1. Should clinicians routinely recommend trastuzumab (Herceptin) as part of the adjuvant therapy for all patients with Her2 positive early breast cancer?
A review of recent data, and reflections on how these results relate to the use of Adjuvant!
The recent announcement of positive results from the three trials evaluating trastuzumab in the adjuvant setting, has caused clinicians to need to address the question of whether their patients who have Her2 positive tumors should receive trastuzumab as part of their adjuvant therapy. An obvious question is how Adjuvant! will handle this new information, assist health professionals weight the risks and benefits of such therapy, and aid health professional / patient communication about this information.
Although the trastuzumab trials have strikingly positive results, they have a critical weakness, short follow-up (1.0, 1.5, and 2.4 years). Thus for a disease like breast cancer where relapse and mortality occur over 10 years and longer, these trastuzumab results must be considered preliminary, with estimates of efficacy at 5 and 10 years a matter of speculation, as is any current estimation of the safety profile, particularly those related to cardiac safety. Because Adjuvant! makes long term outcome estimates, and because critical parameters relating to the long term efficacy and safety are as yet unknown, the decision has been made not to add trastuzumab as a treatment modality that can be selected in Adjuvant! until more follow-up information is available (although admittedly this information may be complex to interpret because of the plans to cross over of some of the control patients).
Nonetheless many clinicians may decide to use trastuzumab as part of the adjuvant therapy for their patients whose tumors express Her2. There are several lines of thinking that would support such present use. First are the positive results themselves showing improvement in early DFS and OS. Second, although the supporting evidence is some ways preliminary, such strong early results from large trials usually hold up over the long term. Third, that the control arms of the trials have been offered trastuzumab reflects confidence in the trialists and some regulatory bodies that the early results will hold up over the long term.
However there are reasons to be cautious about treating patients with trastuzumab in the adjuvant setting. First, the results are based on very early follow-up and occasionally results over the long term are not so positive. Second, regulatory and guideline committees have generally not reviewed and issued statements about whether such therapy is appropriate. Finally, issues of how and who will pay for adjuvant trastuzumab have not been addressed yet in many settings.
What follows is a review of the data recently presented. In addition there is a very speculative model of outcomes with adjuvant trastuzumab. This model is used to illustrate that for some patients the benefit to risk ratio may not be unequivocally positive. In addition this model illustrates that for trastuzumab as an adjuvant modality, just as for adjuvant hormonal therapy and chemotherapy, patients at low risk for recurrence, or at high risk for toxicity, may not experience an overall benefit.

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3. An Interpretation of Adjuvant Herceptin Results Presented at ASCO May 2005
1) Romond EH, Perez EA, Bryant J, et al.
Doxorubicin and Cyclophosphamide Followed by Paclitaxel with or without Trastuzumab as Adjuvant Therapy for Patients with HER-2 Positive Operable Breast Cancer: Combined Analysis of NSABP B31/NCCTG-N9831
2) Perez EA, Suman VJ, Davidson N, et al.
NCCTG N9831 May 2005 Update
3) Piccart MJ
First Results Of The HERA Trial
At a special session of the May 2005 ASCO meeting in Orlando the results of 3 randomized trials testing trastuzumab (Herceptin) in the adjuvant therapy of Her2 positive breast cancer were presented.
Because these three presentations were part of a special last minute session, there are no specific abstracts to refer to although the presentations are on the ASCO website at

4. HERA (Randomization after chemotherapy)
NSABP B-31
Arm 1
Arm 2
NCCTG N9831
Arm A
Arm B
Arm C
HERA (Randomization after chemotherapy)
Arm A No Herceptin
The three trials are being conducted by the NSABP (NSABP B-31), the North American Intergroup (led by the NCCTG, N9831), and an international trial consortium (HERA). All of these trials contained control arms in which patients did not receive trastuzumab, and all patients in the trials received adjuvant (or in the case of some patients in the HERA trial neoadjuvant) chemotherapy. In the HERA trial randomization occurred after adjuvant chemotherapy. In B31 and N9831 trials the patients were randomized prior to getting chemotherapy.
Arm B
(1 yr)
Arm C
(2 yr)
AC q 3 wk * 4
= paclitaxel q 3 wk * 4
= paclitaxel q 1 wk * 12
= trastuzumab q 1 w
= trastuzumab q 3 w

5. Combined analysis of B31 / N9831
Control
Arm 1 (B31)
Arm A (N9831)
Herceptin
Arm 2 (B31)
Arm C (N9831)
Because of the many similarities in eligibility and treatment in the B31 and N9831 trials, the decision was made to do a combined analysis. This combined analysis included results from the control arms of these two trials, and the arms of the trials in which patients received trastuzumab starting concurrently with paclitaxel and continuing for a total of 1 year.
All patients received 4 cycles of doxorubicin and cyclophosphamide (AC * 4), followed by 12 weeks of paclitaxel. A slight difference between the trials was that in the NSABP trial the paclitaxel was given every 3 weeks, and in the Intergroup trial it was given on a weekly basis. Trastuzumab was given weekly starting with the first paclitaxel treatment and continuing for a total of 52 weeks.
Median follow-up was short, only 2.0 years (2.4 years in the B31 and 1.5 years in N9831).
Combined: n = 3,351; median follow-up 2.0 yr
NSABP B-31: n = 1,736; median follow-up 2.4 yr
N9831: n = 1,615; median follow-up 1.5 yr

6. Eligibility NSABP B-31 / N9841
Definitively resected primary adenocarcinoma of the breast.
Axillary node positive (N9841 was amended to allow high risk node negative).
No locally advanced or metastatic disease.
Normal hematologic, hepatic, and renal function.
No prior anthracycline or taxane therapy.
No significant sensory or motor neuropathy.
No past or current cardiac history.
Normal LVEF.
Her2 IHC +++ or FISH + (N9831 by central lab, B31 by approved reference laboratory).
The eligibilty criteria shown in red are of special importance to this trial.
Because of the concern about possible cardiac toxicity, patients with a history of cardiac history were not eligible. Patients also must have had a normal left ventricular fraction (LVEF).
Because of concern about the quality of Her2 determinations done at some sites, a special effort was made to standardize Her2 determinations. To be eligible patients had to have Her2 determined by immunohistochemistry as +++ or to have Her2 gene amplification as determined by FISH. The B31 trial required that the Her2 determination be done at an approved laboratory. The N9831 trial required that the determinations be done at a central laboratory.
[[ No past or active cardiac disease included: history of myocardial infarction, history of congestive heart failure, angina pectoris requiring medication, arrhythmia requiring medication, clinically significant valvular disease, uncontrolled hypertension, LVH, and cardiomegaly on CXR.]]

7. Patient / Tumor: Characteristics
No Imbalances Between Treatment Arms
(numbers shown are % of total)
Age
<
>
Nodes
N0 6
NP (1-3) 53
NP (4-9) 27
NP (> 9) 14
Tumor Size
T < 2cm 39
T cm 45
T > 4 cm 15
ER and PgR Status
ER + 52
ER - 48
PgR + 40
PgR - 59
Most of the patients in this trial were node positive. The N9831 trial had been amended to include high risk node negative patients, so there were a few (6% overall) patients who were node negative.
Median age was approximately 50. About 40% of the patients had T1 tumors. About 50% of the patients were ER positive. Patients who were ER positive received tamoxifen.
There were no imbalances in patient or tumor characteristics between the treatment arms in this combined analysis.

8. Combined Analysis for DFS of
NSABP B-31 / NCCTG – N9831
ACTH
87%
85%
ACT
75% %
67%
N Events
ACT
ACTH
The primary endpoint of the analysis was disease free survival (DFS). There was both a strong statistically significant absolute advantage for trastuzumab (8% at 3 years), and also relative advantage (hazard ratio 0.48). This is a 52% reduction in recurrence and mortality events.
HR=0.48, 2P=3x10-12
Years From Randomization

9. Combined Analysis for DFS of Subset Analysis For DFS
NSABP B-31 / NCCTG – N9831
Subset Analysis For DFS
Herceptin Benefit
In all age subsets
In all tumor size subsets
In all nodal subsets (NN CI very broad)
In ER positive and negative subsets
In both N9831 and B31
Subset analysis was done and showed benefit irrespective of age, tumor size, number of positive nodes (although very few patients who were node negative were included in the analysis), ER status, or which trial they participated in.

10. Forest Plot For DFS: B31/N9831
ALL DATA
Age
≥60
50-59
40-49
≤39
Hormone
Receptor
Positive
Negative
Tumor
Size
≥ 4.1cm cm
<2.0 cm
No.
Positive
Nodes
10+
4-9
1-3
Subset analysis was done and showed benefit irrespective of age, tumor size, number of positive nodes (although patients who were node negative were included in the analysis), ER status, or which trial they participated in.
Protocol
N9831
NSABP B-31
0.2
0.4
0.6
0.8
1.0
1.2
1.4
Hazard Ratio

11. Combined Analysis for DDFS of
NSABP B-31 / NCCTG – N9831
100
ACTH
AC->T+H
90%
90%
90%
90%
90%
90% 90
ACT
AC->T 80
81%
81%
81% %
74% 70
74%
74%
N Events
N Events
ACTH
ACT
AC->T
A secondary endpoint of the analysis was distant disease free survival (DDFS, risk of developing metastatic disease). There was both a strong statistically significant absolute advantage for trastuzumab (9% at 3 years), and relative advantage (hazard ratio 0.47). This is a 53% reduction in the risk of developing metastatic disease. 60
AC->T+H
HR=0.47, 2P=8x10-10
HR=0.47, 2P=8x10-10 50 1 2 3 4 5
Years From Randomization

12. Annual Hazard of Distant Recurrence
120
100
ACT 80
Rate per 1000 Women /Yr 60 40
The annual risk of distant recurrence shows no major difference in the first year, but major differences in years 2 and 3. In year 4 the difference seems to get even larger, but very few patients had been followed for 4 years (the median follow-up was only 2.0 years).
ACTH 20 1 2 3 4
Years From Randomization

13. Combined Analysis for OS of
NSABP B-31 / NCCTG – N9831
ACTH
94%
91%
ACT
92%
87%
N Deaths
ACT
ACTH
A secondary endpoint of the analysis was overall survival (OS, risk of dying). There was both statistically significant absolute advantage for trastuzumab (2% at 3 years), and relative advantage (hazard ratio 0.67). This is a 33% reduction in the risk of dying at short follow-up.
HR=0.67, 2P=0.015
Years From Randomization
B31/N9831

14. Cardiac Monitoring ~ 20% of the patients discontinued Herceptin
because of symptomatic or asymptomatic
heart problems
Herceptin * 12 mns
AC * 4
Taxol * 4
Baseline
3 mns
6 mns
9 mns
15 mns
18 mns
In the initial trials with trastuzumab in the treatment of metastatic disease an increased risk of congestive heart failure was seen, in particular in patients that received concurrent doxorubicin. Although no such concurrent trastuzumab and doxorubicin was planned in any of the adjuvant therapy trials, the two types of therapy were planned to be given within as little as 3 weeks. Therefore all the trials were designed with especially careful monitoring of cardiac safety.
This slide and the following slides draw on data from B31 alone, as the data cardiac data from N9831, and as a combined cardiac safety analysis has not yet been presented. It includes both cardiac safety data presented at the 2005 ASCO meeting and the 2003 SABCS (reference below).
As part of this process all patients received baseline and follow-up cardiac monitoring. In addition a special cardiac safety analysis of the first 1000 patients participating in B31 was undertaken and has been reported. Of interest is that ~ 25% of the patients participating in B31/N9831 had some cardiac abnormality (for the most part asymptomatic falls in LVEF) that necessitating not starting, or discontinuing the trastuzumab.
About 4% of the patients had significant falls in their LVEF after completing the 4 cycles of doxorubicin and cyclophosphamide. These patients never went on to get trastuzumab. During the trastuzumab therapy another 20% of patients had decreases in LVEF necessitating discontinuation of the trastuzumab.
[Geyer, Jr. CE, Bryant J, Romond E, et al. Cardiac safety analysis of the first stage of NSABP B-31, a randomized trial comparing the safety and efficacy of Adriamycin and cyclophosphamide (AC) followed by Taxol to that of AC followed by Taxol plus Herceptin in patients (Pts) with operable, node-positive (N+), HER-2 overexpressing breast cancer (HER2+BC).  Abstract 23, SABCS ]
2.1%
7.7%
10.1%
% stopping Herceptin by time period
~ 4 % of patients never got Herceptin because of developing a low LVEF post AC * 4.
LVEF measurements
This analysis from B31data alone.

15. Rules for action for asymptomatic patients Absolute Decrease in LVEF
Cardiac Monitoring
Rules for action for asymptomatic patients
Absolute Decrease in LVEF
< 10 %
10-15%
> 15%
Normal LVEF
Continue
Hold *
1-5% below LLN of LVEF
> 5% below LLN or LVEF
Continue *
Rules for holding and possibly discontinuing trastuzumab in asymptomatic patients depended on the measurements of the absolute value and change in the LVEF.
* Repeat LVEF assessment in 4 weeks
If criteria for continuation met restart
If 2 consecutive holds of a total of 3 holds, discontinue Herceptin

16. Age and Post AC LVEF were predictors of the risk of developing CHF
Cardiac Safety
Age and Post AC LVEF were predictors of the risk of developing CHF
Risk of CHF (%)
Age younger than 50
Age 50 and older
Initial LVEF
6.3 %
19.1 %
Initial LVEF
2.2 %
5.2 %
Initial LVEF > 65
0.6 %
1.3 %
Fortunately most of these cardiac issues were not associated with congestive heart failure (CHF), with ~ 3% of patients overall developing this problem.
It was possible to refine somewhat the estimates of who was at risk of congestive heart failure, with age and post AC * 4 (pre-trastuzumab) LVEF being predictors of heightened risk.
Women who were younger than 50 and who had an excellent post-AC*4 LVEF had a < 1% risk of developing congestive heart failure. Women who were 50 and older who had a borderline (50-54% LVEF) after AC*4 had nearly a 20% risk of developing CHF.
In both age groups about 10% of the patients had a LVEF of 50-54,
about 50% of the patients had a LVEF of 55-64, and 35% had a LVEF of > 65%. Average risk of early CHF for patient younger than 50 is 2 % and older than 50 is ~ 5%
This analysis from B31data alone.

17. (no strong evidence of an major delayed toxicity)
Risk of Cardiac Events
(no strong evidence of an major delayed toxicity)
End of Herceptin treatment period
One aspect of the risk of congestive heart failure that was somewhat reassuring was that nearly all the instances of CHF seemed to develop during the treatment with trastuzumab, and few instances afterwards. Again it would be more reassuring to have longer term follow-up to be more certain about this crucial point.
The only cardiac death that occurred during this study occurred in a control patient.
This analysis from B31 data alone.

18. Cardiac Safety Analysis For First 1000 Patients
NSABP B-31
Cardiac Safety Analysis For First 1000 Patients
Baseline all patients normal LVEF (median 63%)
After 3 months of AC
LVEF median 61% (lower, p<0.001)
4.2% of patients with LVEF < 50%
Total symptomatic cardiac events during Herceptin
4.28 % in Herceptin group
0.78 % in Control group
Patients with low LVEF did not go on to get Herceptin.
The first 1000 patients in B31 underwent a preplanned cardiac safety analysis. This safety analysis showed on average a small drop in the average LVEF after AC*4, with 4.2% of the patients developing abnormally low LVEFs. These patients were not allowed to go on to treatment with trastuzumab.
In the patients who went on to further therapy there was an excess of caridac events in the patients getting trastuzumab (4.3 % of the patients versus 0.8% in the control group.
of these 33% had LVEF < 30%, 52% LVEF 30-39%

19. NSABP B-31 Cardiac Safety Analysis For First 1000 Patients
Herceptin Related Fall In LVEF Was Largely Reversible
In Patients With A Cardiac Event (n=27)
A somewhat reassuring aspect of the 1000 patient safety substudy of B31, is that most of the symptomiatic cardiac problems were reversible. For patients in the substudy who experienced a cardiac event and a fall in LVEF, most of them had a substantial improvement in LVEF afterwards, and 68% of the women had a resolution of symptoms within 6 months.
Although this analysis is not completely reassuring because long term cardiac safety information is not available, it suggests that much of the acute trastuzumab/anthracycline toxicity is usually reversible or manageable (some patients were still on cardiac medications although asymptomatic) at least in the short term.
~ 68% of the patients had symptoms resolve within 6 months

20. Analysis of Three Arms of N9831
NCCTG N9831
Arm A
Arm B
Arm C
As part of the ASCO presentations, there was a second presentation that focused only on the N9831 trial. This trial is of particular interest because it included an arm (Arm B) in which trastuzumab was started only after all the chemotherapy was completed. This arm is of particular interest because its results can provide insight into whether the added effectiveness of trastuzumab is due to it enhancing the efficacy of paclitaxel (when given at the same time), or whether its effect is evident when it is only given as a single agent.
Again it needs to be kept in mind while reviewing this information is that the median follow-up is very short, only 1.5 years.
n = 2,804; median follow-up 1.5 yr

21. N9831 Disease-Free Survival Control vs Concurrent
AC → T + H → H
100 90 80 70 60 50 40 30 20 10
AC → T %
In this trial there was, as previously presented as part of the combined analysis of both B31 and N9831, a clear DFS advantage for the concurrent arm over the control arm with an approximately 50% reduction in events.
Hazard ratio = 0.55
Stratified logrank 2P =
Years

22. N9831 Disease-Free Survival Control vs Sequential
100 90 80 70 60 50 40 30 20 10
AC → T → H
AC → T %
In the analysis of control (AC * 4 followed by paclitaxel * 4) versus sequential treatment with chemotherapy and then trastuzumab, the hazard ratio was only 0.87 and the benefit of adding trastuzumab was not statistically significant.
This result suggests that much of the benefit of adding trastuzumab arises because of the concurrent use of trastuzumab and paclitaxel. There are two reasons why this conclusion may be premature. First the follow-up of this trial is exceptionally short (only 1.5 years), and secondly the results do not agree with those of the HERA trial in which trastuzumab added substantial benefit even when started after the chemotherapy.
Hazard ratio = 0.87
Stratified logrank 2P = 0.29
Years

23. N9831 Disease-Free Survival Sequential vs Concurrent
AC → T + H → H
100 90 80 70 60 50 40 30 20 10
AC → T → H %
In N9831 the sequential use of trastuzumab and paclitaxel was inferior to their concurrent use. Again it must be emphasized that although this difference is statistically significant, it is based on very short follow-up.
There is one aspect of this which seems potentially favorable and one aspect with is unfavorable.
A possible favorable aspect of this result is that perhaps most of the benefit of adjuvant trastuzumab is attained when it is given with paclitaxel. This suggests that it might not be necessary to give trastuzumab for a year. This could, if true, result in considerable reduction in cost. However this conclusion, while attractive, is premature, given the exceptionally short follow-up of this trial and the fact that the HERA trial seems to support somewhat different conclusions.
Somewhat of a disappointment in this trial is that it suggests that to be most effective trastuzumab needs to be given within 3 weeks of the AC * 4 regimen’s last dose. If additional time between the last dose of AC * 4 and trastuzumab is shown to improve cardiac safety, this trial suggests that this safety stratagem might come at the cost of reduced efficacy.
Hazard ratio = 0.64
Stratified logrank 2P =
Years

24. Cardiac Safety in 9831
Difference in the incidence of cardiac events (CHF and cardiac deaths) between non-H and H arms is < 4%
9 month (post finishing AC * 4) analysis; 500 per arm with normal LVEF or LVEF decrease  15% from baseline (after AC)
0.0% with events (95% CI, %) for control
2.2% with events (95% CI, %) for control vs sequential
3.3% with events (95% CI, %) for control vs concurrent* therapy with paclitaxel
Cardiac safety results from N9831 are still very preliminary given the short follow-up. The reported number of cardiac events shows an excess in the patients treated with trastuzumab, but the excess is < 4 %.
Based on an analysis of the first 9 months of post AC * 4 follow-up there seems to be an slightly higher risk of events in the concurrent arm, but the interpretation of this is complicated by the fact that patients in the concurrent group had started trastuzumab 3 months earlier and therefore had completed 9 rather than 6 months of therapy.
* at month 9, concurrent pts have received 3 additional months of Herceptin compared to sequential

25. HERA (Randomization after chemotherapy)
HERA Trial
HERA (Randomization after chemotherapy)
Arm A No Herceptin
Arm B
(1 yr)
Arm C
(2 yr)
The third adjuvant trastuzumab trial presented at ASCO was the HERA trial. This trial had a different design than the B31 and N9831 trials. In this trial all patients were randomized and started trastuzumab after completing adjuvant chemotherapy. The chemotherapy regimen was not as standardized as in the North American trials, but had to be one of the approved regimens.
The major questions this trial was designed to answer was whether 1 year of trastuzumab improved outcome and whether 2 years of trastuzumab would be even better. This analysis compared the early results of Arm A (no trastuzumab) with Arm B (1 year of trastuzumab).
This trial enrolled 3,307 patients. It was reported at only 1 year of follow-up.
Only Arms 1 and 2 analyzed in this interim analysis
n = 3,307, median follow-up ~ 1 year

26. Eligibility HERA Trial
Definitively resected primary adenocarcinoma of the breast.
Received and completed neoadjuvant and/or adjuvant chemotherapy. Chemotherapy must have been at least 4 cycles of an approved regimen.
If node negative tumor size must have been T1c or larger (for adjuvant patients).
Normal LVEF by MUGA or echo of > 55%.
Her2 IHC +++ or FISH + by central lab.
Known (and centrally reviewed ER status).
The eligibility criteria for this trial were far broader that for the North American Trials. Patients must have received chemotherapy for their early breast cancer, but they could have received it either as adjuvant of neoadjuvant therapy. The chemotherapy received must have been at least 4 cycles of an approved regimen.
Node negative patients could have been included, but they must have had a tumor T1c > 10 mm in size.
Patients must have had a LVEF > 55%.
Her2 must have been confirmed to be +++ by IHC or FISH + by the central lab.

27. HERA Trial: Patient / Tumor: Characteristics
No Imbalances Between Treatment Arms
(numbers shown are % of total)
Age
<
>
Nodes
N0 33
NP (1-3) 29
NP > 4 28
NeoAdj 11
Adjuvant Regimen
Anthracyclines 68
Anathra + Taxane 26
No A or Taxane 6
ER and PgR Status
ER + 51
ER - 49
The median age was approximately 50.
One third of the patients participating in this trial were node negative.
About 95% of the patients participating in this trial had received an anthracycline as part of their therapy.
About one quarter had received a taxane. About 50% of the patients were ER positive. Most of these patients received some form of hormonal therapy.

28. Months from randomization
DFS: HERA Trial
Trastuzumab 1 yr
% alive and disease free
100 90 80 70
Observation 60 50
2-yr DFS % 40
Events HR
[95% CI]
p value 30 20
127
85.8
0.54
[0.43, 0.67]
<0.0001
The HERA trial like the B31 and N9831 trials showed a striking improvement in DFS, reducing the risk of relapse and mortality events by about 50%. This result is statistically significant. The difference in outcome is also large in absolute terms with about an 8% advantage at 2 years of follow-up.
This result is more positive than the sequential chemotherapy trastuzumab arm of N9831. The reason for this difference in results is unclear. 10
220
77.4 5 10 15 20 25
No. at risk
Months from randomization
1694
1472
1067
629
303
102
1693
1428
994
580
280 87

29. DFS In Patient Subsets: HERA Trial
Hazard
Hazard
ratio
ratio n n
All
All
3387
3387
0.54
0.54
Nodal
Nodal
status
status
Any, neo
Any, neo - -
adjuvant chemotherapy
adjuvant chemotherapy
358
358
0.53
0.53
0 pos, no neo
0 pos, no neo - -
adjuvant chemotherapy
adjuvant chemotherapy
1100
1100
0.52
0.52 1 1 - -
3 pos, no neo
3 pos, no neo - -
adjuvant chemotherapy
adjuvant chemotherapy
972
972
0.51
0.51
4 pos, no neo
4 pos, no neo - -
adjuvant chemotherapy
adjuvant chemotherapy
953
953
0.53
0.53
Adjuvant chemotherapy regimen
Adjuvant chemotherapy regimen
No anthracycline or taxane
No anthracycline or taxane
203
203
0.64
0.64
Anthracycline, no taxane
Anthracycline, no taxane
2307
2307
0.43
0.43
Anthracycline + taxane
Anthracycline + taxane
872
872
0.77
0.77
Receptor status/endocrine therapy
Receptor status/endocrine therapy
Negative
Negative
1674
1674
0.51
0.51
Pos + no endocrine therapy
Pos + no endocrine therapy
467
467
0.49
0.49
Pos + endocrine therapy
Pos + endocrine therapy
1234
1234
0.68
0.68
The advantage was evident irrespective of nodal status, hormone receptor status, or age.
All treatment groups benefited. It is interesting but was not commented on (and a purely speculative observation) that the subgroup that benefited least was the group that had gotten both an anthracycline and a taxane, similar in a way to the chemotherapy given in the sequential arm of N9831.
It must be cautioned again that this analysis is based on only 1 year of follow-up.
Age group
<35 yrs
<35 yrs
251
251
0.47
0.47 35 35 - -
49 yrs
49 yrs
1490
1490
0.52
0.52 50 50 - -
59 yrs
59 yrs
1091
1091
0.53
0.53
60 yrs
60 yrs
549
549
0.70
0.70
Trastuzumab
Better
Observation
Better 1 2

30. (very early 1 year median follow-up report)
Cardiac Safety in HERA
(very early 1 year median follow-up report)
Observation
N=1736
1 Year trastuzumab
N=1677
LVEF < 50% and decrease by  10 EF points
2.2 %
7.1 %
CHF grade III/IV, and / or cardiac death
0 %
(95% CI: )
0.5%
(95% CI: )
In the HERA trial there was more cardiac toxicity in the group that got trastuzumab. This was true both when cardiac toxicity was assessed by the measurement of LVEF, or by the percentage of patients that developed CHF.

31. Will Arm 3 (a non-anthracycline adjuvant regimen) be the answer ?
BCIRG 006 (n ~ 3000)
Will Arm 3 (a non-anthracycline adjuvant regimen) be the answer ?
BCIRG 006
Arm 1
Arm 2
Arm 3
Expected efficacy report SABCS December 2005
Current reported cases of Grade 3/4 CHF
Arm 1 / Arm 2 / Arm 3 = 1, 18, 1
Current reported cases LVEF 15% < LLN
Arm 1 / Arm 2 / Arm 3 = 6, 25, 4
There is one additional trial of trastuzumab in adjuvant therapy that should be reported this year. This is the BCIRG trial. This trial is of special interest because the third arm uses an advanced (but as yet untried in the adjuvant arena) regimen that does not include an anthracycline. In this arm patients received docetaxel and a platinum. The trial was amended early in the accrual phase to restrict the platinum used in combination with docetaxel to carboplatin.
Cardiac safety data from this trial was presented at the May 2005 ASCO. In this preliminary report there was 1 case of CHF in the control arm. 18 cases of CHF in the patients who got an anthracycline adjuvant therapy followed by trastuzumab, and only 1 case of CHF in the arm were women got docetaxel/carboplatin followed by trastuzumab. A similar cardio-sparing effect of Arm 3, the docetaxel/carboplatin arm was seen in the effects on the LVEF’s.
Whether carboplatin / docetaxel would be a particularly favorable regimen for the treatment of Her2 positive patients to be treated with trastuzumab awaits the efficacy results of this trial to be reported later this year. If it is as efficacious and has a better cardiac safety profile it might be widely adopted to be used in this context.
AC q 3 wk * 4
= docetaxel/platinum q 3 wk * 6
= docetaxel q 3 wk * 4
= trastuzumab q 1 w
= trastuzumab q 1 w

32. Benefit Due to Herceptin
So Is Adjuvant Herceptin For All Breast Cancer Patients? Informed Speculation !
60 Year Old Women. ER +, Her2 +, average comorbidity.
Competeing mortality about 8%. To Get Tam + CA * 4, T * 4q3w.
Her2 FISH +. Additional RR conferred by Her2 1.5.
Baseline 10 Year OS
With Tam and Chemo
Added Herceptin
Benefit Due to Herceptin
NP (1-3) T2
45 %
64 %
72 %
8 %
NN T2
59 %
74 %
79 %
5 %
NN T1c
81 %
86 %
88 %
2 %
NN T1ab
90 %
91 %
1 %
So should all patients with Her2 positive breast cancer receive adjuvant trastuzumab? Can Adjuvant! project the risk benefit ratio of such treatment?
The answer to the second question is that Adjuvant! cannot be used to make estimates of the benefit of adding trastuzumab to adjuvant regimens for the simple reason that the data from the trastuzumab studies is available only for short follow-up. We simply do not know how the apparent efficacy may change as the trial matures. Because trastuzumab is neither a classic chemotherapy nor a classic hormonal therapy, how its apparent effectiveness will change with time and its effects on late relapses cannot be estimated based on prior experience with this type of therapy. In addition how the cardiac toxicity will evolve over time is as yet unknown. It is possible that it will nearly totally resolve, but there is also a chance that it will worsen with additional time for some patients.
Recognizing these caveats it would still be of interest to attempt some projections just to see if the impact of trastuzumab would be so large as to make it nearly certainly advantageous to all Her2 positive patients.
So let us consider a 60 year old woman with average comorbidity who is ER positive and Her2 positive.
Let us project that she gets the same chemotherapeutic regimen given in the B31 and N9831 trials (AC*4 followed by paclitaxel # 4) followed by tamoxifen.
Let us make the evidence based estimate that Her2 increases her risk of death due to breast cancer by 1.5 fold.
Further let us assume that the effect of trastuxumab is to reduce the risk of death by a proportional 33%.
What this table shows is that for node positive patients there would appear to be a large benefit, but conversely for Stage 1 patients additional benefit due to trastuzumab might be in the 1-2% range. This level of benefit could be possibly be offset by cardiac toxicity depending on the long term effects of trastuzumab.
This slide should not be used to illustrate the probable benefits of trastuzumab. This is not its intent. The slide’s intent is to show that there MAY be low risk groups that experience little or no net benefit, but this conclusion is uncertain given lack of long term follow-up as of yet of the trastuzumab adjuvant studies.
Risk of developing CHF 5%, 2/3 have symptoms resolve in 6 months. Cardiac status at 10 years??

33. CA * 4 then T * 4 Results of 9344, 9741, and B-31 /N9831
Age < 50 60 49 51
NN (0) 6
NP (1 – 3) 46 59 53
NP (4 – 9) 42 29 27
NP >10 12 1 14
T > 2 65 61
ER + 52
DFS (3yr)
79 %
81%
75 %
Her2+++
Some might argue that Her2 positivity confers such a high risk of relapse that adjuvant therapy is always indicated. As previously stated, large studies of the prognostic significance of Her2 generally do not show Her2 status to convey a strong independent relative risk. Patients’ characteristics in the control arm of B31/N9831 (those who got AC * 4 followed by P *4) were similar in many ways to the characteristics of patients who got the same therapy who participated in Intergroup trials 9344 and 9741, except that all patients in B31/N9831 were all Her2 positive, while only a minority of patients in 9344 and 9741 were Her2 positive. Yet the DFS at 3 years was only slightly worse in B31/N9831 than the other trials. Clearly Her2 positivity is not such a bad prognostic feature as to radically change the estimate of prognosis, and justify any level of risk.
No major difference in outcome of this arm between trials.

34. Triumphs and Cautionary Tales
Early Results
Triumphs and Cautionary Tales
Tam vs Obs Her vs Obs
(Overview) (B31/N9831)
Proportional risk reductions at 2 Years for DFS
53 % 52%
Proportional risk reductions at 10 years for DFS
39 % ???
Durable but Durable ?
Late Toxicity Late Toxicity ?
How revolutionary are the results of the trastuzumab trials and how likely are the early results to hold up? There are possibly instructive parallels with the results of the first successful pairing of a target (the estrogen receptor) and a targeted agent, tamoxifen. When viewed at 2 years of follow-up tamoxifen too reduces relapse by more than 50%. However it is less effective against later events and its overall efficacy when viewed at 10 years is slightly less. The initial trials with tamoxifen did not lead to a full appreciation of its toxicities and it was only later that its association with and increased risk of endometrial cancer and thrombotic events became clear.
The early results of the target/targeting agent Her2 trastuzumab pair look similarly encouraging, only more follow-up can give us an accurate picture of the long term efficacy and safety of trastuzumab.

35. Early Results Do Not Always Reflect Late Results In Adjuvant Therapy
Poly Chemotherapy
Tamoxifen (5 yrs)
Proportional Risk Reduction
During Time Interval
That early results may or may not reflect late results can be illustrated by the results published in the Oxford Overview in For example, poly-chemotherapy’s proportional effect of early relapse (years 0-2) in women older than 50 is must greater (36%) than later recurrence between years 5-10 (1%). If one took the long view cumulative view from years time 0 to year 10 then it would be rather different, not the early 36% but about half that at 19%. Some decline in the apparent impact on breast cancer mortality is also seen for poly chemotherapy, where in the first 2 years the proportional risk reduction as 18% but viewed cumulatively over 10 years the result was approximately 12%.
The picture is different for 5 years of adjuvant tamoxifen where the decline in the effect for early versus late was not as great for recurrence (although there was some decline) and there was not a decline in the effectiveness against breast cancer related mortality.
At this point we do not know which pattern of change of effectiveness with time, if either, will followed by trastuzumab, put it would seem probable that mature trial results will not be as positive as early results (at least in terms of proportional effects). There is a considerable uncertainty about the magnitude of trastuzumab’s long term benefits.
Time Periods (yrs)
Time Periods (yrs)
Recurrence
Breast Cancer Specific Mortality

36. NSABP/Intergroup Recommendations For Control Patients
The recommendations were covered in letters to the patients and clinicians. The recommendations were complex because the letter had to deal with the spectrum of possible treatment points that the patient might be at. Of special relevance to patients who were not trial participants were the following:
Patients in the control (non-trastuzumab) arms with adequate cardiac function, and within 6 months of finishing chemotherapy were offered trastuzumab.
The NSABP suggested that trial patients who had not yet started the paclitaxel/trastuzumab, who were > 50 years old and who had a post AC *4 LVEF of 50-54%, consider the option of starting the trastuzumab only after completing the paclitaxel.
Because of the positive efficacy results the NSABP and Intergroup trials were closed to further accrual.
It was unclear whether the control patients would benefit from trastuzumab if their chemotherapy had been finished several months (or even years) earlier, but the decision was made to offer trastuzumab to control patients who had entered the trial by mid April Assuming that most of these patients had completed their chemotherapy in ~ 6 months, this amounted to offering control patients trastuzumab if they were still within 6 months of completing chemotherapy.
The NSABP reacted to the increased cardiac risk seen in the older patients with low normal LVEF’s.
They apparently followed the following logic.
The CHF rate in patients > 50 years of age was possibly unacceptable for patients with LVEF of 50-54%.
The HERA trial with its low rate of CHF suggests that giving the adjuvant paclitaxel and trastuzumab together may contribute to the increased risk of CHF. In addition the HERA trial used a higher LVEF (55%) for inclusion.
Therefore for older patients with borderline post-AC LVEF trastuzumab should consider delaying starting trastuzumab until after completion of the paclitaxel particularly if they had a low normal LVEF.
The NSABP would seem to acknowledge that this logic downplays the results of difference in outcome between the N9831 sequential and concurrent arms. The N9831 trial’s early analysis suggested that the concurrent use of paclitaxel and trastuzumab seemed important to the efficacy of trastuzumab, and the cardiac safety did not seem to be radically affected by whether the use of trastuzumab was concurrent with or after paclitaxel.
Thus the NSABP suggested that for older patients with borderline LVEF’s might want to delay trastuzumab, but recognized that “… some physicians and patients may prefer to proceed with concurrent trastuzumab and paclitaxel based on the N9831 data.”
In a letter to the NSABP investigators sent in late May 2005 the NSABP stated. ““On the basis of the B-31 safety data and the HERA efficacy data, we recommend that women age 50 and older at randomization should not initiate trastuzumab concurrently with paclitaxel unless they meet the criteria specified in Section 12.3 of the current protocol AND their post-AC LVEF value is > 55%. Instead, they should initiate trastuzumab following completion of paclitaxel, assuming the 6 month LVEF remains at or above the LLN. We believe this approach may reduce the risk of CHF for these patients while still providing substantial benefits from receiving trastuzumab.”

37. Should clinicians routinely recommend trastuzumab (Herceptin) as part of the adjuvant therapy for all patients with Her2 positive early breast cancer?
Adjuvant Herceptin should only recommended as a part of a process that includes both information about the early gains and warns the patient that she faces some increased risk of developing CHF. Although early results are very encouraging, information about long term benefits and risks is not yet available.
Thus the Her2/trastuzumab target / targeted agent pairing seems to have over the short term strongly beneficial effects in the predominantly node positive patient population it was tested in.
Adjuvant!’s opinion is stated on this slide.
The balance of risk versus benefit over the long term is more uncertain because we have only short term follow-up. As with most agents used in adjuvant therapy, the value of adding trastuzumab is most uncertain in low risk (stage 1) patients. For these patients the balance of benefit and risk is particularly uncertain, and can only be estimated with any degree of accuracy as more detailed safety and efficacy information becomes available.