Tracks 1-17

Track 1 Introduction Track 2 Importance of waiting for definitive research data before using an unproven treatment approach Track 3 Acceptance of trastuzumab as adjuvant therapy in the United Kingdom Track 4 Biologic rationale for topoisomerase II-alpha (TOPO II) amplification predicting sensitivity to anthracyclines Track 5 TOPO II amplification and the efficacy of anthracycline-based chemotherapy in BCIRG 006 Track 6 Clinical use of TOPO II amplification to select adjuvant chemotherapy for patients with HER2-positive disease Track 7 Lack of reliable HER2 testing in the United States Track 8 Potential benefit of adjuvant trastuzumab monotherapy Track 9 Concurrent versus sequential administration of trastuzumab and chemotherapy Track 10 Sequential use of trastuzumab to abrogate cardiac toxicity Track 11 Duration of adjuvant trastuzumab Track 12 Necessity of clinical trials examining the duration of adjuvant trastuzumab Track 13 Clinical use of adjuvant trastuzumab monotherapy Track 14 Role of cardiac monitoring in treatment decision-making regarding adjuvant trastuzumab Track 15 Use of Oncotype DX™ to determine therapy for patients with ER-positive, HER2-positive disease Track 16 Quality control in ER and HER2 testing Track 17 Efforts to improve national standards for ER and HER2 testing

Select Excerpts from the Discussion

Tracks 4-7

DR LOVE: Mark, what’s your reaction to the TOPO II data that were presented as a part of the BCIRG 006 analysis?

DR PEGRAM: The TOPO II data from BCIRG 006 are retrospective and are the result of a subset analysis of an interim analysis of the efficacy data; ergo, all of the data should be considered exploratory in nature and hypothesis-generating (Press 2005; Slamon 2005). In terms of clinical practice, you have to understand the caveats and limitations of the data set before you make any decisions about its applicability to clinical practice.

The topoisomerase story began with Hy Muss’s publication in the mid-1990s of a CALGB trial looking at different doses of doxorubicin-containing adjuvant chemotherapy (Muss 1994). Among patients with elevated HER2 expression, a dose effect of the different doses of doxorubicin was seen, whereas in the non-HER2-expressing subset no such effect was evident, suggesting that patients with HER2-positive disease uniquely benefit from adjuvant anthracyclines.

This is what really started the whole dogma in clinical practice that patients with HER2-positive disease uniquely benefit from anthracyclines and why clinicians began using HER2 as a marker to predict responsiveness to doxorubicin. However, the question from a research point of view is whether it’s really HER2 that’s driving this phenotype or something else.

We talked to Giovanni Pauletti at UCLA, who was then mapping the HER2 amplicon, and he, as well as others, pointed out that the TOPO II gene is in close physical proximity to the HER2 gene on the long arm of chromosome 17 and that, on occasion, it is coamplified with the HER2 gene.

Inasmuch as TOPO II alpha is the target for the anthracyclines, perhaps this is what’s driving the sensitivity phenotype to doxorubicin rather than HER2 itself.

A number of groups have tested this hypothesis in clinical trials, particularly in neoadjuvant clinical trials. We knew that we’d have an opportunity to test this hypothesis in the BCIRG trial because we had both an anthracycline- and a nonanthracycline-containing trastuzumab arm in this three-arm trial, and amplification of HER2 was an eligibility criterion.

Mike Press has completed the TOPO II analysis for 2,120 of the 3,200 patients in the BCIRG 006 trial. In this cohort, he found that approximately 35 percent of the patients had coamplification of TOPO II and that this coamplification seemed to confer a therapeutic advantage to anthracycline-based trastuzumab regimens.

Patients with HER2-positive breast cancer that was not coamplified for TOPO II, who constituted two thirds of the patients, did not appear to have the same benefit and therefore may be ideal candidates for efficacious nonanthracycline-based trastuzumab regimens, thus avoiding potential cardiac toxicity.

DR LOVE: Dan, you chaired the San Antonio session where Dr Slamon presented these data, and following the talk you made the comment that the TOPO II data were not ready for clinical practice. Could you explain?

DR HAYES: There could be a number of reasons for this to be a false-positive result, and there are a lot of reasons why it could be real. We need longer follow-up and we need other groups to evaluate this in their own trials.

DR PEGRAM: With the complete data set from the BCIRG 006 trial of all 3,200 patients and longer follow-up, the statistical power will be ever increasing, and it may yield a significant result in the end.

Tracks 8-10

DR LOVE: Dr Burstein, could you summarize the issue of concurrent versus sequential trastuzumab with chemotherapy?

DR BURSTEIN: We have a wealth of data from more than 10,000 patients assigned to randomized trials of chemotherapy with or without the addition of trastuzumab, all reported in 2005 and most now in publication (HERA Study Team 2005; Piccart-Gebhart 2005a, 2005b; Romond 2005a, 2005b). All of these trials had remarkably consistent results in terms of the improvement in hazard ratios with the addition of trastuzumab.

The interesting question has been whether it is better to give adjuvant trastuzumab concurrently with chemotherapy or sequentially. In the North American Intergroup trial, NCCTG-N9831, in arm A patients received chemotherapy alone, in arm B they received AC followed by paclitaxel followed by trastuzumab, and in arm C the patients received AC followed by concurrent paclitaxel/trastuzumab and then ongoing trastuzumab.

The analysis comparing arms A and B showed no significant difference in event-free survival, whereas the preliminary comparison of arms B and C — concurrent versus sequential therapy — suggested roughly a 40 percent reduction in the risk of recurrence with concurrent therapy, which was statistically significant (Perez 2005).

In the HERA trial, the patients were randomly assigned to zero, one or two years of trastuzumab, and all trastuzumab was given sequentially to chemotherapy. In contrast to the Intergroup findings, this trial showed roughly a 50 percent reduction in the risk of recurrence with sequential trastuzumab, as measured by disease-free survival (Piccart-Gebhart 2005).

DR LOVE: How does one reconcile the N9831 and the HERA data?

DR BURSTEIN: My own hypotheses are, first, that N9831 remains somewhat underpowered because of the lack of events. Therefore, it’s possible, if not probable, that an ongoing analysis of arms A and B — that is, no trastuzumab versus sequential trastuzumab — might have shown more of an advantage.

Also, all the patients in the N9831 trial received anthracycline- and taxane-based therapy, whereas the HERA trial did not specify the adjuvant chemotherapy to be used.

Whereas the vast majority of patients in HERA received anthracycline-based regimens, only one quarter received a taxane, and those patients who received an anthracycline and a taxane received the least benefit from trastuzumab.

My interpretation of the N9831 and HERA trials is that concurrent therapy might be clinically more efficacious overall than sequential therapy, and sequential therapy is only modestly better than no therapy in patients receiving anthracycline- and taxane-based treatment.

The BCIRG 006 trial also looked at concurrent trastuzumab, and those data suggest that trastuzumab concurrent with chemotherapy is beneficial (Slamon 2005).

DR LOVE: Do you feel single-agent trastuzumab is a reasonable option in the delayed adjuvant setting for patients who did not receive it previously?

DR BURSTEIN: For patients who completed anthracycline- and taxane-based chemotherapy six or 12 months previously and did not receive trastuzumab, few data suggest that the subsequent addition of trastuzumab will significantly lengthen their disease-free survival.

Track 11

DR LOVE: What about using a chemotherapy/trastuzumab combination without a taxane?

DR WINER: I’m not sure that absolutely every patient with HER2-positive breast cancer needs to receive AC followed by paclitaxel, particularly patients who don’t want to receive a taxane or those with a lower risk of recurrence. Based on the HERA data, I believe it’s reasonable to give four cycles of AC followed by a year of trastuzumab. The risk reduction is every bit as large as in the US trials.

DR LOVE: Can anyone identify a patient for whom you would consider adjuvant trastuzumab without chemotherapy?

DR VOGEL: I just had a patient with high-risk, node-negative breast cancer and a concomitant Epstein-Barr virus infection and hepatitis C. She is very well informed and deathly afraid of immunosuppression secondary to chemotherapy, and no one could convince her to receive chemotherapy.

For this patient, even in the absence of data, I thought it was better to administer trastuzumab monotherapy than not to give her trastuzumab.

DR LOVE: What about patients for whom you previously wouldn’t have administered adjuvant chemotherapy because of age or comorbidities?

DR VOGEL: I would consider trastuzumab alone.

DR OSBORNE: I have not given single-agent trastuzumab in the adjuvant setting in practice, but I’m a believer in targeted therapy.

I believe tumors are driven by certain pathways and that, if you block that pathway, you will kill the tumor. We’ve seen that now with hormonal therapy.

For patients with ER/PR-positive tumors, except for those tumors that are resistant, endocrine therapy is very good and chemotherapy doesn’t add anything or it adds, at most, only a tiny benefit. I believe we will find that in the future, for patients with HER2-positive disease, HER2-targeted therapy without chemotherapy will be all we need.

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