The document discusses treatment duration for HER2-positive breast cancer, emphasizing that Herceptin® should be administered until disease progression due to its proven survival benefits and manageable safety profile. It highlights evidence from retrospective studies showing that patients may continue to respond to Herceptin® even after progression, suggesting the feasibility of continued treatment. Ongoing prospective trials aim to clarify the optimal duration and efficacy of Herceptin® beyond progression.

1. Treatment duration
in HER2-positive breast cancer:
when to stop?
Shail Verma
Ottawa Regional Cancer Centre
Ottawa, Canada

2. Duration of anticancer therapy:
current understanding of known agents
 Adjuvant
– randomised controlled trials of hormonal therapy
(e.g. tamoxifen 10 vs 5 years)
– randomised controlled trials of chemotherapy
(e.g. CMF 12 vs 6 cycles, 6 vs 3 cycles)
 Metastatic
– defined by progression (e.g. hormonal agents)
– defined by progression and toxicity
(e.g. anthracyclines – cardiotoxicity; taxanes –
neuro, oedema, fatigue)
 Patient preference

3. Current knowledge on
HER2-targeted therapy
 Overexpression of HER2 is an early event in the
development of breast cancer and is maintained
throughout the course of the disease
 HER2 signalling plays an important role in tumour
development/growth and is associated with high risk
and poor prognosis
 The (pre-clinically) proven synergies of Herceptin®
with various chemotherapeutic agents provides
rationale for different approaches to the disease

4. Herceptin®
randomised clinical trials:
efficacy
CR
PR
H0648g (paclitaxel subgroup)
Slamon et al, 2001*
M77001
Extra et al, 2003
TTP = 6.9 months
TTP = 10.6 months
*All patients
60
50
40
30
20
10
0
Patients
(%)
7
54
8
34

5. Treatment duration
 Treatment until progression is the basis of clinical
trials and has provided data showing significant
patient benefit
 There have been tremendous advances in the
treatment of metastatic breast cancer but
residual/progressive disease remains a problem to
contend with

6. Continuous suppression of HER2
signalling helps control tumour growth
Pietras R, et al. Oncogene 1998;17:2235–49
2,000
1,500
1,000
500
0
Treatment day
0 10 20 30 40 50 60 70
Control
Herceptin®
Tumour
volume
(mm
3
)
Herceptin®
withdrawn

7. Current knowledge on
HER2-targeted therapy: resistance
 Resistance?
– clinical
– cellular
 Level IV/V evidence
– anecdotal reports of responses to different
schedules and doses
– responses to rechallenge
 Resistance to Herceptin®
, cytotoxics or both?
 Immunological phenomenon?

8. Emerging issues regarding
HER2-targeted therapy
 ECD/serum HER2 measures correlate
with response?1
 Does treatment induce alterations in
HER2 expression?2,3
1
Ghani F, et al. Proc Am Soc Clin Oncol 2003;22:32 (Abstract 129)
2
Dowsett M, et al. Proc Am Soc Clin Oncol 2003;22:3 (Abstract 7)
3
Lipton A, et al. Proc Am Soc Clin Oncol 2003;22:3 (Abstract 8)

9. The safety profile of Herceptin®
enables
long-term administration
 Adverse events commonly associated with
chemotherapy are rare with Herceptin®
 Most frequent side effects are infusion-related, seen
with initial doses and rarely thereafter
 No evidence of cumulative toxicity
 Clinically significant side effects of Herceptin®
can be
managed using supportive standard therapy
Cook-Bruns N. Oncology 2001;61(Suppl. 2):58–66

10. Hypotheses on duration of
HER2-targeted therapy
 HER2-positive disease should always be treated
with Herceptin®
, at least until progression
 There is a good rationale that treatment beyond
progression provides further benefit to
these patients

11. Herceptin®
beyond progression:
current data and ongoing prospective trial
 Extension study of patients treated in the pivotal trial
by Slamon et al1,2
 Two retrospective analyses of patients who received
multiple lines of Herceptin®
– multinational study of 105 patients3
– a Greek multicentre review of 80 patients4
 Prospective trial started in Q3/2003 comparing
single-agent Xeloda®
versus Xeloda®
plus Herceptin®
in patients progressing after Herceptin®
1
Slamon D, et al. N Engl J Med 2001;344:783–92
2
Tripathy D, et al. Breast Cancer Res Treat 2000;64:32 (Abstract 25)
3
Gelmon K, et al. Clin Breast Cancer 2004. In press
4
Fountzilas G, et al. Clin Breast Cancer 2003;4:120–5

12. Herceptin®
beyond progression:
extension study
 235 out of 469 patients in the pivotal trial of Slamon
et al., were treated with Herceptin®
plus chemotherapy
(AC or paclitaxel)
 93 of these 235 patients participated in an
extension study after progression on Herceptin®
plus chemotherapy1
 Herceptin®
retreatment consisted of
– Herceptin®
plus chemotherapy – 76% of patients
(paclitaxel, vinorelbine, docetaxel, 5-FU)
– Herceptin®
monotherapy – 24% of patients
1
Tripathy D, et al. Breast Cancer Res Treat 2000;64:32 (Abstract 25)

13. Herceptin®
beyond progression:
extension study (cont’d)
 Efficacy (subsequent treatments)
– overall response rate = 11%
– clinical benefit rate = 22%
– duration of response = 6.7 months
 Safety (subsequent treatments)
– occurrence of adverse events similar to
pivotal trial
– cardiac dysfunction in 2% (1 symptomatic case)
Tripathy D, et al. Breast Cancer Res Treat 2000;64:32 (Abstract 25)

14. Herceptin®
beyond progression:
retrospective review
 Multinational study of 105 patients
– retrospective case analysis of patients having
had at least two Herceptin®
-containing regimens
for MBC
– treatment in 13 centres
– HER2 IHC 3+ and/or FISH+ in 89/105 cases
Gelmon K et al. Clin Breast Cancer 2004. In press

15. Herceptin®
regimens administered
beyond progression
No. of patients
Agent 1st regimen 2nd regimen
None 27 11
Taxane 50 21
Vinorelbine 2 33
Other 26 38
Gelmon K, et al. Clin Breast Cancer 2004. In press

16. Response rates to Herceptin®
treatment
beyond progression
Gelmon K, et al. Clin Breast Cancer 2004. In press
 Similar response rates to the first and second Herceptin®
treatment
45
40
35
30
25
20
15
10
5
0
Monotherapy Plus taxane
Plus vinorelbine Total
Objective
response
(CR+PR)
(%
of
patients)
1st regimen 2nd regimen
(Herceptin®
retreatment)
ND

17. Median time to progression (TTP)
weeks (range)
Regimen n 1st regimen n 2nd regimen
Herceptin®
monotherapy 27 23 (3–73) 10 30.5 (18–68)
Herceptin®
+ taxane 45 24 (0–79) 20 24 (3–72)
Herceptin®
+ vinorelbine – – 33 26 (3–108)
Time to progression:
first and second Herceptin®
regimen
 Median survival from initiation of the first Herceptin
®
regimen was 29.0 months (95% CI: 22.7–56.0)
Gelmon K, et al. Clin Breast Cancer 2004. In press

18. Herceptin®
beyond progression:
retrospective review
 Greek multicentre review of 80 patients
– retrospective case analysis of patients having
received multiple lines of Herceptin®
treatment in
four centres
– no exclusion for previous chemotherapy,
radiotherapy, or hormonal treatment
– HER2 IHC 3+ in 91% of the cases
Fountzilas G et al. Clin Breast Cancer 2003;4:120–5

19. Herceptin
®
regimen
No. of
patients
ORR
(CR+PR) SD
Median TTP
(months) (range)
Second 80 19 (24%) 22 (28%) 5.2 (0.5–1.7)
Third 49 7 (14%) 12 (24%) 3.5 (0–18.3)
Fourth 26 5 (19%) 8 (31%) 4.9 (0.3–21.8)
Fifth 12 1 (8%) 3 (25%) 3.9 (0.3–12.5)
Sixth 2 – – 0.8 (0.5–16.8)
Seventh 1 – – 1.1 (0.8–6.3)
 Comparable responses seen for at least three subsequent
Herceptin®
regimens after progression on the first Herceptin®
treatment
Response rates to Herceptin®
treatment
beyond progression
Fountzilas G et al. Clin Breast Cancer 2003;4:120–5

20.  Patients may respond repeatedly to Herceptin®
-
containing regimens
– a third of the patients responding to an initial Herceptin®
regimen had a second response to a subsequent
Herceptin®
regimen1
 Patients who fail a Herceptin®
-containing regimen can
respond to a subsequent Herceptin®
regimen
– nine of 21 patients who responded to the second had
not responded to the first Herceptin®
regimen1
– in the study by Fountzilas et al., four patients who
progressed during second therapy responded to
further regimens2
Herceptin®
beyond disease progression:
additional findings
1
Gelmon K, et al. Clin Breast Cancer 2004. In press
2
Fountzilas G, et al. Clin Breast Cancer 2003;4:120–5

21. Retrospective studies of Herceptin®
beyond disease progression: summary
 Responses to the second and subsequent
Herceptin®
regimens demonstrate Herceptin®
activity
beyond progression
 Changing concomitant chemotherapy while
continuing Herceptin®
may be an effective approach
 Herceptin®
treatment beyond progression is feasible
and well tolerated
 randomised studies are needed to clarify the role of
Herceptin®
treatment beyond progression

22. Herceptin®
beyond progression:
prospective study (MO17038)
 Randomised multinational trial
 438 patients planned; >60 centres (Germany, Austria)
 Recruitment started in Q4/2003
Patients who have progressed on
Herceptin®
+ taxane (n=438)
Herceptin®
8mg/kg loading  6mg/kg q3w
+ Xeloda®
2,500mg/m2
days 1–14 q3w
until PD
Xeloda®
2,500mg/m2
days 1–14 q3w
until PD
(n=219) (n=219)

23. Treatment duration in HER2-positive
breast cancer: when to stop?
 Herceptin®
should at least be administered until
disease progression
– shown to improve survival
– well tolerated in general
– no evidence of cumulative toxicity
 Retrospective studies suggest efficacy for Herceptin®
beyond disease progression
– treatment beyond progression is feasible, but still an
open question
– responses were seen in subsequent Herceptin®
regimens after
initial responses as well as in prior treatment failures
– duration of treatment with Herceptin®
is being addressed in a
randomised prospective study