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Clinical Investigations |
Department of Medical Oncology, Division of Endocrine Oncology [E. M. J. J. B., J. A. F., S. C. H-L., M. P. L., I. L. v. S., M. E. M-v. G., C. J. C. C., H. P., J. G. M. K.] and Department of Statistics [W. L. J. v. P.], Rotterdam Cancer Institute (Daniel den Hoed Kliniek)/University Hospital Rotterdam, 3008 AE Rotterdam, the Netherlands; Departments of Human and Clinical Genetics [R. V., P. D., B. B.] and Pathology [C. C.], Leiden University Medical Center, Leiden 2300, the Netherlands; and Amersham Pharmacia Biotech, Upsala, Sweden [M. I.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSTumor Samples and PatientsStatistical MethodsRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSTumor Samples and PatientsStatistical MethodsRESULTSDISCUSSIONREFERENCES |
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In two studies on patients with metastatic breast cancer (including 92 and 205 patients, respectively), no significant relation between immunohistochemically assessed P53 expression and response to endocrine treatment was observed (2 , 3) , whereas in another study (on 17 patients), P53 overexpression was associated with a poor response to endocrine therapy (4) . Recently, we have shown a significant relation between P53 accumulation, as measured by a LIA, and poor response to tamoxifen therapy in a series of 401 patients (5) . Moreover, the existing data on TP53 do not clarify its capability to predict resistance to chemotherapy for advanced or recurrent breast cancer (6, 7, 8, 9) . Furthermore, the data on its predictive role in the adjuvant setting are conflicting as well (10, 11, 12, 13, 14, 15, 16) . Studies on the predictive value of TP53 are hampered by a number of methodological issues including immunological versus molecular biological analyses, use of different cutoff levels in the immunohistochemical analyses, or selection of patient groups.
About 20% of the TP53 gene mutations do not result in p53 protein accumulation, whereas, on the other hand, p53 accumulation may also occur without a gene mutation. Therefore we have studied TP53 gene mutations in a relatively large series of 243 patients with advanced disease. Analysis of the various mutations allowed us to investigate the biological significance of particular mutations, which may eventually aid in selecting those aberrations that could be of predictive value in breast cancer. We show that TP53 gene mutations predict a poor response to first-line tamoxifen therapy and probably to chemotherapy in advanced breast cancer. In an exploratory subset analysis, we also observed that mutations in one zinc-binding domain, i.e., loop L3, or in codons that directly contact DNA were related with an even poorer response to tamoxifen.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSTumor Samples and PatientsStatistical MethodsRESULTSDISCUSSIONREFERENCES |
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Assays of ER and PgR.
ER and PgR levels were determined in cytoplasmic extracts (cytosols)
prepared routinely according to procedures recommended by the European
Organization for Research and Treatment of Cancer Breast Cancer
Cooperative Group with ligand binding assays or enzyme immunoassays
(ER-EIA and PgR-EIA; Abbott Laboratories, IL), as described
previously (20)
.
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Tumor Samples and Patients |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSTumor Samples and PatientsStatistical MethodsRESULTSDISCUSSIONREFERENCES |
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). In five cases, the sequence analysis was incomplete, although a
mutation was observed; these samples were included. For nine cases, the
sequence analysis was incomplete, but no gene mutation was observed;
these nine samples were not included because mutations could not be
excluded. In 13 cases (5%), no PCR product could be generated (in two
separate experiments). Consequently, the analysis with respect to
TP53 mutation and response to systemic therapy was performed
on 243 breast cancer patients who developed recurrent disease. The
patient group in the present study is not identical to the population
described previously, i.e., 165 patients were described
previously (5)
. A total of 202 patients (83%) received
first-line tamoxifen therapy, whereas 41 (17%) patients, especially
younger women with ER-negative tumors, received first-line chemotherapy
for advanced disease.
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. The median follow-up of patients who are still alive is 81 months
(range, 51–123 months) from primary surgery and 44 months (range,
8–80 months) from the start of tamoxifen treatment. A total of 163
patients have died (median survival time, 20 months). Tumor progression
occurred in most patients (190 of 202 patients, 94%) during follow-up.
Median time to progression was 7.5 months. After tumor progression on
first-line tamoxifen treatment, 70% of the patients were treated with
one or more additional endocrine agents (mostly high-dose progestins),
whereas 117 patients were subsequently treated with one or more
regimens of chemotherapy after development of hormone resistance.
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. Median follow-up was 33 months (range, 5–107 months) from the date
of primary surgery and 12 months (range, 1–75 months) from the start
of chemotherapy for recurrent disease. Tumor progression occurred in
all but one of the patients (98%) during follow-up after the start of
chemotherapy. Median time to progression was 4 months. After 12 months,
19% of the patients were alive without progression. Response to
systemic treatment was defined by standard Union Internationale Contre
le Cancer criteria as a patient having either CR or PR
or prolonged stable disease of more than 6 months (21
, 22)
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Statistical Methods |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSTumor Samples and PatientsStatistical MethodsRESULTSDISCUSSIONREFERENCES |
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSTumor Samples and PatientsStatistical MethodsRESULTSDISCUSSIONREFERENCES |
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Patient and tumor characteristics are summarized in Table 1
. The
prevalence of TP53 gene mutations is highest in tumors from
younger women (<40 years of age), in patients who experienced a
shorter disease-free interval, and in ER- or PgR-negative (<10 fmol/mg
protein) tumors. The median ER levels are about 10 times lower in the
tumors with mutations than in those without a TP53 gene
mutation (15 versus 144 fmol/mg protein, respectively).
Menopausal status and prior adjuvant therapy were not significantly
related to TP53 gene mutation. Interestingly, if the primary
tumor had a TP53 mutation, the metastases more often
developed in soft tissue (50%) or visceral tissues (46%) than in bone
(26%) as the dominant site of disease. In an exploratory analysis, we
observed a relatively low ratio between missense and nonmissense
mutations in the primary tumor of patients who developed a relapse in
soft tissue (ratio, 1.4) when compared with the ratios in patients who
relapsed to bone or visceral tissues (ratios, 3 and 3.5, respectively)
as the first site of relapse.
TP53 Gene Mutations and Response to Tamoxifen.
We observed a mutation in 65 of 202 (32%) primary tumor samples,
and this resulted in a premature termination of the protein in 13 of
these 65 samples (20%). Of the 202 patients, 55% responded to
first-line tamoxifen therapy (10 CRs, 25 PRs, and 76 cases of stable
disease). Very young patients (<40 years) tended to have a lower
response rate (33%; Table 2
). Furthermore, the presence of bone or
visceral metastasis, a short disease-free interval after primary
surgery, and low ER and PgR levels were significantly associated with
low response rates to tamoxifen, whereas prior adjuvant therapy showed
no relation with response (Table 2)
. Sixty-six percent of the patients
without a TP53 mutation responded to tamoxifen, whereas only 31% of
the patients with a TP53 mutation responded to tamoxifen therapy (OR,
0.22; P < 0.0001; Table 2
). There was no
significant difference between the response percentages of either
missense or nonmissense mutations (29% and 38%, respectively). The
TP53 gene mutations were stratified according to the type of
mutation, i.e., mutations in the zinc-binding domains L2 and
L3 of the protein, or by residues that directly contact DNA in an
exploratory analysis. Five of 12 (42%) patients with mutations
in L2 but only 2 of 13 (15%) patients with mutations in L3 or 2 of 11
(18%) patients with mutations in codons that directly contact DNA
showed a response compared to a response of 66% in patients with a
wild-type TP53 gene.
Multivariate Analysis for Response to Tamoxifen.
The independent relationship of the variables with response to
tamoxifen therapy for advanced disease was studied using multivariate
logistic regression analysis. TP53 gene mutation status (as
a dichotomized variable) was added to the classical variables (see
Table 2
). Disease-free interval, dominant site of relapse, and ER and
TP53 status were significant in this multivariate analysis. There was
no statistically significant interaction between TP53 mutation and ER
levels.
Response in Clinically Relevant Subsets of Patients Stratified by
ER and PgR Status.
We explored the association of TP53 gene status with
response to tamoxifen therapy in clinically relevant subgroups. Subsets
of tumors from patients with low ER levels (<10 fmol/mg protein,
median survival of the patients = 16 months; see Table 2
), intermediate ER levels (
10 fmol/mg protein but <75 fmol/mg
protein, median survival of the patients = 23 months),
and high ER levels (>75 fmol/mg protein, median survival of the
patients = 30 months) were created. In all three
subgroups, according to ER status, the response rate was better in
patients with wild-type TP53 in their primary tumors. The worst overall
response was observed in patients with ER-negative and TP53-mutated
tumors (n = 23), of whom only 22% responded.
The best response was observed in the patients with high ER levels and
wild-type TP53 in their primary tumors (n = 90), of whom 73% responded.
Relationship Between P53 Mutation and PFS after the Start of
Treatment.
Duration of response is perhaps as important as time to treatment
failure because the duration of response contributes directly to the
quality and duration of life. Using Cox univariate regression analysis,
we observed that the presence of a TP53 gene mutation was
significantly associated with a shorter duration of response (16
versus 11 months; P = 0.0006) in
111 patients who responded to tamoxifen. However, TP53
mutation was not significantly associated with survival after the
start of treatment (40 versus 31 months) in the responders.
The median PFS was shorter for patients with a TP53 mutation as
compared with those with wild-type TP53 (3.0 versus 9.6
months). Patients with TP53 gene mutation in their primary
tumors experienced a shorter PFS and an earlier death (relative hazard
rate, 2.61 and 1.99, respectively, both P < 0.001) than those with TP53 wild-type tumors (see Fig. 1
, ALL). In addition (see Table 2
), younger patients
(age < 40 years) and those with visceral metastasis, a
short disease-free interval, low ER or PgR levels, or TP53 mutation
showed a shorter median overall postrelapse survival after the start of
tamoxifen treatment. In the multivariate analysis for survival after
the start of tamoxifen treatment, the presence of a TP53 mutation was
associated with decreased survival (RHR, 1.39; 95% CI,
0.94–2.07; P = 0.10).
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,
ER-medium) subsets of patients but absent in the ER-negative
subset (Fig. 1
, bottom panels).
TP53 Gene Mutations and Response to Chemotherapy.
Of the 113 patients that were evaluable for chemotherapy after
tamoxifen therapy in this study, 51 (45%) responded to chemotherapy (1
CR, 19 PRs, and 31 cases of stable disease). When compared with bone
metastasis and soft tissue, patients with visceral metastasis had the
worst response to chemotherapy after tamoxifen treatment (OR, 0.66). As
shown in Table 3
, patients with TP53 mutations did not respond differently to
chemotherapy after tamoxifen therapy than did patients without
mutations. Stratification according to domain L3 of the protein or by
residues that directly contact DNA (see above) revealed that three of
five patients with mutations in L3 and two of seven patients with
mutations in codons that directly contact DNA showed a response when
compared with an overall response of 42% of patients with the
wild-type TP53 gene.
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, only 36% percent of the 25 patients with a TP53
mutation responded to first-line chemotherapy, in contrast to 63% of
the 16 patients without a TP53 mutation (OR, 0.34). In this exploratory
study on a small number of patients, only menopausal status was
significantly correlated with response to up-front chemotherapy; none
of the other patient and tumor characteristics studied were
significantly correlated with response to up-front chemotherapy.
The median PFS was 3.0 months for those patients with TP53-mutated
tumors versus 3.6 months for patients without TP53 mutation. |
DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSTumor Samples and PatientsStatistical MethodsRESULTSDISCUSSIONREFERENCES |
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Moreover, the relapse tumor could be dissimilar to the primary tumor because it was shown that TP53 mutations found in the primary tumors can be absent in the metastasis.
In the present study, we evaluated the predictive value of TP53 gene mutations, as estimated through cDNA sequencing of the entire coding sequence of the TP53 gene, in a relatively large series of breast cancer patients who were treated with tamoxifen or chemotherapy for advanced disease. We observed TP53 gene mutations in 32% of the 202 primary tumors of tamoxifen-treated patients and in 61% of the 41 patients (with mainly ER-negative tumors) treated with up-front chemotherapy. The observed prevalence is slightly higher than the mean percentage of 25% [range, 15–71%; examined in 1425 breast tumor samples worldwide; reviewed by Hartmann et al. (25) ] and a prevalence of 29% [range, 15–71%; examined in 16 populations by Soussi (26) ]. This difference can be explained by the fact that the entire coding sequence of TP53 was investigated and that only those patients who developed advanced disease were included in the present study. TP53 gene mutation was related with a poor response to up-front chemotherapy in our small series of patients (OR, 0.34) and was similarly but significantly related with a poor response to first-line tamoxifen treatment in both univariate analysis (OR, 0.22; P < 0.0001) and multivariate analysis. In contrast, patients with mutated TP53 in their primary tumors may respond better to chemotherapy (50% versus 42%) after tamoxifen treatment, but they did show a shorter PFS and duration of response.
When evaluating only those reports that have covered TP53 alterations
in relationship with the efficacy of various treatments in breast
cancer, we noticed that there is no agreement on the significance of
the predictive value of TP53. The summary of these 26 studies on almost
6000 breast cancer patients is listed in Table 4
. In 15 reports, there was no significant relation between TP53 status
and type of response (2
, 3
, 6, 7, 8, 9, 10, 11, 12
, 15
, 28
, 30, 31, 32, 33)
,
7 reports described resistance (Refs. 5
, 6 , 14
, 16
, 27
and
29
and this study), whereas the other 4 studies reported
sensitivity (13
, 34, 35, 36)
. However, this survey indicates
that the TP53 genotype, not the immunohistochemical results, is
predictive of response in breast cancer patients: all 5 studies that
used DNA analysis showed a predictive value of TP53, whereas
this was only true in 6 of the 21 immunohistochemical studies,
i.e., 2 studies showed sensitivity, and 4 showed resistance.
Both studies on radiotherapy showed sensitivity to this form of
treatment (34
, 36)
.
The mechanisms that underlie the relationship of p53 alterations and a
poor response to tamoxifen are not clear. Tamoxifen acts as an
antiestrogen via the ER, but some of its effects are thought to be
mediated through the activation of transforming growth factor ß and
by decreasing plasma insulin-like growth factor I levels. Previous data
suggest that the mutant forms of TP53 inhibit the antiproliferative
effect of transforming growth factor ß by interfering with its
signaling pathway. In addition, wild-type TP53 can repress the insulin
receptor and the insulin-like growth factor I receptor promotor in
other cell types. Although the exact mechanisms are unclear, this
complex interplay provides a link between the TP53 gene and
signaling pathways in breast cancer cells (discussed in Ref.
5
). Our finding on the relationship between TP53
gene mutation and poor response to tamoxifen treatment of advanced
disease is well in line with our previous study on p53 protein levels
by LIA in 401 patients with advanced disease (5)
but
disagrees with the studies of Archer et al. (2)
and Elledge et al. (3)
, who assessed p53
expression immunohistochemically and found no relationship with
response to endocrine treatment. Bergh et al.
(14)
and Silvestrini et al. (32)
showed that tamoxifen also appears to be of less benefit in patients
with TP53 gene mutations or overexpression, respectively, in
the adjuvant setting (see Table 4
). The relationship of TP53
gene status with PFS is most apparent in the high ER (>10 fmol/mg
protein) subgroups of our patients. In contrast to our findings,
Elledge et al. (3)
, who studied the
accumulation of p53 using IHC in mainly ER-positive metastatic breast
cancer, did not observe a relation between p53 status and response to
tamoxifen therapy, although they stated that breast tumors with altered
p53 protein are inherently more aggressive, even after they have
metastasized. These conflicting outcomes may again be explained by the
different techniques and study designs.
It is known that some chemotherapeutic agents and ionizing radiation act by inducing apoptosis in tumor cells. Lowe et al. (37) showed that cells expressing mutant TP53 were totally resistant to apoptosis on treatment, whereas cells expressing the wild-type gene were sensitive to these therapeutic agents. In the present study, TP53 gene mutations were related, although not significantly, to a poor response to up-front chemotherapy (36% versus 63%; OR, 0.34). However, the number of patients receiving first-line chemotherapy was small, the regimen is heterogeneous, and the follow-up was relatively short. Based on this, it is not possible to draw firm conclusions. Furthermore, we suspect a better response to chemotherapy after tamoxifen treatment.
Three reported molecular analyses also revealed that TP53 gene mutations predict a response to chemotherapy or adjuvant radiotherapy in breast cancer patients (6 , 33 , 35) . In contrast, all 4 reports on metastatic disease and 7 of 10 reports in the adjuvant setting revealed no predictive value of TP53 when using immunohistochemical analyses.
Various mutations can alter the TP53 protein distinctly and lead to different biological characteristics and tumorigenic potential (38 , 39) . L2 and L3 loops of the TP53 gene contain residues involved in direct DNA contact as well as protein stabilization. In the present study, those patients with TP53 gene mutations in codons that directly contact DNA or with mutations in the zinc-binding domain loop L3 showed the lowest response to tamoxifen (18% and 15% response rates, respectively). Survival analyses showed a significantly reduced survival rate for patients with mutations affecting the zinc-binding domains L2 and L3 compared with patients with mutations outside these regions or with no mutations (40) or for patients with mutations affecting the direct DNA contact (41) . Moreover, Aas et al. (6) showed that mutants affecting the L3 loop were significantly associated with de novo resistance to doxorubicin monotherapy in small subsets of patients. Extending the analysis of these various mutations allows us to focus attention on the biological significance of particular mutations that may assist the selection of residues that could be of predictive value in breast cancer.
IHC is not able to detect every TP53 alteration. In the present study, we have shown that one-fourth of TP53 mutations found are "null mutations" that do not lead to TP53 accumulation. Furthermore, IHC does not us allow to distinguish the heterogeneity of TP53 mutants. Based on the data from the literature and the present results, we conclude that the presence of mutation and the type of mutation have predictive value for response to tamoxifen treatment. Therefore, we reason that, if tissue resources permit, the TP53 mutation status should preferably be included in the daily practice of treatment of metastatic breast cancer patients.
The main conclusion of this study is that TP53 mutation is significantly associated with a poor response to tamoxifen treatment in patients with advanced breast cancer. Based on the present results and the data reviewed, it is tempting to hypothesize that the TP53 genotype in particular and, to a lesser degree, the immunohistochemical analysis are predictive of response to therapy in breast cancer. Prospective studies should be performed to support this conclusion. Besides mutation analyses, a direct functional assay (42) or the measurement of downstream components of the TP53 pathway such as p21 or MDM2 may confirm the TP53 integrity.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported in part by Grant DDHK 96-1234 from the
Dutch Cancer Society. 
2 To whom requests for reprints should be
addressed, at Department of Medical Oncology, Josephine Nefkens
Institute, Room Be 424, P. O. Box 1738, 3000 DR Rotterdam, the
Netherlands. Phone: 31-10-4088370; Fax: 31-10-4088377/365. E-mail: Berns{at}bidh.azr.nl
3 The abbreviations used are: ER, estrogen
receptor; PgR, progesterone receptor; OR, odds ratio, CI, confidence
interval; LIA, luminometric assay; CMF, cyclophosphamide, methotrexate,
and 5-fluorouracil; CAF, cyclophosphamide, Adriamycin, and
5-fluoro-uracil; CR, complete remission; PR, partial remission;
PFS, progression-free survival; IHC, immunohistochemistry.
Received 10/12/99. Accepted 2/17/00.
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H. Millward, W. Samowitz, C. T. Wittwer, and P. S. Bernard Homogeneous Amplification and Mutation Scanning of the p53 Gene Using Fluorescent Melting Curves Clin. Chem., August 1, 2002; 48(8): 1321 - 1328. [Abstract] [Full Text] [PDF]
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K. Conway, S. N. Edmiston, L. Cui, S. S. Drouin, J. Pang, M. He, C.-K. Tse, J. Geradts, L. Dressler, E. T. Liu, et al. Prevalence and Spectrum of p53 Mutations Associated with Smoking in Breast Cancer Cancer Res., April 1, 2002; 62(7): 1987 - 1995. [Abstract] [Full Text] [PDF]
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T. Sorlie, C. M. Perou, R. Tibshirani, T. Aas, S. Geisler, H. Johnsen, T. Hastie, M. B. Eisen, M. van de Rijn, S. S. Jeffrey, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications PNAS, September 11, 2001; 98(19): 10869 - 10874. [Abstract] [Full Text] [PDF]
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N. Keshelava, J. J. Zuo, P. Chen, S. N. Waidyaratne, M. C. Luna, C. J. Gomer, T. J. Triche, and C. P. Reynolds Loss of p53 Function Confers High-Level Multidrug Resistance in Neuroblastoma Cell Lines Cancer Res., August 1, 2001; 61(16): 6185 - 6193. [Abstract] [Full Text] [PDF]
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H. Elsaleh, B. Powell, K. McCaul, F. Grieu, R. Grant, D. Joseph, and B. Iacopetta P53 Alteration and Microsatellite Instability Have Predictive Value for Survival Benefit from Chemotherapy in Stage III Colorectal Carcinoma Clin. Cancer Res., May 1, 2001; 7(5): 1343 - 1349. [Abstract] [Full Text]
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S. Geisler, P. E. Lønning, T. Aas, H. Johnsen, O. Fluge, D. F. Haugen, J. R. Lillehaug, L. A. Akslen, and A.-L. Børresen-Dale Influence of TP53 Gene Alterations and c-erbB-2 Expression on the Response to Treatment with Doxorubicin in Locally Advanced Breast Cancer Cancer Res., March 1, 2001; 61(6): 2505 - 2512. [Abstract] [Full Text]
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