HER2-Positive Disease


Combined analysis:

ASCO 2005

Our conclusions for high-risk HER2- positive breast cancer: Trastuzumab, when given concurrently with paclitaxel following AC chemotherapy, reduces the risk of a first breast cancer event at three years by 52 percent. This benefit should change the standard of care. The benefit was present and of similar magnitude in virtually all subsets of patients analyzed. There is not, however, statistical power to establish efficacy in the node-negative subset. The addition of trastuzumab reduced the probability of developing distant recurrence by 53 percent at three years, and the hazard of developing distant metastases appears, thus far, to decrease over time. Early results at a median follow-up of two years show a statistically significant survival advantage, with a relative risk reduction of 33 percent.

— Edward H Romond, MD et al.
Presentation. ASCO 2005.

Breast Cancer Update 2005 (6)

DR GEORGE W SLEDGE JR: In the joint analysis of NCCTG-N9831 and NSABPB-31, the hazard rates for distant disease recurrence in patients who received trastuzumab appeared to improve with time. It’s still early to analyze these data because few patients in either trial are four years out; however, the distant disease-free survival curve appears to plateau in the trastuzumab arm. If that’s the case, it’s astonishing.

We’ve never seen a true plateau in any adjuvant trial. When we examine disease-free survival curves like this, we need to ignore a fair amount of the right side of the curve because there are so few numbers, but if that is maintained it will be exciting.

HERA: Adjuvant trastuzumab trial

ASCO 2005

In conclusion, at one-year median followup, trastuzumab given every three weeks for one year following adjuvant chemotherapy significantly prolongs diseasefree survival and relapse-free survival and significantly reduces the risk of distant metastasis.

Trastuzumab’s clinical benefits are independent of patients’ baseline characteristics and of type of adjuvant chemotherapy received. Trastuzumab therapy is associated with a low incidence of severe symptomatic congestive heart failure, but, clearly, longer follow-up is needed to better quantify this risk.

All patients continue to be followed for long-term safety. Results regarding optimal trastuzumab duration, two years versus one year, should be available in 2008.

— Martine J Piccart-Gebhart, MD, PhD et al.
Presentation. ASCO 2005.

Initial results of BCIRG 006

Breast Cancer Update: Special NSABP Edition 2005

DR DENNIS J SLAMON: In 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 period of 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 very closely for cardiotoxicity.

Adjuvant trastuzumab in node-negative disease

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 under one centimeter. If the patient’s tumor is ER-negative, the threshold to treat with trastuzumab is lower. On the other hand, 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 really be helpful. If it’s a high-risk tumor, I would add trastuzumab to that regimen.

Breast Cancer Update 2005 (7)

DR ERIC P WINER: The HERA study included patients with node-negative disease as long as their tumors were greater than a centimeter. A third of the patients participating were node-negative. The NSABP trial had no patients with node-negative disease, and in the NCCTG study, patients with node-negative disease accounted for 14 percent of the total population but only six percent of the events.

It’s unlikely that the relative benefits of trastuzumab will differ in patients with node-negative versus node-positive disease. On the other hand, the absolute benefit will differ, because patients with node-negative disease, particularly with small tumors, have a lower risk of recurrence.

In my mind, it’s reasonable to consider trastuzumab for patients who were eligible for the studies. The group of women that I’m a little more cautious about are those with relatively small, ER-positive, node-negative breast cancers.

Breast Cancer Update 2005 (6)

DR EDWARD H ROMOND: The NSABPB- 31 and NCCTG-N9831 adjuvant trastuzumab trials were initially limited to patients with node-positive disease.

However, in May 2003, the Intergroup amended their protocol to include patients with high-risk, nodenegative disease, which were basically ER-negative/HER2-positive or ER-positive/ HER2-positive tumors that were larger than two centimeters.

As a result, in the overall data set, approximately 100 patients in each arm had node-negative disease. The relative risk reduction in the combined data analysis of patients with node-negative disease was approximately 0.48 — the same as the entire data set.

The problem is that with 100 or fewer patients with node-negative disease in the arms of the N9831 protocol, the confidence interval goes out forever and crosses one.

That does not mean there is no biologic effect; it probably exists, but it’s difficult to pin down how much benefit we gain by using trastuzumab in patients with node-negative disease. The HERA trial may be a better data set to examine the benefit of adjuvant trastuzumab in that population, because one third of those patients had node-negative disease.

Selection of chemotherapy to combine with trastuzumab

Breast Cancer Update: Special NSABP Edition 2005 (10)

DR SLAMON: In terms of nonprotocol 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 non-anthracycline regimen.

There are a number of different drugs that interact very 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.

Duration of and delayed implementation of adjuvant trastuzumab

Breast Cancer Update 2005 (8)

DR PETER M RAVDIN: The HERA trial is evaluating the duration question. In their trial, one arm has no trastuzumab, the second arm has one year and the third arm has two years of trastuzumab after chemotherapy. Because the data at this point addresses one year of trastuzumab, I believe that’s the appropriate length of time.

As for the delayed implementation of trastuzumab in the Intergroup trial, they’re supplying trastuzumab to the control group of patients who want to cross over out to one year of follow-up. There are theoretical arguments that a year is somewhat of an arbitrary length.

The peak in relapses occurs at about two to three years, so I could see a rationale for treating beyond a year, particularly patients at high risk with multiple nodes. However, that rationale is going beyond the data we have and is somewhat speculative.

Breast Cancer Update 2005 (6)

DR SLEDGE: The HERA trial suggests that administering trastuzumab after chemotherapy may be beneficial, so the question becomes, how long after chemotherapy will it be beneficial?

In the case of estrogen receptors, we have two European randomized trials that evaluated the late use of tamoxifen in patients with estrogen receptorpositive breast cancer, and both were positive.

Will we see a similar benefit with delayed adjuvant trastuzumab? It’s a reasonab le and important question, particularly for those patients in the control arms of N9831 and B-31 who are more than 18 months out from treatment. I’m not going to be dogmatic about this, but I do believe it’s reasonable to discuss the option of trastuzumab with such patients.

Clinical impact of adjuvant trastuzumab trial data

Breast Cancer Update 2005 (6)

DR SLEDGE: As a result of the data presented at ASCO in 2005, trastuzumab became a standard of care in the adjuvant setting for HER2-positive breast cancer.

We saw a stunning validation of the biology of HER2 and the concept that we could diminish the likelihood of recurrence and improve overall survival through the use of targeted therapy.

This validates 15 years of preclinical and clinical research, from Slamon’s initial observation in the late 1980s that HER2 was a bad actor in breast cancer to the pivotal metastatic trial led by Slamon and now the adjuvant trial data.

We have consistently seen that when HER2 is overexpressed or amplified, it markedly increases a patient’s risk of early relapse.

In the HERA trial, we saw that by two years after randomization, one quarter of the patients in the control arm had relapsed. In the joint analysis of NCCTG-N9831 and NSABPB- 31, around 25 percent had relapsed by approximately three years. This is a bad disease, and partly because of that, we see a high event rate early in these trials. A striking benefit was seen with trastuzumab, including survival with a median follow-up of just two years.

That is unprecedented in any adjuvant trial. It’s interesting to imagine what the impact of the estrogen receptor trials would have been if we had enrolled 3,000 patients on those studies two or three decades ago. The data probably would have been similar to the adjuvant trastuzumab trial data.

The message is that if we understand biology and target it appropriately, we obtain a great result, whereas when we use relatively nonspecific therapies, we can tweak them — changing dose duration, dose density and dose intensity — and obtain slightly better results, but we’ll never achieve the revolutionary results that we saw in the adjuvant trastuzumab trials.

Concurrent or sequential trastuzumab administration with chemotherapy

Breast Cancer Update: Special NSABP Edition 2005 (10)

DR WOLMARK: The only test of concomitant versus sequential treatment was from N-9831, and when you look at 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 2005 (6)

DR SLEDGE: In the HERA trial, all the patients received trastuzumab after rather than concurrent with chemotherapy, and those data were positive, with an impressive 45 percent reduction in hazard rate. On the other hand, in the Intergroup trial, it appears that concurrent therapy is superior to the sequential schedule. These are different data sets, and both trials have a short median follow-up and a relatively small number of events, so we shouldn’t make too much of this yet.

Concurrent therapy after the anthracycline is probably better. I base that belief on the results of the pivotal trials and on a large body of preclinical data that suggest trastuzumab is a good amplifier of chemotherapy-induced apoptosis. Also, considering how rapidly the efficacy curves separate in the joint analysis data, it almost makes one want to start trastuzumab about 10 seconds after a core biopsy is obtained.

Cardiac safety of adjuvant trastuzumab

Breast Cancer Update 2005 (4)

DR EDITH A PEREZ: Although our trial demonstrated that clinical cardiac events are observed in patients receiving adjuvant trastuzumab, the difference is less than four percent compared to the control arm. The numbers are actually a bit lower than the numbers in NSABPB- 31 but statistically quite similar. At this point, we have not seen any difference in cardiac events between the two trastuzumab-containing arms. Not every patient has a reversal of their cardiac events, but most patients definitely improve not only in terms of the clinical symptomatology but also measurable left ventricular ejection fraction.

Breast Cancer Update 2005 (7)

DR WINER: The downside with receiving trastuzumab, apart from the fact that it requires a year’s worth of therapy, is the cardiac toxicity, which was defined as symptomatic congestive heart failure, so we’re not talking about asymptomatic drops in ejection fractions. We’re talking about real problems that we hope can improve over time, but about which we have relatively limited, if any, information regarding the long-term consequences. I generally tell patients that the risk of congestive heart failure is probably in the range of two to four percent, based on what we know so far, specifically in women who receive AC followed by paclitaxel with trastuzumab.

There was some suggestion that the cardiac toxicity may be less when trastuzumab is administered sequentially, as in the NCCTG trial where paclitaxel was given and then trastuzumab followed. Maybe that relates to a longer period of time from when the anthracycline is given to the beginning of trastuzumab. There was also the suggestion of less cardiac toxicity in the HERA trial, where chemotherapy and trastuzumab were not concurrent.

In the NSABP analysis, there was the suggestion that cardiac toxicity was more of a problem in older women, specifically in women who had borderline ejection fractions at baseline versus those who had better, stronger, higher ejection fractions. All of this needs to be sorted out.

In the BCIRG trial, in the group of women who received docetaxel, carboplatin and trastuzumab, the cardiac toxicity was substantially less than in women who received the anthracycline followed by docetaxel and trastuzumab. I think all of us are very hopeful that nonanthracycline-containing regimens will be the wave of the future, but we will just have to wait for the efficacy data. We need those data from the BCIRG trial, and I’m told that we will have those some time over the next several months — certainly at San Antonio, if not before.

Continuing trastuzumab after disease progression

Breast Cancer Update 2005 (5)

DR TRIPATHY: Right now, in the absence of data, we have to use our best knowledge and extensions of the clinical and laboratory data to guide our patients. I personally believe there may be a role for continuing trastuzumab with another chemotherapeutic agent. My patients also usually feel strongly about it, and we often elect to go that route. I don’t use this approach with all of my patients, and I certainly explain to them that we don’t know the answer.

In this situation, trastuzumab appears to be safe. The rate of cardiotoxicity on the extension trial was very low in the patients who were already on trastuzumab and hadn’t developed cardiac problems. I generally continue trastuzumab, but not indefinitely. Once a patient goes through two or three combinations, I think it’s probably prudent to stop trastuzumab and try either single- agent or combination chemotherapy.

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