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Small, Node-Negative Tumors

DR HUDIS: In the adjuvant trastuzumab trials, we accrued patients with HER2-positive tumors larger than one centimeter, in some cases two centimeters if they were also ER-positive. I believe the responses in Figure 25 regarding the use of chemotherapy/trastuzumab for tumors one to two centimeters in size are consistent with what we know from those studies.

However, with HER2-positive tumors less than one centimeter in size, we’re right back to this problem of deciding whether biology or anatomy drives the cancer. Historically, for subcentimeter breast cancers, we have used the anatomic distinction to decide that these tumors are low risk.

Therefore, adjuvant therapy doesn’t matter much and we don’t recommend it. However, if biology drives it, then in invasive cancer you want to target HER2 almost independent of the tumor size. It’s important that we figure out what the real risk is in this setting.

Dana Farber is running a nonrandomized registration trial for patients with subcentimeter, HER2-positive, node-negative breast tumors. The patients are receiving chemotherapy and trastuzumab, just to get a sense of the event rate and to see whether it’s even possible to conduct a trial in that group of patients. If the event rate is low, that will probably tell us that this is not a ripe area for research.

Based on all the data, including the HERA trial data, which showed the same point estimate for benefit in all node groups and a sizable number of node-negative tumors, I recommend an anthracycline/taxane/trastuzumab regimen for any patient with a 1-cm or larger tumor or with positive nodes.

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For patients with HER2-positive, ER-positive tumors that are one centimeter in size, I am uncertain whether it is chemotherapy that is needed rather than trastuzumab for reducing residual recurrence risk. We know that when we add trastuzumab to the existing regimen, we appear to cut the risk of recurrence in half.

For example, a patient with a small tumor may have a 15 percent risk of recurrence and maybe with chemotherapy that will be reduced to 10 percent. By adding trastuzumab, I may be lowering the risk by another five percent, based on the data we have.

Selection of Chemotherapy

DR HUDIS: I don’t think we have enough evidence to be dogmatic about which chemotherapy regimen to use with adjuvant trastuzumab. The basic backbone for the clinical trials was the AC/taxane combination, and the data from ECOG-E1199, evaluating every three-week AC followed by docetaxel versus paclitaxel, every week versus every three weeks, give us a good sense that it doesn’t matter a whole lot what you do. We have evidence that a risk reduction of approximately 50 percent occurs when trastuzumab is added to virtually any regimen.

One of the issues that I believe Slamon’s TCH presentation brings up is the generic question of whether chemotherapy selection matters at all once you’re in “HER2-positive land” and you’re using trastuzumab. It may be that the trastuzumab has such a profound and overarching effect that it no longer matters in a nuanced way which chemotherapy you use.

The data that suggest anthracyclines matter are from a trastuzumab-naïve population, and when Dan Hayes evaluated paclitaxel in CALGB-9344 and showed HER2-associated benefit, that too was in a trastuzumab-naïve population. Thus, it’s conceivable that all of this is about nothing and that once you’re in the realm of trastuzumab-based therapy, your narrow chemotherapy choice isn’t so important.

As for the concerns over cardiac safety when using anthracyclines and trastuzumab, I believe we have a lot of noise and not so much fact at the moment. I don’t want to be accused of self-dealing because dose-dense therapy has been our pet project for a long time, but I want to highlight something here.

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One of the comments you hear all the time is that 10 percent of patients have a decline in ejection fractions (EF) from receiving AC and then they are no longer candidates for trastuzumab use. I don’t know how much of that’s real and how much of that’s noise from multiple centers and lack of consistent technique in terms of the testing.

We have submitted a study for publication in which 70 patients were treated with dose-dense therapy and a baseline EF of 55 percent or greater was an eligibility criterion. In that trial, we had zero dropouts during the AC phase, and I believe that’s because all the testing was done in a single center, maybe with a single reader. That suggests that more than simply the real toxicity may be at work here for that dropout number.

If you factor that out of the equation, then the incidence of cardiac toxicity and the limitation on trastuzumab delivery decrease dramatically. We only had one case of congestive heart failure among the 70 patients in this Phase II trial and no cardiac deaths. That’s below a level at which you would predict that there’s any elevated risk compared to the other regimens right now.

I’m concerned that there is a dearth of good prospective data on the meaning and impact of these modest EF declines and that we may be denying patients trastuzumab for no good reason due to local laboratory testing variations.

Our data suggest that the patient’s risk of not getting to the trastuzumab is zero, but I admit that they are relatively modest numbers, although it is sized specifically to eliminate an increase in risk compared to the conventional treatments. However, in the retrospective analysis of CALGB-9741, the cardiac event rate with dose-dense therapy was half of the every three-week event rate, so this innate bias that it must be more toxic is not supported by any data.

If 700 patients were treated, instead of 70, I am confident that we’d see some more cardiac toxicity. It’s important to remind folks that we conducted this trial in response to a request for the data when the randomized trials of trastuzumab could not be modified to accommodate dose-dense therapy. This was the best way we could get at the evidence.

As for the ER-negative subset in the dose-dense trial, the magnitude of the benefit in terms of three-year disease-free survival is in the double-digit range, and it’s similar to the magnitude of the benefit you see when you add trastuzumab globally. I don’t think we should be so dismissive of the possibility that both schedule optimization and the biologic therapy matter for these patients.

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