Download emergency for HER-2 positive patients

A THERAPEUTIC EMERGENCY FOR HER-2 POSITIVE PATIENTS
WHO HAVE BEEN GIVEN EXTENDED TAMOXIFEN THERAPY
prepared by
Michael J. Halliwell, Ph.D.
California State University
Long Beach CA 90840
Home address:
2930 Colorado Ave. # D-18
Santa Monica, CA 90404-3647
Home phone: 310-829-2821
Home fax: 310-828-9174
TABLE OF CONTENTS
INTRODUCTION. . . . . . . . . . . . . . . . . . . . . . . . . .
1
A. Impact of HER-2 Amplification among Untreated Patients. . .
2
B. Interaction between HER-2 Status and Tamoxifen Therapy. . .
7
C. Interplay between Host Defense and Body Tumor Burden. . . . 23
D. Elevated Proliferation Rate of HER-2 Positive Tumors. . . . 26
E. Immune Surveillance Effects on Early-Stage HER-2+ Tumors. . 28
F. Adjuvant Chemotherapy Avoids HER-2 Stimulation by Tamoxifen 33
REFERENCES. . . . . . . . . . . . . . . . . . . . . . . . . . . 36
INTRODUCTION
De Placido et al (1998) review the adjuvant effects of HER-2:
Borg et al (1994) reported the survival in 737 patients with
primary breast cancer: 445 had received tamoxifen after
radical surgery. Among patients treated with adjuvant tamoxifen, survival was significantly worse for patients with cerbB2 amplified tumors (46% vs 67%, p<0.0001), while no
significant difference was observed in the 292 patients
treated with surgery alone (59% for c-erbB2-positive vs 66%
for c-erbB2-negative; p = 0.34). Similarly, Tetu and Brisson
(1994) found that c-erbB2 overexpression (determined by
immunohistochemistry) played a prognostic role in a consecutive series of 888 cases of primary breast cancer, 656 of
which were given some form of adjuvant therapy after surgery.
. . . This suggests that the unfavorable prognostic role of
c-erbB2 overexpression is relevant especially when endocrine
therapy is given. A similar result has been very recently
reported by Sjogren et al (1998). Id. at 148-149.
After reviewing GUN-1 findings, De Placido et al continue:
In summary, although these results have been obtained from
either non randomized or small trials, all available data
suggest that c-erbB2 overexpression is predictive of
decreased tamoxifen efficacy. Id. at 150.
If a drug has been found to cause bad results for a group of
patients, many ethicists object to risking further use to refine
such a finding. As a result data relating to such a misuse of a
drug is usually too sparse to allow much clarification through use
of subgroup analysis. Allred et al (1992) discuss this problem:
We recognize that the process of subset analysis is fraught
with difficulties.
The small number of patients in many
subsets reduces the power to detect significant differences,
but the multiple statistical tests greatly increase the
likelihood of finding a significant result by chance alone.
Therefore, to interpret more confidently findings based on
subset analyses, a biologic basis for the subset and the
result should be proposed and the hypothesis should be
confirmed in other data sets. Id. at 603.
The various strands of evidence analyzed below clearly show
the peril from adjuvant tamoxifen for HER-2+ patients.
1
A. Impact of HER-2 Amplification among Untreated Patients
Slamon et al (1989) summarize their pioneering findings:
In the current study, we collected a total of 668 human
breast cancer specimens.
Of these, 526 had sufficient
clinical follow-up to allow for evaluation of an association
between gene amplification and disease outcome. Id. at 709.
We evaluated 345 patients with node-positive disease in a
blinded fashion (Table 1). Of these, 101 (27%) had evidence
of HER-2/neu amplification.
Univariate survival analysis
showed amplification of the HER-2/neu gene to be a significant predictor of both disease-free survival and overall
survival for these patients (Table 1). Id.
We also evaluated DNA from tumors of 181 node-negative
patients with a median follow-up of 59 months (62 months for
those still alive). Of these, 45 (25%) had amplification of
the HER-2/neu gene. Univariate and multivariate analysis did
not show an association between gene amplification and
disease outcome in this group of patients. Id.
Patterson et al (1989) analyze data from 158 breast cancers:
The presence of HER-2/neu oncogene amplification was as good,
if not better than nuclear grade and tumor size in predicting
relapse in this group of retrospectively selected nodenegative patients.... However, the amplification of HER-2/neu
oncogene occurs quite infrequently (about 15% of cases) in
this group of retrospectively analyzed node-negative patients
using microtomed sections from paraffin blocks.
Costantino et al (1994) provide 5-year disease-free survival
(DFS) data from NSABP Trial B-14 for tamoxifen-treated patients
(78% in aneuploid tumors, 88% in diploid tumors) which suggests an
overall 5-year DFS of 82%. Since 470 tamoxifen patients were evaluated for c-erbB-2, if 15% were positive, the standard error for
comparing them with the whole would be 4.6% (.82 x .18/70)1/2. The
reported p = 0.3 in the c-erbB-2+ test of significance is consistent with a DFS one standard error below the population value,
or 77.4%.
These trends are merged with NSABP B-14 data (Figure 2
2
and Table 3) from Fisher et al (1989b) in the following table:
A.01
NSABP B-14 Five-Year Distant Recurrence Rates
(Estrogen-Receptor Positive, Node-Negative Breast Cancer)
HER-2 Negative
Fail Rate TOT
Rand #1
HER-2 Positive
Fail Rate TOT
Overall
Fail Rate TOT
5-Yr Tam
31
7.8%
399
8
11.3%
71
39
8.3%
470
Placebo
48
12.0%
399
9
12.7%
71
57
12.1%
470
Tam/Plac
0.65
0.89
0.68
Borg et al (1994) report that among 292 South Swedish breast
cancer patients treated with surgery alone five-year survival was
59% for c-erbB2-positive vs 66% for c-erbB2-negative tumors with p
= 0.34.
Data in Figure 3 shows that the strongest trend in the
control group was for PgR-positive, node-positive patients where
the survival disadvantage for erbB-2+ patients is 54% vs 66% with
p = 0.26.
Because this report gives the group sizes and trend
probabilities for the components of the control group in Figure 2,
one can deduce the values for PgR-positive, node-negative patients
from the overall control-group margin:
A.02
South Swedish Five-Year Death Rates
(Progesterone-Receptor Positive Breast Cancer)
No Therapy
Node-Negative
Dead Rate TOT
Node-Positive
Dead Rate TOT
Overall
Dead Rate
TOT
HER-2 Pos.
3
21%
14
5
45%
11
8
32%
25
HER-2 Neg.
15
19%
78
17
33%
51
32
25%
129
HER+/HER-
1.11
1.36
1.28
Sjogren et al (1998) report overall survival (OAS) data for
3
Uppsala patients, mostly (84%) denied systemic adjuvant therapy:
In the 202 lymph node-negative patients, statistically
nonsignificant trends of shorter OAS were seen for c-erbB-2positives compared with c-erbB-2-negatives: 76% versus 88% at
5 years, respectively (P = .07; data not shown. Similar differences in OAS with regard to c-erbB-2 status were seen in
the two larger treatment groups; the 94 treated with
radiotherapy alone (P = .01; data not shown) and the 74 who
did not receive adjuvant treatment (P = .1; data not shown).
No difference was seen in relapse-free survival. Id. at 468.
A.03
Uppsala Five-Year Death Rates
(Mixed ER-Status, Node-Negative Breast Cancer)
No Adjuvant
Dead Rate TOT
Radiotherapy
Dead Rate TOT
Overall
Dead Rate TOT
HER-2 Pos.
3
20%
15
4
25%
16
7
23%
31
HER-2 Neg.
7
12%
59
9
12%
78
16
12%
137
HER+/HER-
1.7
2.1
1.9
McCann et al (1991) contrast significant and insignificant
trends in data from seven years of breast cancer patients treated
(mostly without adjuvant therapy) at an Irish hospital:
Of those patients with pathologically confirmed lymph-node
(LN) status, 115 had metastases to the regional lymph nodes
and 113 were LN negative. For those patients with LN+
disease, c-erbB-2+ tumors identified a poorer prognostic
group (P = 0.003; Fig. 5).
Overexpression of c-erbB-2
oncoprotein did not predict a worse disease outcome in LNdisease (P = 0.27). Id. at 3298.
A.04
Irish Nine-Year Death Rates
(Progesterone-Receptor Positive Breast Cancer)
Node-Negative
Dead Rate TOT
Node-Positive
Dead Rate TOT
Overall
Dead Rate
TOT
HER-2 Pos.
6
50%
12
19
100%
19
25
81%
31
HER-2 Neg.
35
35%
101
58
60%
96
93
47%
197
HER+/HER-
1.43
1.67
4
1.72
The node-negative results are almost entirely from patients
who received no adjuvant chemotherapy or hormonal therapy.
The
shift from the South Swedish 1.21 adverse impact observed in fiveyear deaths for HER-2 positive tumors, to a 1.43 fold increase in
deaths at nine years in the same subgroup of Irish breast cancer
patients, may indicate a gradual erosion of the body's anti-tumor
defenses.
Liu et al (1992) note HER-2/neu findings from prior studies:
In large studies, 15-40% of node-positive (stage II) cases
exhibit HER2 gene amplification, which is associated with a
poorer prognosis. Analysis of node-negative (stage I) breast
lesions
reveals
a
similar
10-30%
incidence
of HER2
amplification [6 citations].Id. at 1029-1030.
Ravdin and Chamness (1995) review HER-2 status and prognosis:
Examination of 11 studies of node-negative patients (Tables V
and VI) suggests little clinical utility in this group. In
only one of these 11 studies is there a positive finding in
multivariate analysis. Even in the univariate analyses the
correlations appear weak.
Thus there seems to be little
support for the use of ErbB-2 in node-negative patients,
which is the group for whom prognostic factors are most
important for making adjuvant treatment decisions. Id. at 23.
The proportion of breast cancers with HER2 gene amplification
is
set
at
the
midpoint
of
reported
ranges
for
node-positive
(27.5%) and node-negative (20%) tumors from Liu et al (1992).
These tables also incorporate a small increase with time in the
adverse impact of this gene and a much larger impact among nodepositive tumors (consistent with Slamon et al, 1989; Costantino et
al, 1994; Borg et al, 1994; Sjogren et al, 1998; and McCann et al,
1991).
5
A.05
Composite Distant Recurrence Rates
(Estrogen-Receptor Positive, Node-Negative Breast Cancer)
HER-2 Negative
Fail Rate TOT
HER-2 Positive
Fail Rate TOT
Overall
Fail Rate TOT
5 Years
28
13.0%
216
6
13.0%
46
34
13.0%
262
10 Years
49
22.7%
216
12
26.1%
46
61
23.3%
262
15 Years
68
31.5%
216
16
34.8%
46
84
32.1%
262
A.06
Composite Distant Recurrence Rates
(ER-Negative and/or Node-Positive Breast Cancer)
HER-2 Negative
Fail Rate TOT
HER-2 Positive
Fail Rate TOT
Overall
Fail Rate TOT
5 Years
79
27.2%
290
37
35.6%
104
116
29.4%
394
10 Years
132
45.5%
290
63
60.6%
104
195
49.5%
394
15 Years
166
57.2%
290
79
76.0%
104
245
62.2%
394
Borg et al (1991) comment on the prognostic impact of ERBB2:
The reason for failure to predict disease outcome in nodenegative breast cancer is unclear.
Possibly ERBB2 is
involved in cell proliferation and thus confers a growth
advantage in the early stages and in local cancer. Though,
to express its full potential in systemic disease, the gene
may have to act in concert with other events which render the
cell also capable of metastasizing. Id. at 137.
It seems likely that the eventual failure of natural killer
cells to harvest metastases is the key "other event" which must
occur to allow distant metastases to become established.
There is
no doubt that breast cancer cells shed into the blood by nodenegative patients reach the lymph nodes.
If failure to establish
tumor colonies there were an unchanging inability to complete the
metastatic process, the increasingly early detection and removal
of
the
primary
tumor
on
account
of
widespread
mammographic
screening, would not produce the large increase in the proportion
6
of node-negative tumors which has been observed.
B. Interaction between HER-2 Status and Tamoxifen Therapy
Benz et al (1992) report mouse innoculation experiments which
confirm the growth sustaining effects of tamoxifen on a line of
breast cancer cells (MCF/HER2-18) with a 45-fold overexpression of
the HER2 receptor.
When athymic nude mice were injected with five
million cells of this and several other lines, daily intravenous
tamoxifen caused an immediate and sustained cessation of tumor
growth for the other lines, while the MCF/HER2-18 tumors showed an
accelerated growth rate lasting weeks.
The tripled tumor volumes
for the MCF/HER2-18 line after 80 days were said by the authors
to
support
the
possibility
that
HER2
overexpression
in
human
breast cancers may be linked to similar tamoxifen effects.
Horwitz (1993) reports results of an experiment comparing the
eight-week growth of a breast cancer cell line with and without
exposure to 1 micro-mole of tamoxifen.
While tamoxifen suppressed
cell growth by 40%, reflecting a complete loss or decrease in the
level of progesterone receptor (PgR), Horwitz notes:
Our data suggest that subsets of cells may actually be
stimulated by tamoxifen. . . . This subpopulation represents
5.2% of the cells in this experiment and contains an average
PgR [level] greater than one million PgR molecules per cell - levels that none of the untreated cells attains. Thus
tamoxifen, while decreasing PgR levels in a majority of
cells, appears paradoxically to increase PR levels in a
selected subset of cells. The ominous consequence of tumor
cell populations that may be stimulated by tamoxifen requires
little comment. Id. at 70.
Perren (1991) notes the prognostic impact of HER-2 status:
7
Some papers find the prognostic effect of c-erbB-2 expression
to be restricted to the node positive subset (Slamon et al,
1989; Tandon et al, 1989; Borg et al, 1990) and similar
results are described by O'Reilly et al (1991) who, however,
show that the independent prognostic effect of c-erbB-2
expression was restricted to recurrence free survival
analysis.
Other groups have made the potentially very
important observation that there is a significant prognostic
effect of c-erbB-2 expression in groups that would generally
be considered to have a good prognosis.
This includes the
node negative subset where an association between c-erbB-2
expression and poor survival is described in papers by Wright
et al (1989a) and Ro et al (1989).
Paik et al (1990)
demonstrated that the maximum prognostic effect of c-erbB-2
expression, in terms of survival, was seen in those patients
who had well differentiated tumors, particularly in those who
were also node negative.
A similar effect was noted in a
study of 79 node negative patients (Richner et al, 1990)
where although there was no overall association between cerbB-2 expression and overall survival, such an association
was found in the ER positive subset (P = 0.001). Id. at 330.
It is not clear how c-erbB-2 expression exerts its prognostic
effect and it may be simply that tumor cells positive for cerbB-2 have a growth advantage over cells negative for this
oncogene.
There may, however, also be some relationship
between c-erbB-2 and responsiveness to treatment. Id.
Ravdin and Chamness (1995) note the impact of HER-2 status:
The suggestion that ErbB-2 may be more predictive of overall
survival (OS) than of disease-free survival is provocative,
because in general it would be expected that a prognostic
factor indicating aggressive tumor behavior would at least be
as significant a predictor of recurrence as of survival -indeed, because relapse occurs before death from breast
cancer, the event rate for relapse would be higher especially
in shorter studies, so that significance might show up
earlier.
In addition death (OS) is confounded in many
studies by natural mortality. That the predictive value of
c-erbB-2 is nevertheless greater in predicting OS, and is
also greater in node-positive populations (most of whom
receive adjuvant therapy), is suggestive that ErbB-2 level
may be a predictor of treatment resistance. Id. at 24.
Pegram et al (1998) note HER-2/neu resistance to tamoxifen:
The first report of an association between HER-2/neu overexpression and failure to respond to tamoxifen therapy [for
relapsing patients] was by Nicholson et al (1990). Id. at 70.
8
The first randomized clinical study with long term follow-up
to demonstrate a significant interaction between HER-2/neu
overexpression by immunohistochemistry and treatment response
to adjuvant tamoxifen was reported by Carlomagno et al
(1996).... The [GUN study] authors caution that the apparent
detrimental effect of tamoxifen in the HER-2/neu positive
group was based on a very small subgroup of patients, so that
it cannot be definitively concluded that tamoxifen treatment
worsens prognosis in HER-2/neu-positive patients.
Recently, Sjogren el al (1998), reporting on data from 312
consecutive primary breast cancers, found that HER-2/neu
overexpression . . . . showed a stronger correlation with
survival that did ER status in node positive women treated
with adjuvant tamoxifen. . . . Although these findings are
considered preliminary in light of the comparatively small
number of patients in the subset analysis, the results
nevertheless are consistent across all of the clinical
studies analyzed to date. Id. at 71.
Hormonal therapy (primarily tamoxifen) given after relapse
does so little to extend survival it is termed palliative.
While
few clinical trials have an untreated control group in such dire
circumstances, the modest benefit of treatment suggests that a
sharp reduction in progression-free survival is evidence of tumor
stimulation by the therapy.
data
on
the
odds
ratio
De Laurentiis et al (2000) compile
(OR)
for
treatment
failure
in
HER-2
positive patients (compared to HER-2 negatives) who were given
endocrine therapy to treat metastatic breast cancer:
An overall estimate of the OR was computed by the MantellHaenszel method.
Seven studies were included in the
metanalysis (1110 patients). The overall OR was 2.46 (95% CI
= 1.81-3.34).
Nicholson et al (1990) discuss HER-2/neu's impact on therapy:
There was a policy of first-line treatment with tamoxifen for
relapsing
patients
without
immediate
life-threatening
visceral disease.
In 61 such patients, immunochemical
assessment of neu expression was carried out. Id. at 811.
9
The correlation of neu expression with response to tamoxifen
in
patients
with
recurrent
disease
was
assessed
immunochemically.
Response rate [see Table 5 infra] was
reduced in the presence of neu from 50% to 17% for ER+ cases
and from 26% to 0% for ER- cases. Id.
Nicholson Table 5. Neu and Tamoxifen Response
Neu-/ER+
Neu-/ER-
Neu+/ER+
Neu+/ER-
Responders
12
6
1
0
Non-Responders
12
17
5
8
Berns et al (1995) discuss their post-recurrence therapy:
Noticeably in our study is the low response rate and short
progression free survival (PFS) of patients with HER-2/neuamplified tumors to endocrine treatment with tamoxifen. Only
two (12%) of the 16 patients with an exclusive [this is the
only mutation] HER-2/neu amplification, but 17% of all 23
patients with HER-2/neu amplification (either combined or
exclusively) in their tumors showed a response to endocrine
therapy. Moreover, amplification of the HER-2/neu gene was
related to a shorter PFS (p=0.004; Table II and Fig. 2A).
Progressive disease from start of endocrine therapy at three
months occurred in 79% of the patients with HER-2/neuamplified tumors and only in 47% of the patients without this
amplification (Fig. 2A). This difference continued over 12
months (Table II). Id. at 15-16.
Soble et al (1997) analyze treatment of 43 Chicago patients:
the HER-2 gene encodes a transmembrane growth factor receptor
and is overexpressed in 30% of human breast cancers. Early
reports suggest that overexpression correlates with reduced
effectiveness of adjuvant tamoxifen and diminished response
to palliative tamoxifen. . . . Disease-free interval (DFI)
for adjuvant patients and progression-free interval (PFI) for
palliative patients were calculated by the Kaplan-Meier
method and log-rank analyses were used to compare DFI and PFI
for HER-2 positive vs negative patients. The median DFI was
67 weeks for HER-2 positive vs 204 weeks for HER-2 negative
patients (p <.001). The median PFI was 13 weeks for HER-2
positive vs 62 weeks for HER-2 negative patients (p = .045).
Tetu and Brisson (1994) analyze the treatment of 888 patients
with node-positive breast cancer treated over a seven year period
in Quebec, Canada.
Cox-adjusted distant metastasis free survival
10
(DMFS) and overall survival (OS) were calculated to compensate for
prognostic imbalances among those choosing the various treatments:
The curves reveal that the difference between negative and
positive (membrane) staining was most significant in the
subgroups of patients treated with adjuvant chemotherapy and
hormone therapy, whereas, the difference did not reach
significance in the group of patients who received no
adjuvant therapy (Fig. 4).
For patients submitted to
adjuvant chemotherapy or hormone therapy (Fig. 5) the 5-year
DMFS for negative tumors was 57% as opposed to 35% for
positive cases (P < 0.0001). Similarly the 5-year OS was 69%
for negative tumors and 41% for those expressing HER-2/neu (P
= 0.0001). After adjustment by multivariate analyses for
other prognostic factors, the hazard ratio for occurrence of
distant metastasis or death was 2.110 for those submitted to
adjuvant therapy (Table 1).
This means that HER-2/neu
oncoprotein expression was associated with a 2.11-fold
increased risk of dying or developing distant metastases
during the follow-up period, compared with the absence of
expression of the marker.
However, surprisingly, no
difference in DMFS and OS was found in the subgroup of
patients treated with both chemotherapy and hormone therapy.
Id. at 2362-2363.
B.01
Quebec Cox-Adjusted Five-Year Distant Recurrence Rates
(Node-Positive Breast Cancer)
HER-2 Negative
Fail Rate TOT
HER-2 Positive
Fail Rate TOT
Overall
Fail Rate
TOT
CMF x 6
84
39.8%
211
25
61.0%
41
109
43.3%
252
Tamoxifen
71
42.8%
166
26
81.2%
32
97
49.0%
198
CMF + TAM
67
39.0%
172
16
47.1%
34
83
40.3%
206
No Adjuv.
101
51.5%
196
21
58.3%
36
122
52.6%
232
Total
323
43.4%
745
88
61.5%
143
411
46.3%
888
Borg et al (1991) note an important trend in their data:
Furthermore, erbB-2 amplification was correlated to poor
prognosis mainly in the patient group receiving adjuvant
tamoxifen (data not shown). Id. at 141.
Borg et al (1994) amplify findings of their earlier study:
11
We have previously reported erbB-2 amplification to be
associated with poor disease-free and overall survival mainly
in steroid receptor-positive breast cancer (Borg et al,
1991). In an extended study, we now demonstrate that this
effect may be due to an unresponsiveness of the erbB-2
expressing receptor-positive tumors to adjuvant tamoxifen
therapy, and that tamoxifen in fact may enhance the
aggressiveness of those tumors. Id. at 138.
Borg et al (1994) discuss the effects of adjuvant tamoxifen
therapy (mostly 20 mg per day for 1 or 2 years):
Analyzing the material as a whole with regard to clinical
course, DFS and OS were significantly reduced in the group of
patients with erbB-2+ tumors compared to the erbB-2- group
(5-year OS, 50% vs 65%; P < 0.0001). If adjuvant therapy was
also taken into consideration, this effect was found to be
entirely confined to the subgroup of 445 patients receiving
adjuvant tamoxifen (5-year OS, 46% vs 67%; P < 0.001; Fig.
1a). Id. at 139.
Borg et al (1994) point out their strongest tendency:
Thus when analyzing N+PgR+ patients, erbB-2 was a highly
significant predictor of early recurrence and death in the
group receiving adjuvant tamoxifen (5-year OS, 34% vs 73%; P
< 0.0001; Fig. 3a). Id. at 141.
Sjogren et al (1998) present (in Figure 3) five-year overall
survival for 47 node-positive Uppsala breast cancer patients who
were treated with adjuvant tamoxifen therapy.
Of the ten who were
HER-2 positive nine died (90%), of the 37 who were HER-2 negative
ten died (27%); thus amplification of the HER-2 gene raised the
death rate by a factor of 3.33. McCann et al (1991) show (in
Figure
5)
that
among
105
Irish
node-positive
breast
cancer
patients (who were mainly treated with adjuvant tamoxifen therapy)
the last of the 19 HER-2 positive patients died at the 5 1/2 year
mark, at this time deaths were only 43% of the 96 HER-2 negative
12
patients (a risk ratio of 2.32).
If five-year death rates for
untreated patients would have been about the same (50% for HER-2
positives and 33% for HER-2 negatives) as in the South Swedish
data, adjuvant tamoxifen therapy almost doubled mortality (for
both studies combined) among the HER-2 positive patients and had
little net impact in the HER-2 negative group.
Bianco et al (2000) report fifteen years of follow-up for the
node-positive
premenopausal
patients
in
GUN-2
(all
of
whom
received 9 cycles of adjuvant CMF) where no interaction between
tamoxifen therapy and HER-2 status was found.
Since Carlomagno et
al (1996) separate out node negative patients in the GUN-1 trial,
the overall relationships reported by Bianco et al (1998) can be
extrapolated from 14 to 15 years and subdivided as follows:
B.02
GUN-2 Trial Fifteen-Year Distant Recurrence Rates
(Premenopausal, Node-Positive Breast Cancer)
HER-2 Negative
Fail Rate TOT
CMF x 9
HER-2 Positive
Fail Rate TOT
Overall
Fail Rate TOT
2-Yr Tam
26
60%
43
10
62%
16
36
61%
59
Controls
34
74%
46
13
76%
17
47
75%
63
Tam/Cont
B.03
0.81
0.82
0.81
GUN-1 Trial Fifteen-Year Distant Recurrence Rates
(Postmenopausal, Node-Positive Breast Cancer)
HER-2 Negative
Fail Rate TOT
HER-2 Positive
Fail Rate TOT
Overall
Fail Rate TOT
2-Yr Tam
25
50%
50
16
94%
17
41
61%
67
Controls
36
84%
43
12
86%
14
48
84%
57
Tam/Cont
0.60
1.10
13
0.73
B.04
GUN-1 Trial Fifteen-Year Distant Recurrence Rates
(Node-Negative Breast Cancer)
HER-2 Negative
Fail Rate TOT
HER-2 Positive
Fail Rate TOT
Overall
Fail Rate TOT
2-Yr Tam
12
24%
50
15
75%
20
27
39%
70
Controls
32
50%
64
13
46%
28
45
49%
92
Tam/Cont
0.48
1.63
0.80
Dividing this table to fit data (shown on slides at the 1998
ASCO convention) from Bianco et al (1998) produces these trends:
B.05
GUN-1 Trial Fifteen-Year Distant Recurrence Rates
(Estrogen-Receptor Positive, Node-Negative Breast Cancer)
HER-2 Negative
Fail Rate TOT
HER-2 Positive
Fail Rate TOT
Overall
Fail Rate TOT
2-Yr Tam
5
16%
32
8
67%
12
13
30%
44
Controls
20
48%
42
8
44%
18
28
47%
60
Tam/Cont
B.06
0.33
1.50
0.63
GUN-1 Trial Fifteen-Year Distant Recurrence Rates
(Estrogen-Receptor Negative, Node-Negative Breast Cancer)
HER-2 Negative
Fail Rate TOT
HER-2 Positive
Fail Rate TOT
Overall
Fail Rate TOT
2-Yr Tam
7
39%
18
7
87%
8
14
54%
26
Controls
11
50%
22
5
50%
10
17
53%
32
Tam/Cont
The
0.78
above
relationships
1.75
are
somewhat
1.01
conservative
with
respect to the impact of HER-2 status, because only 57% (245 of
433) had this status determined.
Bianco et al (2000) found
mortality risk ratios (tam/cont) for the GUN-1 patients of 0.54
(CI = 0.35-0.84) among HER-2 negative cases and 2.23 (CI = 0.95-
14
5.23) for the HER-2 positive group.
patients
(where
no
adjuvant
The same GUN-1 categories of
chemotherapy
was
given)
are
consolidated below:
B.07
GUN-1 Trial Fifteen-Year Distant Recurrence Rates
(Mixed ER- and Nodal-Status Breast Cancer)
HER-2 Negative
Fail Rate TOT
HER-2 Positive
Fail Rate TOT
Overall
Fail Rate TOT
2-Yr Tam
37
34%
100
31
84%
37
68
50%
137
Controls
68
64%
107
25
60%
42
93
62%
149
Tam/Cont
0.58
1.41
0.80
The 0.58 ratio for HER-2 negative tumors is close to the 0.54
reported by Bianco et al (2000) for these cases, not surprising
for this large, statistically stable category.
There is simply no
room for a 2.23 ratio in the GUN-1 HER-2 positive tumors, since a
100% failure rate in the tamoxifen arm would only yield a ratio of
1.67.
Carlomagno et al (1996) reports on most of the GUN-1 tumors
whose HER-2 status is known, and confirms an unusually large
amount of "room for failure" in the HER-2 positive arm; Figures 1
and 2 show that for untreated patients the fifteen-year mortality
rate was 38% for 102 HER-2 negative patients, but only 16% for 43
HER-2 positive patients.
Nordenskjold et al (1999) report a similar tendency in their
analysis of data from the Swedish Breast Cancer Cooperative Group
(1996) for the impact of extending tamoxifen therapy from two
years to five years: "Whereas HER2-neu-negative patients showed
benefit from prolonged treatment (relative risk = 0.65, 95% CI
15
0.42-1.02), no benefit was evident for HER2-neu-positive patients
(relative risk = 1.9, 95% CI 0.54-6.6)."
Applying these ratios to
the 1996 trends for the fraction (1/8) of patients (and the
experience base) with reported HER-2 data produces these tables
for the 87% of such patients with a negative HER-2 rating and the
13% with tumors found to be HER-2 positive:
B.08
Swedish Third-to-Tenth Year Distant Recurrence Rates
(Postmenopausal, Any Nodal- or ER-Status Breast Cancer)
HER-2 Negative
Fail Rate TOT
HER-2 Positive
Fail Rate TOT
Overall
Fail Rate TOT
5-Yr Tam
24
19.2%
125
16
84.2%
19
40
27.8%
144
2-Yr Tam
37
30.6%
121
8
44.4%
18
45
32.4%
139
5yr/2yr
0.63
1.90
0.86
Nordenskjold et al (1999) note that if Estrogen-Receptor negative
cases in the 1996 data (21%) are excluded from the analysis, the
tendency reaches borderline statistical significance (p = 0.044).
These
tables
for
ER-positive
patients
reflect
this
situation
(where chi-square = 4.05):
B.09
Swedish Third-to-Tenth Year Recurrence Rates
(Postmenopausal, ER-Positive, Mixed Nodes Breast Cancer)
HER-2 Negative
Fail Rate TOT
HER-2 Positive
Fail Rate TOT
Overall
Fail Rate TOT
5-Yr Tam
16
16.0%
100
11
78.6%
14
27
23.7%
114
2-Yr Tam
28
28.9%
97
6
46.2%
13
34
30.9%
110
5yr/2yr
0.55
1.70
0.77
One can use data from one of the centers (Stockholm) which
contributed to the Swedish Breast Cancer Cooperative Group (1996)
16
trials, which are reported by Rutqvist et al (1987) at 261, to
fill in the shared early years for the two arms of the above
tables and a control group of untreated patients:
B.10
Stockholm Five-Year Distant Recurrence Rates
(Postmenopausal, Node-Negative, < 31 mm Breast Cancer)
ER-Negative
Fail Rate TOT
ER-Positive
Fail Rate TOT
Overall
Fail Rate
TOT
2-Yr Tam
14
17.9%
78
32
10.3%
311
46
11.8%
389
Controls
13
17.3%
75
54
17.9%
302
67
17.8%
377
Tam/Cont
B.11
1.03
0.58
0.66
Swedish Ten-Year Distant Recurrence Rates
(Postmenopausal, Node-Negative Breast Cancer)
ER-Negative
Fail Rate TOT
ER-Positive
Fail Rate TOT
Overall
Fail Rate TOT
5-Yr Tam
28
28.3%
99
58
13.2%
439
86
15.6%
538
2-Yr Tam
25
23.6%
106
72
17.7%
407
97
18.9%
513
Controls
30
29.1%
103
97
22.9%
423
127
24.1%
526
The relationships in Table 4 of the 1996 Swedish report can
be used to estimate parallel trends for node-positive patients:
B.12
Swedish Ten-Year Distant Recurrence Rates
(Postmenopausal, Node-Positive Breast Cancer)
ER-Negative
Fail Rate TOT
ER-Positive
Fail Rate TOT
Overall
Fail Rate TOT
5-Yr Tam
62
55.9%
111
161
35.1%
458
223
39.2%
569
2-Yr Tam
50
47.6%
105
222
46.2%
481
272
46.4%
586
Controls
67
62.0%
108
254
54.2%
469
321
55.6%
577
Applying the trends in Tables B.07 and B.08 to the 1996
Swedish data in Tables B.11 and B.12 produces these HER-2 effects:
17
B.13
Swedish Ten-Year Distant Recurrence Rates
(Postmenopausal, ER-Positive, Node-Negative Breast Cancer)
HER-2 Negative
Fail Rate TOT
HER-2 Positive
Fail Rate TOT
Overall
Fail Rate TOT
5-Yr Tam
31
8.3%
373
27
40.9%
66
58
13.2%
439
2-Yr Tam
51
14.8%
345
21
33.9%
62
72
17.7%
407
Controls
81
22.6%
359
16
25.0%
64
97
22.9%
423
B.14
Swedish Ten-Year Distant Recurrence Rates
(Postmenopausal, ER-Negative, Node-Negative Breast Cancer)
HER-2 Negative
Fail Rate TOT
HER-2 Positive
Fail Rate TOT
Overall
Fail Rate TOT
5-Yr Tam
14
16.9%
83
14
87.5%
16
28
28.3%
99
2-Yr Tam
14
15.9%
88
11
61.1%
18
25
23.6%
106
Controls
23
26.7%
86
7
41.2%
17
30
29.1%
103
B.15
Swedish Ten-Year Distant Recurrence Rates
(Postmenopausal, ER-Positive, Node-Positive Breast Cancer)
HER-2 Negative
Fail Rate TOT
HER-2 Positive
Fail Rate TOT
Overall
Fail Rate TOT
5-Yr Tam
72
19.7%
366
89
96.7%
92
161
35.1%
458
2-Yr Tam
151
39.2%
385
71
74.0%
96
222
46.2%
481
Controls
190
50.7%
375
63
67.0%
94
254
54.2%
469
B.16
Swedish Ten-Year Distant Recurrence Rates
(Postmenopausal, ER-Negative, Node-Positive Breast Cancer)
HER-2 Negative
Fail Rate TOT
HER-2 Positive
Fail Rate TOT
Overall
Fail Rate TOT
5-Yr Tam
38
44.2%
86
24
96.0%
25
62
55.9%
111
2-Yr Tam
31
37.8%
82
19
82.6%
23
50
47.6%
105
Controls
50
59.5%
84
17
70.8%
24
67
62.0%
108
below,
the
In
the
consolidated
table
18
0.70
risk
ratio
(5yr/2yr) in the HER-2 negative subgroup is slightly closer to
parity than the 0.63 reported by Nordenskjold because of the
addition
of
the
shared
first
statistics for both arms.
two
years
of
tamoxifen
to
the
The 1.26 risk ratio in the HER-2
positive subgroup is more affected by the shared two years of
tamoxifen therapy because of the tumor stimulus which it produces;
at this elevated level the maximum possible ratio is 1.63, so the
sizeable influence of random factors on the Nordenskjold 1.90
ratio is more likely to have made the ratio too large than too
small.
B.17
Swedish Ten-Year Distant Recurrence Rates
(Postmenopausal, Mixed ER- and Nodal-Status Breast Cancer)
HER-2 Negative
Fail Rate TOT
HER-2 Positive
Fail Rate TOT
Overall
Fail Rate TOT
5-Yr Tam
174
19.2%
908
154
77.4%
199
328
29.6% 1107
2-Yr Tam
247
27.4%
900
122
61.3%
199
369
33.6% 1099
Controls
344
38.1%
904
103
51.8%
199
447
40.5% 1103
The only adjuvant studies of tamoxifen therapy where this
drug's impact has not been disastrous for HER-2 positive patients
(the GUN-2 trial reported by Bianco et al, 2000 and the CALGB 8541
trial reported by Berry et al, 2000) have given an extensive
amount of adjuvant chemotherapy to tamoxifen patients (which must
have dealt a serious blow to the fast-growing tumor cells likely
to be responsible for the tamoxifen-stimulus effect).
It is
entirely possible that extending tamoxifen therapy for ten or
fifteen years wipes out all HER-2 positive patients, however good
19
their prognosis may have been without such therapy.
Since no one
has reported results subdivided according to HER-2 status for such
extended tamoxifen therapy, and no one is likely to institute any
such trial, one can only use indirect methods to estimate the HER2
influence
on
ten-year
tamoxifen
trials
such
as
NSABP
B-14
(Fisher et al, 2001) and the fifteen-year Scottish durational
trial (Stewart et al, 2001).
In the following table this is done
for the estrogen-positive/node-negative category, where tamoxifen
therapy has been shown to be most effective, by extrapolating the
disparity between two years and five years of tamoxifen therapy.
B.18
Composite Ten-Year Distant Recurrence Rates
(Estrogen-Receptor Positive, Node-Negative Breast Cancer)
HER-2 Negative
Fail Rate TOT
HER-2 Positive
Fail Rate TOT
Overall
Fail Rate TOT
10-Yr Tam
16
7.3%
219
20
42.6%
47
36
13.5%
266
5-Yr Tam
20
9.1%
219
16
34.0%
47
36
13.5%
266
2-Yr Tam
34
15.5%
219
14
29.8%
47
48
18.0%
266
Controls
49
22.7%
216
12
26.1%
46
61
23.3%
262
Since there was no stimulation from continuous tamoxifen in
this category after only five years of follow-up (Table A.01), the
level of stimulation from two years of tamoxifen is assumed to be
less after ten years than at fifteen years (Table B.05).
There is
not enough HER-2 status data in the other ER/nodal categories to
justify individual tables, so a composite table is derived below
by
subtracting
the
ER+/N-
trends
trends.
20
in
Table
B.18
from
overall
B.19
Composite Ten-Year Distant Recurrence Rates
(ER-Negative and/or Node-Positive Breast Cancer)
HER-2 Negative
Fail Rate TOT
HER-2 Positive
Fail Rate TOT
Overall
Fail Rate TOT
10-Yr Tam
86
29.2%
295
86
81.9%
105
172
43.0%
400
5-Yr Tam
89
30.2%
295
77
73.3%
105
166
41.5%
400
2-Yr Tam
120
40.7%
295
74
70.5%
105
194
48.5%
400
Controls
148
51.0%
290
72
69.2%
104
220
55.8%
394
To estimate the impact of fifteen years of tamoxifen on HER-2
negative
tumors
breast
which
cancer,
produce
aggressive
as
continuous
tamoxifen
it
is
assumed
detectable
follow-up
to
distant
continues.
these
that
If
patients
the
control-group
metastases
giving
stops
ten
all
are
less
years
of
but
1/4
(8.2%/22.2%) of distant metastases appearing in the ER+/N- control
group during this decade, it is reasonable to assume that all but
1/6 of the next such failures are delayed by continuing tamoxifen
for another five years.
B.20
Composite Fifteen-Year Distant Recurrence Rates
(Estrogen-Receptor Positive, Node-Negative Breast Cancer)
HER-2 Negative
Fail Rate TOT
HER-2 Positive
Fail Rate TOT
Overall
Fail Rate TOT
15-Yr Tam
20
9.1%
219
32
68.1%
47
52
19.5%
266
10-Yr Tam
26
11.9%
219
29
61.7%
47
55
20.7%
266
5-Yr Tam
33
15.1%
219
23
48.9%
47
56
21.1%
266
2-Yr Tam
52
23.7%
219
19
40.4%
47
71
26.7%
266
Controls
68
31.5%
216
16
34.8%
46
84
32.1%
262
If the GUN-1 2.23 risk ratio for two years of tamoxifen
raised the control-group fifteen-year failure rate to 77.6%, the
21
Swedish 5yr/2yr risk ratio of 1.90 would easily raise the failure
rate for five years of tamoxifen all the way to 100%.
Where ten
or fifteen years of tamoxifen therapy is given, the stimulation of
the HER-2 positive tumors must account for such a large fraction
of failures, that there is little reason to believe that such
extended therapy is unsafe for HER-2 negative patients.
In the
"other" category the distant metastasis rate for HER-2 positive
tumors at fifteen years is already 80% in the control group, so
the rate approaches 100% with only a few years of tamoxifen
therapy.
B.21
Composite Fifteen-Year Distant Recurrence Rates
(ER-Negative and/or Node-Positive Breast Cancer)
HER-2 Negative
Fail Rate TOT
HER-2 Positive
Fail Rate TOT
Overall
Fail Rate TOT
15-Yr Tam
131
44.4%
295
94
89.5%
105
225
56.2%
400
10-Yr Tam
132
44.7%
295
90
85.7%
105
222
55.5%
400
5-Yr Tam
133
45.1%
295
84
80.0%
105
217
54.2%
400
2-Yr Tam
148
50.2%
295
82
78.1%
105
230
57.5%
400
Controls
166
57.2%
290
79
76.0%
104
245
62.1%
394
Rutqvist et al (1987) report (at 261) an adverse 1.16 risk
ratio for two years of tamoxifen versus controls among estrogenreceptor negative tumors at only 4 1/2 years of median follow-up
(too soon for a substantial HER-2 effect).
While other patient
populations (such as in the NATO trial) show a substantial benefit
for ER- tumors at this stage, this adverse tendency becomes strong
enough with the longest durations to outweigh the benefit for
22
added therapy in the ER+/N+ segment of this consolidated category.
C. Interplay between Host Defense and Body Tumor Burden
Since the tamoxifen-stimulus effects documented above often
reach detectable levels long after tamoxifen therapy has ended,
there must be some sort of anti-tumor defense which slows down the
rate of tumor growth.
There are several studies which evidence
such a tumor colony attrition mechanism.
Veronesi
et
al
(1990)
cite
findings
of
a
Milan
Tumor
Institute breast-conservation trial that "local recurrences do not
influence the appearance of distant metastases" and "survival in
the two groups was identical (Fig. 1)." Id. at 673.
al
also
note
that
NSABP
Trial
B-6,
a
Veronesi et
comparison
of
total
mastectomy with breast resection without radiotherapy by Fisher et
al (1989e), "did not show any difference in the rate of distant
metastases and in survival." Id.
The lumpectomy operation in
Trial B-6 left so much tumor tissue in the breast that Fisher
(1992) notes:
After more than 9 years of follow-up . . . 43% of the women
treated by lumpectomy without breast irradiation . . .
experienced a breast tumor recurrence. Id. at 2375.
Since there is no reason to suppose that breast recurrences
do not seed distant metastases, their contributions must have been
swamped by the micrometastases that existed at the time of primary
surgery.
Obviously long-term survival from breast cancer is due
to control of micrometastases by host defenses, with only rare
cases actually lacking such tumor colonies.
23
(It would be a
strange quirk of cancer biology if there existed a large group of
node-positive patients with body tumor burdens which very soon
become clinically apparent, while node-negative patients usually
had few disseminated cancer cells, with relatively few cases in
between.)
It is likely that nodal status is such a powerful
prognostic indicator because it reflects the "cleaning up" of
tumor cells which reach the lymph nodes, and presumably other
parts of the body.
The influence on relapse rates of host defenses maintaining
node-negative status, is clear in this data from Valagussa et al
(1978) on 716 consecutive Milan mastectomy patients:
C.01
Milan "Surgery Only" Recurrence Rates
(Mixed Estrogen-Receptor and Nodal-Status Breast Cancer)
5-Yr Relapses
Node- Node+ Total
10-Yr Relapses
Node- Node+ Total
< 2 cm
7.7%
36.8%
18.9%
19.9%
49.8%
31.5%
2-5 cm
24.3%
64.1%
45.9%
30.2%
75.9%
55.0%
> 5 cm
18.7%
78.5%
55.3%
25.1%
82.4%
60.2%
Total
21.0%
63.6%
43.9%
27.9%
75.5%
52.9%
The much better prognosis of small tumors reflects the lesser
time they have had to shed metastases into the circulatory system.
Among node-positive tumors the top size category has the highest
relapse
rate,
which
dissemination potential.
is
what
one
would
expect
from
its
However, tumors larger than 5 cm which
have maintained their node-negative status have only 3/4 as many
5-year relapses and only 5/6 as many 10-year relapses as those in
24
the 2-5 cm group.
This cannot be because the largest tumors have produced fewer
metastases, and must mean that there is some ability to eradicate
tumor colonies that does not exist in the counterpart category
among node-positive tumors.
This ability may be limited to small
tumor burdens; as Hengst and Mitchell (1987) note (at 67), "the
immune response by itself is able to overcome only a limited
number of tumor cells, perhaps no more than 1000 to 10,000 cells
in mice [citation].”
Further analysis by Retsky et al (1997) of Milan data from
surgical trials (where no chemotherapy was given) also supports
the existence of a host-defense effect:
Recent analysis of relapse data from 1173 untreated early
stage breast cancer patients with 16-20 year follow-up shows
that frequency of relapse has a double peaked distribution.
There is a sharp peak at 18 months, a nadir at 50 months and
a broad peak at 60 months. Patients with larger tumors more
frequently relapse in the first peak while those with smaller
tumors relapse equally in both peaks. Id. at 193.
The timing of relapses is what one would expect from a low limit
on the tumor cell burden which can be contained by host defenses,
where a linear rate of relapses is bottled up for a while, and
then released (as when a dam bursts). Retsky et al note, "No
existing theory of tumor growth predicts this effect." This lends
support
to
the
idea
that
this
is
a
matter
of
tumor
colony
attrition.
Measurement of this effect is provided by Hamlin (1968), who
uses histological appearance to analyze tumor grade and strength
25
of host immunological response.
She found that death rates at ten
years among those with 211 highly malignant tumors were strongly
linked to immunological response; 43.6% (24/55) of those with a
very strong defense died, as did 64.8% (57/88) in the intermediate
category and 94.1% (64/68) with a weak defense. Id. at 390.
D. Elevated Proliferation Rate of HER-2 Positive Tumors
To
manifest
a substantial stimulus effect which persists
after the source of the stimulus is removed, a variety of tumor
cells must have a high intrinsic growth potential, which manifests
itself
after
overcome.
small
the
body's
tumor-attrition
mechanisms
have
been
While HER-2 (also c-erbB-2) status accounts for only a
fraction
of
SPF
variability,
tumors
oncogene have a substantially elevated SPF.
positive
for
this
Borg et al (1991)
report results (at 138) for a large panel of invasive breast
tumors:
ERBB2 amplification was strongly correlated to an increased
rate of cell proliferation, measured as a high percentage of
cells in SPF [S-Phase Fraction]. This connection was seen in
both diploid and non-diploid tumors, though the former group
had a significantly lower mean SPF than the latter (Table 3).
D.01
South Swedish S-Phase Fraction vs HER-2 Amplification
(Mixed Estrogen-Receptor and Nodal-Status Breast Cancer)
SPF
Non-Diploid
cases
% Ampl
SPF
Diploid
cases
% Ampl
< 7%
68
5.9%
< 7%
142
9.9%
7-12%
75
13.3%
> 7%
43
27.9%
>12%
159
32.7%
Total
302
21.9%
185
14.1%
26
Borg et al (1991) report key growth-related attributes:
ERBB2 amplification was significantly correlated to the
presence of axillary lymph node metastases and, within the
node-positive group, also to an increased number of involved
nodes. ERBB2 amplification was also significantly correlated
to larger size of primary tumor, to the presence of distant
metastases at diagnosis and, consequently, also to stage of
disease. Id. at 138.
Gusterson et al (1992) analyzed links with c-erbB-2 status
for 1506 patients entered into International Breast Cancer Study
Group
Trial
V
and
found
significant
correlations
between
overexpression of HER-2 protein and growth indicators such as high
tumor grade (in both nodal groups) and larger tumor size (for
node-negative cases). Id. at 1050-1051.
Slamon et al (1987) analyzed alterations of the HER-2/neu
gene in 189 primary breast cancers, finding a significantly lower
degree of gene amplification for 0 to 3 positive nodes than for >3
positive nodes. Id. at 179.
Slamon et al (1987) also report:
A strong and highly statistically significant correlation was
found between the degree of gene amplification and both time
to disease relapse (P < 0.0001) and survival (P = 0.0011)
(Table 4). . . . It is easy to speculate that a gene encoding
a putative growth factor receptor, when expressed in
inappropriate amounts, may give a growth advantage to the
cells expressing it. Id. at 180-181.
O'Reilly et al (1991) analyze flow cytometry findings for 153
breast cancer patients treated at Guy's Hospital between 1980 and
1983:
There was a significant association between c-erbB-2 staining
and an SPF above the median using Chi-squared analysis (P =
0.003).
In addition, the median SPF of c-erbB-2 positive
tumors was significantly higher than the median SPF of cerbB-2 negative tumors (10.5 vs 7.9, P = 0.02). Id. at 445.
27
Muss
et
al
(1994)
analyze
flow
cytometry
data
on
proliferation rates for 302 primary breast cancers from CALGB
trial 8869 and find (at 1262) a similarly significant association
(P = 0.03).
Allred et al (1992) note that higher growth rates are usually
found in those most likely to receive adjuvant tamoxifen therapy:
Borg et al (1990) have recently shown that in overexpression
of HER-2/neu, a putative growth factor receptor is associated
with high proliferation rates (flow cytometric S-Phase) in
ER- positive tumors, but not ER-negative tumors, providing
circumstantial evidence that HER-2/neu may be functioning as
a growth factor receptor primarily in ER-positive tumors.
This finding may partially explain the apparently aggressive
behavior of ER-positive, node-negative lesions overexpressing
HER-2/neu. Id. at 604.
E. Immune Surveillance Effects on Early-Stage HER-2+ Tumors
There is direct evidence of retardation of the growth of HER2 positive tumors by the body's anti-tumor defenses:
Liu et al (1992) describe their HER-2/neu evaluation process:
Amplification and overexpression of the HER-2 (c-erbB-2)
oncogene was assessed in paraffin-embedded specimens from 27
in situ carcinomas of the breast and from 122 stage II breast
cancers. . . . Coded sections of the paraffin-embedded
tissues were distributed such that the immunohistochemical
and molecular analyses were performed in a blinded fashion.
Id. at 1027.
Liu et al (1992) note HER-2/neu findings from prior studies:
In large studies, 15-40% of node-positive (stage II) cases
exhibit HER2 gene amplification, which is associated with a
poorer prognosis. Analysis of node-negative (stage I) breast
lesions
reveals
a
similar
10-30%
incidence
of HER2
amplification [6 citations].Id. at 1029-1030.
If one were to extrapolate this trend back to stage 0 (DCIS)
tumors, one might expect to find 5-20% in the HER-2/neu+ group.
28
However, Liu et al (1992) find HER-2/neu+ is much more common in
in situ tumors than in node-negative invasive tumors, and even
more common than in node-positive tumors:
To extend this analysis to earlier forms of breast cancer, 27
cases of in situ breast cancers without invasive disease were
subjected to detailed molecular and immunohistochemical
analyses.
The results showed that nearly twice as many in
situ carcinomas harbored increased HER2 gene copies as seen
in the node-positive carcinomas (48% vs 21%, p< 0.01).
Earlier studies have reported 42-61% of ductal CIS tumors
with HER2 overexpression as compared with 14-21% of stage II
breast cancers [5 citations]. Id. at 1030.
To explore this situation further, Liu et al (1992) check on
the possibility that HER2 expressiveness changes an individual
patients breast cancer as it proceeds toward a more advanced
stage, and found that:
there was excellent concordance between the level of HER2
protein staining in the ductal CIS component and that of the
invasive component in the subset of 77 node-positive tumors
with coexisting in situ and invasive lesions (r = 0.86, p <
0.0001). Id. at 1028.
When one compares (at 1028 and 1029) the tumors with at least
some HER2 gene amplification at either end of the invasiveness
continuum, it becomes apparent (chi-square = 17.3 p < 0.001) that
degree of gene amplification increases with invasiveness:
E.01
CALGB Levels of HER-2 Gene Amplification
(Mixed Estrogen-Receptor and Nodal-Status Breast Cancer)
Tumors
Total
Degree
of
Gene
two-fourfold
Ductal CIS
9 (69%)
N+ Tumors
11 (43%)
Amplification
in
four-eightfold
4 (31%)
10
29
(38%)
HER-2/neu-Positive
eightfold
&
more
0 (0%)
13
5 (19%)
26
Liu et al (1992) are perplexed by their findings:
A widely accepted model of breast tumor progression suggests
that stage II carcinomas arise from stage I carcinomas, which
in turn arise from in situ carcinomas [citation].
Within
this conceptual framework, the only explanation for our
molecular data is that in situ lesions bearing HER2 gene
amplification lose their excess gene copies as the tumor
progresses from preinvasive to invasive cancer. Though the
loss of an amplicon containing an oncogene has been described
in vitro [citation], such a process has not been documented
in vivo. . . . These findings suggest that there is
considerable stability in the pattern of HER2 expression as
tumors progress from in situ to invasive disease. Since HER2
correlates with the degree of gene amplification for both in
situ and invasive breast cancer, we suspect that the property
of HER2 gene amplification as seen in CIS lesions represents
a stable genetic alteration that is maintained during the
progression to invasive breast cancer. Id. at 1030-1031.
One explanation for this data is that the immunoreactivity
which Liu et al and other researchers use to recognize HER2 gene
amplification is also used by the human body to target and destroy
breast cancer cells.
If this host defense is a) less effective
against tumors with only normal HER2 characteristics, and b) less
effective against the faster-growing HER2+ tumors with the most
highly amplified oncogenes; this would account for a) the observed
large reduction in the fraction of invasive tumors which are HER2+
compared to their antecedents, and b) the large increase in the
degree of HER2 overexpression among invasive HER2+ tumors compared
to the in situ tumors which are HER2+.
Another factor in favor of
this explanation is the fact that many breast cancers become quite
large without overcoming the host defenses which confine them to
the mammary duct system.
Thus Silverstein et al (1996) give data
for 425 DCIS cases, very few of which ever produce nodal or
30
distant metastases, where about one-fourth were larger than 3 cm.
Allred et al (1992) discuss their immunohistochemistry study
of 613 breast cancer patients with long-term clinical follow-up
enrolled in Intergroup Study 0011:
Several recent studies have demonstrated that HER-2/neu is
amplified and/or overexpressed in 10% and 35% of human breast
carcinomas, and that these manifestations of oncogene
activation are associated with poor prognosis in patients
with node-positive disease [12 citations]. However, studies
evaluating the prognostic significance of HER-2/neu in nodenegative patients have yielded conflicting results [14
citations]. The present study was undertaken to help clarify
the latter issue by studying overexpression of HER-2/neu in a
large series of node-negative breast cancer patients with
long-term clinical follow-up. Id. at 600.
Just as human host defenses employ antibodies, Allred et al
(1992) used a polyconal primary antibody (21N-SAT) to identify
breast cancer cells overexpressing HER-2/neu:
While all [649] tumors evaluated were composed of invasive
carcinoma, they were heterogeneous with regard to the
concurrent presence of noninvasive carcinoma.
The rate of
overexpression was higher in [237] tumors containing
significant in situ carcinoma (estimated as at least 10%
total tumor cellularity) as compared with [412] without a
significant in situ component (estimated as < 10% tumor
cellularity). These values were 21.5% and 11.2%, respectively
(P <.001). Id. at 601.
Allred
et
al
(1992)
analyze
these
node-negative
breast
cancers in terms of the interplay between HER-2/neu status and an
in situ component (of at least 10%) where about half of high-risk
patients received adjuvant chemotherapy:
In this context, there were no associations between overexpression and clinical outcome in the low-risk, high-risk,
or combined-risk patient groups with tumors containing
significant amounts of in situ carcinoma (data not shown).
Id. at 601-602.
31
In all of these circumstances host defenses are still able to
exert
some
including
tumors.
restraining
the
enhanced
influence
on
tumor
proliferative
growth,
tendency
of
apparently
HER-2/neu+
However, in the low-risk group (ER-positive tumors < 3 cm
in size) Allred et al find a very different situation (where no
adjuvant therapy was given):
In contrast, a strong association emerged between overexpression and outcome in an analysis of low-risk patients
with predominantly invasive tumors (n = 179, Fig 3), where
the possible contributions from having both a significant in
situ component and high risk [ER- and/or >3 cm] features were
eliminated. The 5-year DFS for patients of this group with
HER-2/neu-positive tumors (n = 14) was only 41%, compared
with over 80% for those with HER-2/neu-negative tumors (n =
165; P < .0001 by log-rank test; P = .0002 by Peto and Peto
exact test). A similar decrease was observed in the OS of
low-risk patients with HER-2/neu-positive tumors composed of
predominantly invasive carcinoma (P = .0001 by log-rank test;
P = .0004 by Peto and Peto exact test). Id. at 602.
The overall trend for the low-risk group in Figure 4 and the
trend for its predominantly invasive component in Figure 3, allow
the data not shown for its invasive-plus-in-situ component to be
found by subtraction:
E.02
Intergroup Trial 0011 Five-Year Recurrence Rates
(ER-Positive, Node-Negative, < 3 cm Breast Cancer)
No Therapy
In Situ+Invasive
Fail Rate TOT
Invasive Only
Fail Rate TOT
Overall
Fail Rate TOT
HER-2 Pos.
5
19%
26
8
57%
14
13
32%
40
HER-2 Neg.
19
19%
102
31
19%
165
50
19%
267
HER+/HER-
1.00
3.00
1.68
Allred et al comment on possible explanations for these findings:
The biologic basis behind our observation that overexpression
32
of HER-2/neu influences prognosis in node-negative invasive
carcinomas without a significant in situ component is unknown. These lesions may represent a relatively late stage in
tumor progression compared with tumors containing significant
amounts of in situ carcinoma and, therefore, may be more
closely related to node-positive breast cancer, where there
is a strong (but poorly understood) correlation between overexpression and unfavorable prognosis. [12 citations.] Id. at
604.
The lesions where there is a clear in situ component are
those where host defenses can latch onto HER-2 features on cell
membranes; here the prognosis is the same is for breast cancer
with normal HER-2 status.
The tumors which have become completely
invasive are those where the body tumor burden has overwhelmed
host defenses (as is the case with node-positive tumors) and like
them, the prognosis of the patient tends to deteriorate.
F. Adjuvant Chemotherapy Avoids HER-2 Stimulation by Tamoxifen
Fortunately,
beneficial
for
adjuvant
HER-2
tamoxifen
positive
therapy
patients,
because
can
the
be
made
original
minority of HER-2 overexpressing tumor cells which are stimulated
by tamoxifen is vulnerable to attrition by chemotherapy.
Berns et al (1995) discuss their post-relapse chemotherapy:
We used the Gehan-Wilcoxon test for detection of early
differences for progression-free survival, and observed that
patients with HER-2/neu-amplified primary tumors showed a
better response to chemotherapy when compared to those having
normal HER-2/neu gene copy numbers (p=0.03; Fig. 2B).
The
median length of tumor progression after chemotherapy was 90
days in patients whose primary tumors were not amplified,
compared to 287 days in patients with HER-2/neu-amplified
primary tumors, i.e., a difference of 6.5 months. Id. at 16.
Due to the lack of response to endocrine therapy,
chemotherapy could be considered to be offered to patients
with HER-2/neu-positive tumors, whereas endocrine therapy
could be preferably offered to patients with [other types of
33
breast cancer]. Id. at 17.
When Bianco et al (2000) separated out the premenopausal
women with node-positive tumors given 9 cycles of CMF in GUN-2
they found that two years of tamoxifen benefitted both HER-2
categories. Among HER-2 negative patients the (TAM+CMF/CMF only)
mortality risk ratio was 0.76 (CI = 0.32-1.79); for HER-2 positive
patients it was 0.65 (CI = 0.29-1.42). Apparently the nine months
of chemotherapy given shortly after primary surgery depleted the
more aggressive tumor cells in HER-2 positive tumors to such an
extent that two years of tamoxifen was insufficient to create a
net stimulative effect.
(2000)
all
In a CALGB study reported by Berry et al
node-positive
patients
received
cyclophosphamide,
doxorubicin, and fluorouracil shortly after primary surgery; the
reduction in the risk of disease recurrence or death for 155
patients given tamoxifen was 39% with normal expression of HER2/neu and 32% with overexpression.
Menard et al (2001) give 20-year data for 386 Milan patients:
Bayesian analysis
treatment . . .
ratios were equal
specific survival
for HER2-positive
. . . indicated a clinical benefit from CMF
estimates of relapse-free survival hazard
to 0.484 and 0.641 and estimates of cancer
hazard ratios were equal to 0.495 and 0.730
and -negative tumors, respectively.
Moliterni et al (2001) cite another Milan clinical trial:
HER2 overexpression was found to predict a good response of
breast carcinoma patients treated with doxorubicin (DOX). We
recently put into evidence that node positive patients
respond to cyclophosphamide, methotrexate and fluorouracil
(CMF) regardless to HER2 status (ASCO 1999). We address now
the issue of whether therapy regimens including CMF and DOX
vs CMF alone, have the same therapeutic effects in patients
with HER2+ and HER2- tumors, in terms of relapse free (RFS)
and overall survival (OS). Methods: archival specimens of
34
primary tumors from 506 of the 552 patients (92%) enrolled in
a prospective clinical trial were stained with anti HER2
monoclonal antibody CB11 and 19% of the specimens were
classified as HER2+. Originally, patients were randomly
allocated to receive either 12 courses of intravenous CMF or
8 courses of the same regimen followed by 4 cycles of DOX.
RFS and OS were analyzed by a Cox model considering
treatment, HER2 status and the interaction between treatment
and HER2 status, adjusting for the effect of other known
clinical and bio-pathological factors (T stage, age, PgR, ER,
p53). Results: an apparent benefit from DOX was observed in
HER2+ tumors. At a median follow-up of 15 years, the Hazard
Ratio (HR) with 95% confidence interval (CI) for RFS was 0.83
(CI 0.46-1.49) in HER2+ tumors and 1.22 (CI 0.91-1.64 in
HER2- tumors. The effect of treatment appeared more evident
on OS in HER2+ patients (HR = 0.61; CI 0.32-1.16) with
respect to HER2- (HR = 1.26; CI 0.89-1.79). Present data
suggest that HER2+ tumors are sensitive to doxorubicin and
that, in this patient subset, doxorubicin-containing regimens
can improve long-term treatment outcome compared to CMF-alone
chemotherapy.
This advantage from the substitution of doxorubicin for onethird of the rounds of CMF did not manifest itself at all until
many years after chemotherapy was completed.
This is what one
would expect if the stronger therapeutic agent reduced mediumsized tumor burdens to below the threshold where they could be
contained by host defenses, with the advantage becoming apparent
only
when
such
cases
in
the
other
arm
produced
widespread
metastases and death.
Pegram et al (1998) observe that the bad results of tamoxifen
when used to treat HER-2/neu positive tumors may be counteracted
by a more powerful drug (herceptin) which is tailored to this
specific mutation.
Furthermore, the demonstration that HER-2/neu-associated
tamoxifen resistance may be at least partially reversed by
anti-HER-2/neu antibodies suggests this may be an important
therapeutic strategy that warrants future study in the
35
clinic. Id. at 72.
In
view
of
the
catastrophic
rates
of
recurrence
and
death
resulting from giving tamoxifen therapy to patients with HER-2
amplification, the only hope for many of them is probably adjuvant
herceptin.
One hopes that the future study envisioned in 1998 has
been done by now, and that adjuvant herceptin will soon become
available to this imperiled group of breast cancer patients.
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