Track 2

DR LOVE: What’s your overall reaction to the clinical trial data on adjuvant trastuzumab that have become available in the last few months?

DR SLAMON: The data are quite stunning and are unlike a lot of adjuvant data we’ve seen in the past. The action part of this regimen is the biologic agent, trastuzumab, and it’s giving us remarkable results. We all hoped for good results, but we were blown away by the degree of the results. I believe these data are going to hold up. We obviously need further follow-up, but these curves are pretty striking.

DR LOVE: Norm, what are your thoughts about the distant disease-free survival data from the combined NSABP-NCCTG analysis? Are we talking about cure?

DR WOLMARK: Everyone is hesitant to speak in terms of superlatives because we’ve been there and we’ve been disappointed. But certainly, we wait a lifetime to see curves separate in this way, with the treated line approaching the horizontal. So it is our sincere hope that we are talking about cure. There are sufficient data to suggest that is in fact what is happening.

As Ed Romond has pointed out, to see a survival difference with approximately two years of follow-up is extraordinary. There’s every reason to believe that what we’re seeing in disease-free survival and distant disease-free survival is going to be translated to overall cure. But, echoing Denny’s admonitions, we ought to continue the follow-up as planned.

DR LOVE: One of the practical clinical questions is the issue of the patient with a node-negative tumor. We’ve discussed applying the relative risk reduction concept in adjuvant systemic therapy across the spectrum of risk, yet most of the patients who have been reported on so far have had node-positive disease. Dr Geyer, can we apply the relative risk reduction concept to smaller, node-negative tumors?

DR GEYER: That would have been a contentious point in the absence of the HERA data. However, the HERA data speak adequately to that issue. In that study, roughly a third of the patients had node-negative disease, and the Forest plot indicated that the lower boundary was to the left of one. Therefore, I believe that is a reasonable concept.

Track 3

DR LOVE: Do you think that docetaxel/carboplatin/trastuzumab (TCH) is a reasonable consideration for adjuvant therapy in the clinical setting?

DR GEYER: If you have a patient in whom the administration of anthracyclines is a concern, yes, without doubt, TCH makes a lot of sense. There are patients with whom you clearly would be concerned about utilizing doxorubicin due to pre-existing heart disease.

DR LOVE: Dr Slamon, what do we know about the side effects and toxicity of TCH versus AC/docetaxel or paclitaxel?

DR SLAMON: We have a lot of experience with taxanes and platinum salts based on studies in ovarian cancer and lung cancer. Therefore, we are pretty comfortable with the idea that they can be administered together. Myelotoxicity is the most significant adverse effect. I believe that TCH can be given safely, especially with growth factors. In treating a patient with a HER2- positive tumor, I’m less concerned with utilizing TCH than perhaps an anthracycline- based regimen, due to the potential cardiotoxicity.

DR LOVE: Ed, Chuck Vogel studied trastuzumab monotherapy in the metastatic setting. At present, we don’t have data on trastuzumab without chemotherapy in the adjuvant setting. For an older patient for whom you’re concerned about chemotherapy, do you think it’s justifiable to consider trastuzumab monotherapy?

DR ROMOND: Trastuzumab would be a consideration if you were concerned about administering chemotherapy. However, sometimes we undertreat older patients with chemotherapy because of their age. I have not had difficulty giving chemotherapy to 75-year-old women who are in good health. However, if you had major concerns about toxicity in a patient with HER2- positive breast cancer, I certainly think trastuzumab monotherapy would be appropriate.

DR LOVE: Dr Slamon, what are your thoughts about trastuzumab monotherapy in the adjuvant setting?

DR SLAMON: Trastuzumab monotherapy is certainly an option if you have patients with coexisting medical issues that cause concern with administering chemotherapy. I absolutely agree that chronologic cutoffs are arbitrary. Our colleagues who practice oncology in a geriatric setting have taught us that there are performance analyses that can be done that will tell you whether or not a patient can tolerate chemotherapy. In this older population, many more patients than we previously thought can tolerate chemotherapy, especially with some of the agents that we have to administer along with chemotherapy.

DR LOVE: Dr Kaufman, there is a lot of dose-dense AC/paclitaxel being given right now in this country. It is the most common regimen currently being utilized for patients with node-positive disease. What are your thoughts regarding dose-dense chemotherapy with trastuzumab?

DR KAUFMAN: That’s an interesting question, and I’ve been asked that quite frequently since the data were presented. We have to be cautious with the use of trastuzumab in the setting of dose-dense therapy. In CALGB, we did not see an increased incidence of cardiotoxicity with dose-dense AC, but we did not carefully monitor cardiac safety in that trial. Cardiac monitoring was based on clinical symptomatology.

In theory, it’s conceivable there may be an increased incidence of cardiotoxicity with dose-dense anthracyclines, even with sequential trastuzumab. Currently, it’s probably safest and most appropriate to not use dose-dense anthracyclines with trastuzumab.

Track 4

DR LOVE: Dr Slamon, if you were evaluating a patient in her early fifties, perfectly healthy, no heart disease, with an ER-negative, PR-negative, node-negative tumor under one centimeter, would you discuss trastuzumab with her?

DR SLAMON: If it’s a HER2-positive tumor, the critical thing is that the patient receives trastuzumab-based therapy. However, I am somewhat biased.

All of the other parameters that we evaluate and discuss — tumor size, node positivity or negativity, ER positivity or negativity — are not irrelevant but are less relevant than HER2 positivity. If I’m confronted with a patient with a HER2-positive tumor, I am going to recommend trastuzumab-based therapy. The choice of chemotherapy at this point is “dealer’s choice.”

DR LOVE: Dr Kaufman, a lot of people want to apply the criteria for clinical trial eligibility in treatment decision-making. The patient I’ve just described would not have been eligible for the HERA or NCCTG trials because the tumor was too small. Would you offer trastuzumab to that patient?

DR KAUFMAN: I agree with Dr Slamon that we really have to look at the HER2 positivity, but the cutoff for trial eligibility was a one-centimeter tumor. In this situation, we have to exercise some judgment. The issue is the size threshold. If the patient presents with a one- or two-millimeter tumor, I’m not sure I would recommend trastuzumab. But certainly, in a patient who is close to the eligibility criteria across the studies, it is very reasonable to consider recommending trastuzumab.

DR WOLMARK: I have more limited enthusiasm than my colleagues for recommending trastuzumab in that situation. The patient population in the NSABP-B- 21 study did extremely well, regardless of HER2 status. Granted, that was a predominantly ER-positive population, but even the patients with small, ER-negative tumors had a good outcome. This underscores the fact that we need more objective parameters to determine risk in this subset of patients.

DR LOVE: Ed, what are your thoughts about the use of delayed trastuzumab, perhaps one or two years after the initial diagnosis?

DR ROMOND: A major consideration is the level of residual risk after that period of time. When you look at the curves of patients with a large number of positive lymph nodes, they continue to have events for a long period of time. If you have a patient with HER2-positive breast cancer whom you estimate still has significant residual risk, delayed trastuzumab is a consideration.

You also need to consider whether or not the patient has a potential risk for cardiac toxicity if you administer trastuzumab at this point, which shouldn’t be any major consideration if you’re using it by itself, and then what kind of incremental efficacy you could expect to see there.

But with the patients I see, if they have four or five positive nodes or something similar, and they’re out even two or two and half years, I think they still have considerable residual risk.

The problem is that there are no absolute cutoffs. It has to come down to balancing these factors and discussing this with the patient.

Track 5

DR LOVE: It was interesting that in the NCCTG-N9831 trial, the sequential arm showed a 13 percent risk reduction, which is nonstatistically significant. Yet in the HERA study, utilizing a similar treatment strategy, there was 50 percent reduction. Norm, can you put this all together for us?

DR WOLMARK: No. I don’t believe we can put it all together, because we do not have the power — divine or statistical — to do so. However, if we look at the data that Dr Kaufman presented on the N9831 trial, one can’t remain neutral. Administering trastuzumab concomitantly with chemotherapy clearly resulted in a 36 percent reduction. Giving trastuzumab sequentially after chemotherapy resulted in a 13 percent reduction. Clinicians are going to be swayed by these data. If you delay trastuzumab beyond chemotherapy, you are going to pay a price in terms of efficacy.

Are these data inconsistent with the HERA data? Not necessarily. One explanation that Brian Leyland-Jones gave for the fact that the taxanes have a hazard rate of 0.77 — the lowest benefit from trastuzumab — is not because we’re dealing with a low-risk population but because the patients received more cycles of chemotherapy. Therefore, the trastuzumab was delayed.

The data from the HERA study and from N9831 are not inconsistent with one another, although, granted, we’re not speaking from any standpoint of statistical power. There is a certain consistency. If you’re going to yield the greatest benefit of trastuzumab, it should be administered as soon as possible and should be given concomitantly with chemotherapy.

DR LOVE: Dr Slamon, your preclinical work showing the synergy between trastuzumab and chemotherapy was part of the impetus to investigate sequential versus concomitant treatment. What are your thoughts about these data?

DR SLAMON: I’m obviously intrigued by this apparent dichotomy in the two data sets, but Norm addressed the issue quite well. The HERA investigators have always been open about the fact that the randomization occurred after chemotherapy, so keep this in mind as we evaluate the data. We are in the uncomfortable position of trying to make assumptions without having mature data.

We are not going to have to wait for years, but certainly, we’re going to have to wait months for at least one updated analysis to be able to answer the question definitively. My preconceived notion based on the biologic data that we have is that administering trastuzumab with chemotherapy will make a difference.

Select publications