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C.Links of Host Defense Efficiency with Tumor Burden and Age
Hamlin (1968) uses histological appearance to analyze tumor
grade (high malignancy = M++, lower = M+) and strength of host
immunological response (very strong defense = D++, strong = D+,
weak = D-) for 272 breast carcinomas. In Table II Hamlin shows
that good immunological response does extend survival:
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Interplay of Malignancy and Defense on Breast Cancer Mortality
M++ graded tumors
Dead at
Dead at
5 years
10 years
Patients
55 D++
20 36.4%
24 43.6%
88 D+
46 52.3%
57 64.8%
68 D-
52 76.5%
64 94.1%
118 55.9%
145 68.7%
211 Total
Patients
M+ graded tumors
Dead at
Dead at
5 years
10 years
27 D++/D+
9 33.3%
12 44.4%
34 D-
10 29.4%
15 44.1%
61 Total
19 31.1%
27 44.3%
In Table III Hamlin shows a weaker host defense with aging:
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Immunological Response to Breast Cancer
Host Defense
Ages 30-44
Ages 45-59
Ages 60+
Total
Weaker (D-)
19
33.9%
49
37.4%
36
42.4%
104
38.2%
Stronger (D+/D++)
37
66.1%
82
62.6%
49
57.6%
168
61.8%
Quan and Mitchell (1995) note that natural killer cells are a
nonspecific tumor control agent that may be most effective with
small tumor burdens. They cite clinical observation of immunologic
reactivity against human cancer which include cases of spontaneous
tumor regression, shrinkage and dormancy of metastases after removal of the primary tumor, increased incidence of certain tumors
in immunosuppressed patients and higher incidence of cancer in the
elderly (who have weaker immune systems).
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Because host defenses
work best with a low body tumor burden, they probably reinforce
the effects of adjuvant chemotherapy most in patients with small
node-negative breast cancer.
Thus Zambetti et al
(1992) report
seven-year results from the Milan node-negative trial:
It is worth mentioning that in the control group, 5 of ten
patients presenting with tumors measuring 1.5 cm or less
developed new disease manifestations compared to 2 of 15 in
the CMF group.
Because of overexpression of the HER-2 gene on the cell membrane, HER2+ tumor cells may be easier for natural killer cells to
recognize and destroy. O'Reilly et al (1991) found that the median
S-Phase Fraction (SPF) of HER2+ tumors (10.5%) was significantly
higher than the median SPF for HER2- tumors (7.9%). While HER-2
(also c-erbB-2) status accounts for only a small fraction of SPF
variability, tumors positive for this oncogene have a substantially elevated SPF. 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).
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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%
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However, HER2+ tumors have a characteristic which is usually
associated with slower growing tumors, a larger share of ductal
carcinoma in situ (DCIS).
Thus Liu et al (1992) note that HER2+
status is much more common in DCIS tumors than in invasive nodenegative tumors, and even more common than in node-positive ones:
The results showed that nearly twice as many in situ carcinomas harbored increased HER2 gene copies as seen in the nodepositive 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.
It is probably the overexpression of HER2 protein which gives
natural killer cells a way to distinguish this variant of breast
cancer from normal tissue, and helps inhibit its spread beyond the
milk duct where it originated. Host-defense vulnerability of HER2+
tumors also helps to explain the weak prognostic impact of HER2
status among node-negative patients (Slamon, 1989; O'Reilly et al,
1991), since these patients have the strongest host defenses.
Because adriamycin-based adjuvant chemotherapy produces the
greatest attrition of metastatic tumor colonies, it may extend
survival (even after relapse, as Giordano et al, 2002 have shown).
Recently Moliterni et al (2001) reported evidence from a Milan
clinical trial that when more intensive chemotherapy reduces the
body tumor burden below the host-defense-containment level, the
lasting benefit is greater among HER2-positive tumors.
This gain
from substituting doxorubicin for one-third of the rounds of CMF
did not manifest itself at all until many years after adjuvant
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chemotherapy was completed.
This is what one would expect if the
recognition and attrition of tumor cells which overexpress HER2
protein is effective only at low levels of body tumor burden, with
the advantage becoming apparent only when such borderline cases in
the other arm produced widespread metastases and death.
If HER2+
tumors were simply more sensitive to doxorubicin, the advantage
would not have taken seven years to become apparent.
Before adjuvant chemotherapy was commonly used, there is evidence that host defenses by themselves could delay a substantial
number of relapses.
Demicheli et al (1996) analyzed the timing of
recurrence for 1173 Milan Tumor Institute breast cancer patients
treated from 1964 to 1980 with mastectomy alone and no adjuvant
therapy. The authors of this study note an effect like the bursting of a dam:
In particular, a first major peak at about 18 months from
surgery, a second minor peak at about 60 months and a tapered
plateau-like tail extending up to 15 years were clearly
detectable. . . . This general pattern of hazard rate curves
appeared substantially unchanged when different strata of
patients were considered (Figures 3-5). Id. at 179.
In Figure 2 a "bottling up" of distant recurrences is quite
apparent around four years, where the hazard rate is about 1/3
lower than it would be in a linear interpolation between the rates
at three and five years.
Fisher et al (1996) report sites of treatment failure for the
five-years-of-tamoxifen-vs-placebo randomization (in Table 3) that
fit the hypothesis that tamoxifen reinforces the efforts of host
defenses best when the tumor burden is at a low level (as it is
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more likely to be with small tumor colonies left in the ipsilateral breast than with contralateral tumors which may be approaching
the detection threshold when tamoxifen therapy starts):
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Ten-Year Data for NSABP Trial B-14
(Ipsilateral Relapses vs Contralateral Breast Cancers)
Ipsilateral
Contralateral
Total
1404 Tamoxifen Patients
18
24.7%
56
40.6%
74
35.1%
1414 Placebo Patients
55
75.3%
82
59.4%
137
64.9%
2818 Total of Patients
73
100.0%
138
100.0%
211
100.0%
Tam/Plac
As
data
0.33
0.68
2p = 0.021
for contralateral breast cancers which contrasts
experience for five years of tamoxifen with a placebo in NSABP
Trial B-24 (Fisher et al, 1999) illustrate (in Table 2), adjuvant
tamoxifen therapy has a greater ability to restrain the growth of
tumors to detectable dimensions, when the tumors are still at the
non-invasive (DCIS) stage than when they have progressed to the
invasive stage (INVBC):
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60-Month Data for NSABP Trial B-24
(Noninvasive vs Invasive Contralateral Breast Cancers)
DCIS
899 Tamoxifen Patients
INVBC
Total
3
18.8%
15
39.5%
18
33.3%
899 Placebo Patients
13
81.2%
23
60.5%
36
66.7%
1798 Total of Patients
16
100.0%
38
100.0%
36
100.0%
Tam/Plac
0.23
0.65
1p = 0.072
Parallel tendencies can be seen in trends for contralateral
(usually early stage) tumors and distant (usually more advanced)
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recurrences in NSABP Trial B-14: here Fisher et al (2001) report
that the longer-tamoxifen arm has only 5/6 as many contralateral
breast cancers (2.9% vs 3.5%), but 1 1/2 times as many distant
recurrences (4.5% vs 3.0%).
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