Breast Cancer Update 2006 (3): Miami Breast Cancer Conference Tumor Panel Discussion

DR SLEDGE: Data from the HERA trial comparing observation versus one year of trastuzumab show a significant benefit in the addition of trastuzumab, with a risk reduction of about 50 percent and a strikingly positive p-value. It is interesting that this trial included no specified chemotherapy regimen and approximately one third of the patients had node-negative disease.

In contrast to the HERA trial, early analysis of the N9831 trial demonstrated that the result from the sequential arm, in which trastuzumab was administered after completion of chemotherapy, was not statistically significant, with a p-value of 0.01. From a purely statistical standpoint, this did not meet the boundaries required for early reporting.

The median follow-up in this trial is short, and the number of events is small, so which regimen is better is still an unanswered question. In the arm in which trastuzumab was administered concurrently with chemotherapy, the result was highly significant.

In the BCIRG 006 trial, both of the trastuzumab-containing arms were superior to the nontrastuzumab-containing arm. The nonanthracycline arm may be minimally inferior to the anthracycline-containing arm, but this is not yet a statistically significant difference and requires further follow-up.

If we examine all these trials as a group and include the FinHER trial, a small Finnish trial of adjuvant trastuzumab, in every single study we see significant benefits with the addition of trastuzumab to chemotherapy. As a result, trastuzumab has become the standard of care for patients receiving adjuvant therapy who have HER2-positive disease.

Breast Cancer Update: Special NSABP Edition 2005

DR NORMAN WOLMARK: The only test of concomitant versus sequential treatment with trastuzumab was from N9831, and when you evaluate the curves presented and the comparisons, one can’t remain neutral. The concomitant arm (with paclitaxel) has a hazard rate that falls in line with what we’re seeing in the other trials, whereas the sequential arm is, peer-wise, not statistically significant. It is not inappropriate for a medical oncologist to evaluate those data and be more impressed with concomitant therapy.

Breast Cancer Update: Special NSABP Edition 2005

DR DENNIS J SLAMON: The initial BCIRG 006 efficacy data are based on the first interim analysis of a three-arm trial with 300 events. We recognize that we’re walking a fine line here, but still, both trastuzumab arms crossed their efficacy boundaries. The relevant question will be, how does the TCH arm, the nonanthracycline arm, look relative to the anthracycline-containing arm?

The risk reduction in the TCH arm is 0.39, and the risk reduction in the ACTH arm is 0.51 — almost identical to what was seen in the trials reported at ASCO for that type of combination. That’s based on very few event differences between the two arms. We need to wait until the data mature, and it won’t take a long time. Physicians should basically do what they feel most comfortable with at this point. If they feel more comfortable with the ACTH data, they should go with that arm, recognizing that those patients will have to be watched closely for cardiotoxicity.

In terms of clinical chemotherapy-trastuzumab combinations, at this point we try, whenever possible, to avoid anthracycline-containing regimens because of the known interaction in terms of cardiac safety of trastuzumab with anthracyclines, and we’re not restricted to TCH when using a nonanthracycline regimen. There are a number of different drugs that interact well with trastuzumab. However, we usually do use TCH in the adjuvant setting and will continue to do so until we see that it is inferior and the safety profile doesn’t make up for that inferiority.

Breast Cancer Update 2006 (2)

DR BURSTEIN: The seminal question for the BCIRG 006 adjuvant trial was how the triplet — docetaxel, carboplatin and trastuzumab (TCH) — would compare with AC followed by docetaxel/trastuzumab and whether we could avoid using an anthracycline.

Although the numbers were not statistically significant, it struck me that there is still an advantage for the anthracycline-based chemotherapy. The trade-off that Dr Slamon reported is that there seems to be a slightly greater risk of cardiac toxicity for the women who received the anthracycline-based regimen but only about a one percent difference in terms of clinical cardiotoxicity events.

I think the findings from the TCH regimen are provocative, and we should continue to watch the data as they mature. However, for the moment I will continue to use AC followed by a taxane with trastuzumab as my principal adjuvant regimen for HER2-positive disease.

Breast Cancer Update 2006 (2)

DR JOHN MACKEY: The intent of the BCIRG 006 trial was to see if the preclinical synergy seen between docetaxel, carboplatin and trastuzumab would be borne out in the adjuvant setting and whether we could avoid major problems with cardiotoxicity by eliminating the anthracycline.

The trial demonstrated that both the ACTH arm and the novel arm of TCH outperformed the control arm, with hazard ratios of 0.49 and 0.61, respectively. No statistically significant difference appeared between the two experimental arms.

Interview, March 2006

DR CLIFFORD HUDIS: We are conducting a Phase II trial at Memorial with 70 patients treated with dose-dense AC/paclitaxel and trastuzumab. Our goal is to demonstrate a low or zero incidence of cardiac events, sufficient to convince us and the world that this regimen is safe. We are close to accomplishing that goal; however, the trial’s not quite finished.

Now that we have evidence that dose-dense chemotherapy is a little bit better than conventional chemotherapy, we don’t want to be in a position of choosing a less effective chemotherapy regimen when deciding to administer trastuzumab. That’s the gap we’re trying to close.

Breast Cancer Update 2006 (1)

DR PETER A KAUFMAN: We don’t know the precise approach for the use of adjuvant trastuzumab in patients with node-negative disease, but any patient who meets the protocol-defined eligibility criteria is a reasonable patient for whom we should discuss the risks and benefits of trastuzumab.

I will caution that the number of patients with node-negative disease in our NCCTG-N9831 trial was modest — about 10 to 12 percent of the patients overall. So the findings are way too early for us to start looking at subsets, but I think trastuzumab is reasonable for patients who meet the criteria.

Meet The Professors 2005 (6)

DR WINER: I think the HERA results are impressive and stand on their own without a lot of difficulty. It is quite possible that concurrent may be better than sequential, but we don’t know at the moment. The only reason we know anything from N9831 about sequential versus concurrent therapy is that when the DSMV met and decided to release the data about trastuzumab, as a practice management question in terms of what to tell doctors whose patients were on the trial, they asked to evaluate those two arms so that they could give doctors a sense of what to do for patients who had been treated on the trial and didn’t receive trastuzumab.

Although there is a statistically significant difference between the concurrent and sequential arms on Edith’s trial, and the sequential arm wasn’t significantly better than no trastuzumab, it did not meet any boundary in terms of early stopping. We just need more data.

We know there’s benefit from HERA. The risk reduction in HERA was similar to what we’ve seen in all of the studies. All of them — other than that one arm in N9831 — have shown that the use of trastuzumab either with or following chemotherapy reduces the risk of disease recurrence by about half, and the results are shockingly consistent.

Breast Cancer Update: Special NSABP Edition 2005

DR WOLMARK: I still have trepidation about using adjuvant trastuzumab in patients with node-negative disease and tumors of less than one centimeter. If the patient’s tumor is ER-negative, the threshold to treat with trastuzumab is lower. However, for those with ER-positive disease, I would probably want to do an Oncotype DX™ because I believe that is a reliable method to determine risk and would be helpful. If it’s a high-risk tumor, I would add trastuzumab to that regimen.

Breast Cancer Update 2006 (3): Miami Breast Cancer Conference Tumor Panel Discussion

DR JOYCE O’SHAUGHNESSY: If the tumor is greater than a centimeter in size and the patient has no contraindications to trastuzumab, I recommend it. For patients with tumors less than a centimeter, it depends on what I think their residual risk will be. For example, if a tumor is eight or nine millimeters but ER-negative and PR-negative, Grade III and HER2-positive by FISH, I recommend trastuzumab. For patients at higher risk, I always use AC followed by paclitaxel or docetaxel with trastuzumab, but for patients at lower risk, I consider TCH because it has less cardiac toxicity.

Breast Cancer Update 2006 (2)

DR PICCART-GEBHART: Women with HER2-positive tumors were allowed to enter the HERA trial if the tumor size was greater than one centimeter. This was the only criterion. We didn’t require other aggressive features — it was purely based on pathological size.

Of course, now the problem we have is with young women coming to us with eight-millimeter tumors and negative nodes. Usually, when you look at the pathology, you see other features of aggressiveness — for example, a high proliferation rate, Grade III tumors and so on.

I don’t see why these women would not derive a substantial benefit from trastuzumab. Provided these women are well informed about cardiotoxicity risk, we are discussing with them the possibility of trastuzumab.

Breast Cancer Update 2006 (2)

DR SANDRA M SWAIN: In NCCTG-N9831, about 10 percent of the patients had node-negative disease, and none of those patients had tumors that were less than a centimeter. Probably one of the questions I am asked the most right now is, “What do you do with a patient who has a three-millimeter, HER2-positive tumor?”

In BCIRG 006, about 30 percent of the patients had node-negative disease, and some of those patients did have very small tumors. There was not a size limitation, but it’s still, again, limited in number. In the HERA trial, approximately 30 percent of the patients had node-negative disease. The HERA trial was very strongly positive for efficacy with sequential trastuzumab in the patients with node-negative disease.

Hence, strong data support the use of adjuvant trastuzumab in patients with node-negative disease. The nuances of its use are really about the tiny tumors.

The data indicate that a patient with a two- or three-millimeter tumor has an extremely good prognosis. I have not been recommending adjuvant trastuzumab for those very tiny tumors because of the risk of cardiac toxicity. It’s not like tamoxifen, with which you have minimal risk. You do have risk, and it requires intravenous therapy for a year.

Breast Cancer Update 2006 (1)

DR KAUFMAN: We don’t know whether women with a HER2-positive tumor smaller than one centimeter need adjuvant trastuzumab. We do need to be respectful of the fact that these women have a better prognosis because their tumors are so small. For women whose tumors are ER-positive and less than one centimeter, I’ve not offered trastuzumab.

For patients with ER-negative disease, I suppose one could consider trastuzumab, although the quantifiable gains from adding this agent are not known. It would be interesting to conduct a study evaluating trastuzumab with or without chemotherapy in patients with very small tumors.

Maybe we can begin to eliminate chemotherapy for the lower-risk patient population if we can alter the natural history of their disease. Data exist suggesting that trastuzumab may enhance the apoptotic function of a number of cytotoxic agents.

Dennis Slamon and Mark Pegram did much of the groundbreaking work demonstrating synergistic interactions between trastuzumab and a number of conventional cytotoxic agents that we use widely in breast cancer — docetaxel, paclitaxel and vinorelbine.

So if that preclinical finding was accurate, one would speculate or hypothesize that administering trastuzumab concurrently with cytotoxics might give you a much greater bang for your buck and much more clinical activity than waiting until the completion of chemotherapy to start trastuzumab.

In terms of the difference between sequential therapy versus no therapy with trastuzumab, we found in N9831 a 13 percent relative improvement in disease-free survival favoring sequential therapy that did not achieve statistical significance. Our data indicate a trend but not a definitive improvement or benefit with sequential therapy.

The HERA trial, which also looked at sequential therapy, did demonstrate a highly statistically significant improvement with the administration of trastuzumab in sequence with chemotherapy, after its completion.

Time will tell. My prediction is that a benefit does exist with trastuzumab administered sequentially after the completion of chemotherapy. The HERA trial data are impressive, and it’s a large study.

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Meet The Professors 2006 (1)

DR HUDIS: I have not treated any patients with adjuvant trastuzumab monotherapy, but if I’d ever be tempted, it would be for an older patient with a high degree of ER-positivity. Data for such cases are desperately needed and would fill an important gap. Frankly, the remarkably consistent impact of trastuzumab raises the question of the contribution of the chemotherapy.

Breast Cancer Update 2006 (1)

DR SWAIN: I probably wouldn’t use adjuvant trastuzumab without chemotherapy. Even if there’s comorbidity, paclitaxel can be tolerated very well if you use it weekly.

Such a large amount of synergy data exists with trastuzumab, even though the HERA trial is positive with sequential use, I believe Dennis Slamon’s laboratory data that indicate the synergy is important.

So I would try to use paclitaxel with trastuzumab in those patients, and if you’re concerned about the anthracycline, just don’t use that.

Breast Cancer Update 2006 (1)

DR CHARLES E GEYER JR: Right now, I would shy away from using adjuvant trastuzumab monotherapy, although it’s easy to come up with scenarios where one would do that. The real rigid position is that we just don’t know what trastuzumab does by itself or with hormonal therapy. However, the magnitude of what we’re seeing with adjuvant trastuzumab, particularly in the HERA trial on which it was administered by itself, makes it difficult to take that position.

If I have a patient who is older and I don’t want to use TCH or doxorubicin, seeing the TCH data and knowing that weekly carboplatin and weekly paclitaxel are very well tolerated, I would be more inclined to make that sort of substitution.

If somebody is healthy enough that I want to provide her with the benefits of adjuvant trastuzumab, I would tend to recommend something like weekly carboplatin/paclitaxel rather than avoid chemotherapy altogether.

In terms of delayed trastuzumab, the HERA data suggest that trastuzumab as monotherapy beyond adjuvant treatment has a very low risk to it. So from the patient advocacy perspective, I see little downside to offering patients a year of trastuzumab if you know they have a substantial annual residual risk, which, for me, would be patients with node-positive disease.

The more difficult question is, how far out? I don’t have an answer. It would be hard for me to justify it beyond five years. I think at that point patients have had enough time that they’re likely to be beating the odds, so to speak.

It looks as though sequential AC followed by concurrent taxane/trastuzumab probably presents an increase in significant cardiac events of about three percent over baseline.

The cardiac events, as an endpoint in our study, meant that the patients died from cardiac causes or developed New York Heart Association Class III or IV heart failure. They experienced symptoms of heart failure with normal activity or at rest.

We will have to continue to follow the patients on these large adjuvant studies longer to obtain information regarding the long-term effects of trastuzumab after treatment is finished. NSABP-B-31 and NCCTG-N9831 were designed to check left ventricular function at 18 months, which was three months after trastuzumab ended and substantially longer from when the chemotherapy ended.

We are seeing encouraging results there, in that over time the slight decrements in ejection fraction across the groups diminish, and we do not see a great deal of difference looking at median ejection fractions. Even among the patients who did develop cardiotoxicity, in which their ejection fractions dropped to 30 percent or less, virtually all are up at least to 40 percent.

Recovery clearly occurs. It will take time to see what happens four and five years out. We also noted that relatively few new cardiac events are happening beyond the end of trastuzumab treatment.

In BCIRG 006, they reported a 1.3 percent event rate with TCH versus 2.3 percent with AC followed by docetaxel/ trastuzumab. The difference was one percent.

The sequential AC taxane regimens have a cardiac event rate of about one percent. When you throw trastuzumab into that mix, you’re probably adding on two or three percent.

I don’t think there’s a big difference between these numbers in terms of the absolute rate. I don’t think that AC paclitaxel/trastuzumab is more cardiotoxic than AC docetaxel/trastuzumab. We reported four percent; they reported two percent, but these are different trials.

Cardiotoxicity with TCH is less; they reported an incidence of 1.3 percent. In the HERA trial with trastuzumab by itself following doxorubicin, it was 0.5 percent. It’s interesting to see the TCH at the level of the ACT — both of them higher than what HERA was reporting.

It’s always problematic to compare absolute numbers across protocols, but the HERA number was strikingly the lowest number. If you want safety to be your dominant concern, then the HERA regimen seems, based on the data, to be the safest.

Breast Cancer Update 2006 (1)

DR GEYER: When we performed our cardiac safety analysis, we looked for predictors of the cardiac events. The things that held up in multivariate analysis were the age going in and the post-AC LVEF. For instance, patients 50 years old and older who had a post-AC ejection fraction of 50 to 54 percent had a cardiac event rate of 20 percent in our study. The lower boundary of that confidence interval was 11 percent, so that’s a very high number.

Based on our data and what I’ve seen, I think the post-AC ejection fraction provides an extra measure of safety, coupled with the fact that it does seem as if no matter how trastuzumab is administered, it provides substantial benefits. So if I can do that and minimize toxicity, to me, that’s important.

Slamon D et al. Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (ACT) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (ACTH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study. SABCS 2005;Abstract 1.

With over 23 months of follow-up, the primary endpoint of disease-free survival in both experimental arms of BCIRG 006 was achieved. The secondary endpoint of overall survival is not yet mature enough to report differences.

The cardiac safety data show a statistically significant higher instance of cardiac events in the ACTH arm compared to either the ACT or the TCH arm, but also importantly, there are persistent LVF declines in the anthracycline-containing Herceptin arm compared to the non-anthracycline Herceptin arm TCH.

For the global safety, they were tolerated well. Nonhematologic toxicity was evenly distributed, and all three regimens were well tolerated. The final observations are that the LV declines sustained with ACT and ACTH do last up to 550 days at the point of the last follow-up for a significant number of these patients.

Coamplification of the TOPO II gene with HER2 may identify a subset of the HER2-amplified that might benefit from anthracycline, making it worth the risk of cardiac dysfunction. Conversely, 65 percent of the patients do not have TOPO II amplification, and they may be ideal candidates for an efficacious nonanthracycline-containing regimen.

Smith I, on behalf of the HERA Study Team. Trastuzumab following adjuvant chemotherapy in HER2-positive early breast cancer (HERA trial): Disease-free and overall survival after 2 year median follow-up. ASCO 2006.

In conclusion, trastuzumab following adjuvant chemotherapy significantly improves overall survival among women with HER2-positive breast cancer. The disease-free survival gain reported after the one-year median follow-up is maintained after two years’ median follow-up, and the risk of cardiotoxicity remains low. Long-term follow-up will provide continuing safety data, important information on duration of trastuzumab treatment — one year versus two years — and, perhaps, information on the effect of delayed switching to trastuzumab in the observation arm.

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