You are here: Home: BCU 5 | 2006: Edith A Perez, MD

Edith A Perez, MD

Tracks 1-22
Track 1 Introduction
Track 2 Impact of adjuvant trastuzumab data on breast cancer management
Track 3 Importance of waiting for definitive clinical trial data before using an untested therapy
Track 4 Rationale for combined analysis of NCCTG-N9831 and NSABP-B-31 adjuvant trastuzumab trials
Track 5 Design and results of NSABP-B-31 and NCCTG-N9831
Track 6 Incidence of brain metastases in trials of adjuvant trastuzumab
Track 7 Similarities and differences between the HERA trial and the combined NSABP/NCCTG analysis
Track 8 Benefit of concurrent versus sequential administration of chemotherapy and trastuzumab observed in NCCTG-N9831
Track 9 BCIRG 006: Adjuvant trastuzumab with a nonanthracycline-containing regimen
Track 10 Schedule of adjuvant trastuzumab following initial chemotherapy
Track 11 Incidence of false-positive HER2 results with FISH testing
Track 12 Potential correlations between cMYC overexpression and response to trastuzumab
Track 13 Differences in eligibility criteria and definition of cardiac events among adjuvant trastuzumab trials
Track 14 Incidence of cardiac toxicity with adjuvant chemotherapy and trastuzumab
Track 15 Clinical use of adjuvant docetaxel/ carboplatin/trastuzumab (TCH)
Track 16 Dose-dense ACpaclitaxel in combination with adjuvant trastuzumab
Track 17 Delayed adjuvant trastuzumab
Track 18 Current role of adjuvant trastuzumab monotherapy
Track 19 Adjuvant trastuzumab for patients with node-negative disease
Track 20 Future NCCTG adjuvant trial for patients with HER2-positive disease
Track 21 Potential benefit of combining lapatinib and trastuzumab
Track 22 Role of trastuzumab in the management of ER-positive, HER2-positive disease

Select Excerpts from the Interview

Track 5

DR LOVE: Can you summarize the key findings from the combined analysis of NSABP-B-31 and NCCTG-N9831?

DR PEREZ: With a median follow-up of two years, the data demonstrated a significant — not only statistical but clinical — improvement in disease-free, distant disease-free and overall survival for the patients who were assigned to receive concurrent paclitaxel/trastuzumab compared to those assigned to paclitaxel alone.

Another interesting aspect, which has been demonstrated in the other trastuzumab trials, is that the benefit of adding trastuzumab applied to all subgroups of patients with breast cancer. The benefit was irrespective of tumor size, nodal status or estrogen-receptor status (Romond 2005).

DR LOVE: The distant disease-free survival curve from the combined analysis was very striking (2.1). What do you think this means?

DR PEREZ: Dramatic — that’s the best word I can use — although not unexpected in terms of showing a difference. What’s unexpected is the magnitude of the difference. A clear benefit is irrefutable, even with this short median follow-up. This is important for patients and physicians because many times patients or physicians or regulatory agencies say, “In the adjuvant setting, you need to wait 10 or 20 years to make a decision about therapy based on the ultimate outcome.”

In these studies, even with the short median follow-up, the improvements in disease-free, overall and distant disease-free survival (2.2) are so dramatic that we cannot wait if we want to be ethical in our approach to patients. It is my belief that the difference in survival we have observed so far, which is already statistically significant, will increase in the future.

2.1

DR LOVE: It was interesting that the distant disease-free survival curve looked flat at around 90 percent for the trastuzumab arm (2.1).

DR PEREZ: Yes. One of the things we are looking at is the hazard ratio over time. It appears trastuzumab is working very quickly in terms of preventing relapses in these patients with this aggressive type of breast cancer. Their relapses are reaching a plateau, although we have to be careful because the follow-up is short. However, in the control arm, the relapses continue occurring at a higher rate.

2.2

Track 7

DR LOVE: Can you discuss the HERA trial?

DR PEREZ: HERA is an important trial that is complementary to the studies we conducted in the United States. The HERA investigators conducted a three-arm trial in which trastuzumab was always administered sequentially to chemotherapy and radiation therapy.

The three arms included chemotherapy/radiation therapy as per standard of care, another arm that allowed trastuzumab for one year and another arm that allowed trastuzumab for two years. In that trial, trastuzumab was administered once every three weeks (Piccart-Gebhart 2005), whereas in our studies, we used it once per week (Romond 2005).

Some real issues related to HERA are important for clinical practice. Only about 26 percent of the patients in HERA received both anthracyclines and taxanes in the adjuvant setting (2.3). Therefore, the chemotherapy administered was quite different from the chemotherapy we administered in the US studies. About six percent of patients didn’t even receive anthracyclines (Piccart-Gebhart 2005; [2.3]). We need to continue following the curves, in terms of outcomes for the HERA trial.

I’m concerned that despite 32 percent of the patients enrolled in HERA having node-negative breast cancer, which would have led, in my opinion, to a better ultimate outcome for patients in the control arm, it appears that the patients in the control arm of the HERA trial did a little worse than the patients in the control arm of the US studies.

This may be a reflection of the differential outcomes for patients based on the country in which they were treated. It may also be that chemotherapy, especially the use of anthracyclines and taxanes, plays an important role in the setting of HER2-positive breast cancer. Seventy-four percent of the patients in HERA did not receive taxanes (Piccart-Gebhart 2005).

DR LOVE: For those who did receive taxanes — and, of course, now we’re getting into smaller numbers and subgroups — the effect of trastuzumab didn’t seem to be as great.

DR PEREZ: That’s a very good point, which has been missed by many people. This is critically important, because NCCTG-N9831 did not show a dramatic benefit with the use of trastuzumab in a sequential fashion following chemotherapy (Perez 2005).

Our data are not that dissimilar from the data in the HERA study for the patients who received both anthracyclines and taxanes.

2.3

Track 8

DR LOVE: Can you review what NCCTG-N9831 showed in terms of concurrent versus sequential trastuzumab?

DR PEREZ: Although we did not plan to conduct an analysis this early, we have approximately 25 percent of the events required to be firm about the statistical conclusions. We found, statistically, a better disease-free survival rate for patients who received trastuzumab concurrently with paclitaxel compared to those who received trastuzumab at the completion of paclitaxel (Perez 2005; [2.4]).

Based on our data and this important trend, we recommend that patients receive concurrent trastuzumab with a taxane as adjuvant therapy for HER2-positive breast cancer.

DR LOVE: How can you make this conclusion with only a quarter of the events that you originally were targeting for this analysis?

DR PEREZ: We still reached a nominal p-value for the difference between the concurrent and sequential arms. At this time, to be strict from the statistical standpoint, we have a strong trend showing that concurrent is better than sequential (Perez 2005; [2.4]). But again, it follows the data that exist both in preclinical models and the metastatic setting.

2.4

Track 9

DR LOVE: What are your thoughts about BCIRG trial 006?

DR PEREZ: BCIRG 006 evaluated AC followed by docetaxel, AC followed by docetaxel with concurrent trastuzumab, and a third arm without an anthracycline — specifically the TCH regimen, a combination of docetaxel, carboplatin and trastuzumab. The results, as presented at the 2005 San Antonio Breast Cancer Symposium, demonstrated a better outcome for the two trastuzumab-containing arms compared to the control arm (Slamon 2005), which was similar to what we saw in the other studies. I see an important trend in benefit with AC followed by docetaxel/trastuzumab compared to TCH. Specifically, three-year disease-free survival was 86 percent for the patients who were assigned to AC followed by docetaxel/trastuzumab versus 80 percent for those assigned to TCH (Slamon 2005).

Based on the results from BCIRG 006, we can say that no statistical difference exists between AC followed by docetaxel/trastuzumab and TCH. However, this trend should be taken into consideration when counseling patients. At this time, I would not favor TCH over an anthracycline/taxane/trastuzumab regimen.

Track 13

DR LOVE: Can you summarize the cardiac risk associated with trastuzumab-containing regimens?

DR PEREZ: The cardiac side effects associated with trastuzumab are minimal compared to its efficacy in terms of disease-free and overall survival. At the same time, we take cardiac risk very seriously, because we would like to administer therapies that have no side effects. However, we cannot forget the tremendous improvement in the lives of patients that we have achieved with the use of trastuzumab.

I would like people to remember that it is not appropriate to do cross-study comparisons related to cardiac toxicity. The eligibility, based on age, and the definition of cardiac toxicity varied between the different trials. So it is dangerously incorrect to put tables together comparing the cardiac toxicity in BCIRG 006, HERA, NCCTG-N9831 and NSABP-B-31.

For NSABP-B-31, NCCTG-N9831 (Romond 2005) and HERA (Piccart-Gebhart 2005), we did not have an upper age limit for enrollment. In BCIRG 006, patients had to be 70 years old or younger (Slamon 2005). In the FinHER trial, patients had to be younger than 66 years of age (Joensuu 2006).

If we look at the enrollment according to left ventricular ejection fraction (LVEF) in NSABP-B-31 and NCCTG-N9831, the baseline LVEF had to be above the lower limit of normal (Romond 2005) or above 50 percent, whereas in HERA it had to be greater than 55 percent (Piccart-Gebhart 2005).

Additionally, let’s look at the definition of cardiac events. In the NCCTG-N9831 trial, NSABP-B-31 and BCIRG 006, if a patient developed one episode of decreased LVEF, that patient was counted in that group. In HERA, patients had to have a persistent decrease. So if the patient had only one decrease of LVEF, she was not counted in the group who developed decreases in LVEF.

Another important factor with HERA is that they divided patients with congestive heart failure into two groups — a mild and a severe group (Piccart-Gebhart 2005). When we reported our data from NCCTG-N9831, we combined the mild and severe cases. It’s going to be very important for us to compare apples to apples. We had a meeting with the cardiologists from HERA, NSABP-B-31 and BCIRG 006, and we’re trying to come up with common definitions of cardiac toxicity.

Track 14

DR LOVE: What would you tell a patient who asks, “What is the chance I’m going to have a serious cardiac event with trastuzumab?”

DR PEREZ: It’s about three percent. We’re finding out that this three percent incidence appears to plateau. No differences appear between years two and three in terms of the incidence of cardiac toxicity (Tan-Chiu 2005). It’s specifically 3.5 percent in the AC followed by paclitaxel/trastuzumab arm of NCCTG-N9831. I believe most of the cardiac toxicity events are appearing quite early, but follow-up will be needed. The majority of these patients get better quickly.

DR LOVE: What would you say about cardiac safety to a patient who’s considering TCH?

DR PEREZ: In BCIRG 006, no statistical difference in cardiac toxicity appeared between TCH and AC followed by docetaxel/trastuzumab. I believe in terms of cardiac toxicity, either regimen is pretty safe. I would not favor one over another, based on the information presented by Dr Slamon at San Antonio (Slamon 2005).

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