have a less cardiotoxic regimen to use.

In that same regard, I found the data Soon Paik presented from the NSABP on cMYC overexpression (Kim 2005; [1.3]) extremely exciting and, once again, biologically plausible.

cMYC is an oncogene that is generally upregulated when cells are stimulated to grow; it is part of the growth response. When cMYC is overexpressed in tumors, it can transform other cells to become cancerous, and it is clearly overexpressed in about 20 to 25 percent of human breast cancer cases.

The question is, why is it that many patients with tumors that unquestionably overexpress HER2 do not respond to trastuzumab? Even in previously untreated patients, the response rates are only about 35 percent.

Dr Paik’s data showed rather conclusively that only in those patients whose tumors coexpressed cMYC and HER2 was a response to trastuzumab seen (Kim 2005; [1.3]). Those data must be replicated, but if that is the case, this observation would be tremendously insightful.

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Editor’s Note:
Reality check

Marc E Lippman, MD
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C Kent Osborne, MD
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I Craig Henderson, MD
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Charles E Geyer Jr, MD
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Frank A Vicini, MD
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Miami Beach Cancer Conference Tumor Panel Discussion on Systemic Therapy of Metastatic Disease
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