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Clinical Cancer Research Vol. 9, 5582-5588, November 15, 2003
© 2003 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

TP53 Gene Mutations Predict the Response to Neoadjuvant Treatment with 5-Fluorouracil and Mitomycin in Locally Advanced Breast Cancer

Stephanie Geisler1, Anne-Lise Børresen-Dale4, Hilde Johnsen4, Turid Aas2, Jürgen Geisler1, Lars Andreas Akslen3, Gun Anker1 and Per Eystein Lønning1

1 Department of Medicine, Section of Oncology, and
2 Departments of Surgery and
3 Pathology, The Gades Institute, Haukeland University Hospital, Bergen; and
4 Department of Genetics, The Norwegian Radiumhospital, Oslo, Norway


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: Recent studies have found an association between certain TP53 mutations and resistance to anthracycline-based primary medical therapy in breast cancer. The purpose of this study was to investigate whether TP53 mutational status also might influence the response to a non-anthracycline-containing regimen in primary breast cancer.

Experimental Design: Thirty-five patients with locally advanced breast cancer were investigated for TP53 mutations before receiving combination chemotherapy with 5-fluorouracil (1000 mg/m2 on days 1 and 2) and mitomycin (6 mg/m2 on day 2), administered every 3 weeks for 2–10 cycles in the neoadjuvant setting.

Results: Mutations in the TP53 gene, in particular those affecting loop domains L2 or L3 of the p53 protein, were associated with lack of response to chemotherapy (i.e., increase in the diameter product of tumor lesion by >=25%; P = 0.177 for all mutations and P = 0.006 for those affecting L2/L3 domains, respectively). No statistically significant correlation between TP53 LOH and response to therapy was seen.

Conclusion: This study revealed a significant association between lack of response to 5-fluorouracil and mitomycin and mutations affecting the L2/L3 domains of the p53 protein. Together with our previous finding that such mutations predict resistance to weekly doxorubicin, our data suggest that mutations affecting this particular domain of the p53 protein may cause resistance to several different cytotoxic compounds applied in breast cancer treatment.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The mechanisms causing resistance to chemotherapeutic drugs are poorly understood. At present, the evidence suggests that most anticancer drugs kill cells by inducing apoptosis (1 , 2) , and this has led to an increasing focus on defects in the apoptotic machinery as a cause of chemoresistance.

Earlier studies revealed that overexpression of p53, the protein coded for by the TP53 gene, is a prognostic factor in breast cancer (3 , 4) . Because defects in p53 function have been shown to influence response to chemotherapy both in vitro (5) and in vivo (6) , efforts have been undertaken to study its usefulness as a predictive factor for chemotherapy sensitivity in different malignancies. Because mutated protein might accumulate in cells, immunohistochemical staining has been a popular surrogate marker for TP53 mutational status (7) . Most studies evaluating p53 status by use of immunohistochemistry have failed to show a predictive value of p53 disturbances regarding chemoresistance in breast cancer (8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21) . This may be explained by previous observations from our own group (22) and others (23) revealing that ~30% of all mutations in primary breast cancer, in particular those of the nonsense type, are not detected by immunohistochemistry. In contrast, authors of studies evaluating TP53 status by DNA sequencing have reported mutations that predict resistance to anthracyclines in breast cancer (24 , 25) as well as therapeutic failure in hematological malignancies (26, 27, 28) .

We recently reported TP53 gene mutations, in particular those affecting or disrupting the L2/L3 loop domains of the protein (codons 163–195 and 236–251, respectively), that predict for resistance to doxorubicin monotherapy in locally advanced breast cancer (22) . Here we report the predictive value of TP53 mutations, TP53 LOH,5 and histological grading in 35 patients with locally advanced breast cancer receiving primary medical treatment with 5-FU and mitomycin in concert.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients.
Thirty-five patients treated with 5-FU and mitomycin for locally advanced breast cancer (T3/T4 and/or N2 tumors) were studied. Most patients received this regimen for medical or logistical reasons (medical contraindications to anthracyclines or logistical difficulties regarding weekly doxorubicin administered on an outpatient basis; Ref. 22 ). The median age was 67 years (range, 37–82 years). Eleven patients suffered from concomitant minor distant metastases at the time of diagnosis.

Tissue Sampling.
Before commencing chemotherapy, each patient had an incisional tumor biopsy as described previously (22) . All tissue samples were snap-frozen in the theater immediately on removal. The scientific protocol (tissue sampling and laboratory analysis) was approved by the Regional Ethical Committee, and each patient gave written informed consent to the procedure.

Histopathology.
Of the 35 tumors, 30 were invasive ductal carcinomas, whereas 5 were classified as "other histological types" (lobular or poorly differentiated carcinomas). Tumor grading was performed based on the criteria of Page et al. (29) , considering the degree of tubular structures, nuclear pleomorphism, and mitotic figures. The mitotic rate was also recorded separately in 10 high-power fields (x400 magnification).

Treatment Regime and Staging.
Primary treatment consisted of 5-FU (1000 mg/m2 on days 1 and 2) and mitomycin (6 mg/m2 on day 2) administered at three-week intervals (FUMI regimen). Treatment was scheduled for four cycles with a possibility for extension based on clinical decisions. Clinical response was assessed before each treatment cycle. Because the patients were enrolled between 1993 and 2001, the UICC criteria (30) and not the more recent RECIST criteria (31) were consistently used. Thus, responses were classified as CR (complete disappearance of all tumor lesions), PR (reduction >=50% in the sum of all tumor lesions, calculated for each as the product of the largest diameter and the one perpendicular to it), PD (increase in the diameter product of any individual tumor lesion by >=25%), and StbD (anything between PR and PD). As discussed previously (22) , the terms StbD and PR are pragmatic terms that describe a status of tumor "growth arrest" with or without a certain degree of macroscopic reduction in tumor size; the discrimination between the two may often be arbitrary (several patients had a modest reduction in size of their tumors). On the other hand, in progressing tumors, the bulk of the tumor cells lack sensitivity to treatment. Thus, the PD tumors should be considered distinctive and easily discriminated clinically from the other groups (32) . To analyze for the predictive value of the different parameters, we compared PD tumors with the combined group of tumors classified as StbD/PR/CR (22) . Therapy with FUMI was terminated immediately in case PD was revealed.

Before commencing therapy, each patient underwent a staging consisting of X-rays of the chest, spine, and pelvis; a liver ultrasound examination; and a bone scan.

The clinical response to FUMI treatment could not be classified in one patient for technical reasons (patient FU21), leaving 34 patients for response evaluation. Median follow-up time (42 months; range, 10–103 months) was defined from inclusion in the study up to December 31, 2001.

Mutation and LOH Analysis.
Mutations in the TP53 gene were analyzed with use of genomic DNA and the TTGE strategy as described previously (33 , 34) and applied (22) elsewhere. Genomic DNA was extracted from fresh-frozen tissue by the phenol–chloroform extraction protocol on a 340A Nucleic Acid Extractor (Applied Biosystems, Foster City, CA). DNA fragments covering exons 2–11 were amplified, all with a GC clamp on one of the primers, and submitted to analysis by TTGE. DNA fragments melt in a sequence-specific manner under denaturing conditions during PAGE. A fragment containing a mutation will have a melting property different from that of the wild type, resulting in altered mobility. If both a mutant and the wild type are present, heteroduplexes will be formed and detected as two extra bands with decreased mobility (33 , 34) . All samples with aberrantly migrating bands on TTGE were submitted to direct sequencing of a new PCR product with standard dideoxy sequencing reaction using the Dye Terminator Cycle Sequencing kit with AmpliTaq FS and an ABI 373 sequencer (Applied Biosystems). The sensitivity in detecting mutations present in only a small fraction of the sample is ~10% at the homoduplex level and 1–3% at the heteroduplex level (34) . For samples where the mutation analyses on genomic DNA revealed a mutation affecting the splice site, cDNA prepared with use of total RNA, isolated by TRIzol Reagent (Invitrogen), and reversed transcribed by the GeneAmp RNA PCR Core Kit (Applied Biosystems) was sequenced to determine the effect of mutation at the mRNA level.

Blood samples to assess LOH of the TP53 gene were available from 26 patients. Among these, 23 were found to be informative (heterozygotes) for one or both of the two markers used: one a variable number tandem repeat in intron 1 (35) , the other a CA repeat in the nontranslated 3' end of the gene (36) . Fluorescently end-labeled primers were used in the PCR, and the PCR products were analyzed on an ABI PRISM 310 Genetic Analyzer. The data were analyzed by comparing normal and tumor tissue allele peak-height ratios. A sample was scored as having LOH when a reduction in peak height of one allele in the tumor sample was at least 19% compared with that of blood DNA from the same patient.

Statistical Analysis.
Mutations of the TP53 gene, LOH for the TP53 gene, and histological grading were correlated with response to chemotherapy and to each other with use of the {chi}2 method, including Yates correction for a limited number of observations. In addition, the differences in the distribution of TP53 mutation among patients revealing a PD and the remaining groups were analyzed with use of Fisher’s exact test. Because of the limited time of follow-up and the fact that patients with an inferior response to FUMI received different forms of second-line chemotherapy (see Table 2Citation ), no formal statistical assessment of relapse-free or overall survival was performed. However, details regarding outcome in individual patients are shown in Table 2Citation to make them available to the reader.


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  		Table 2 Clinical characteristics of all patients included in the study

 

   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Eighteen of the 35 patients (51.4%) harbored mutations of the TP53 gene in their tumors. Of the 18 mutations detected, 8 were missense (3 transversions and 5 transitions), 1 was a nonsense, 2 were splice mutations, 4 were deletions, 2 were insertions giving frameshifts, and 1 was an in-frame insertion (Table 1)Citation . Eight of these mutations (the two splices, three deletions, two insertions, and one missense) were novel and have not been reported previously in breast cancer or any other tumor type (IARC database: http://www.iarc.fr/p53/). Three of the missense mutations, one of the splices, and five of the deletions/insertions directly or indirectly affected the L2 and/or L3 domains of the p53 protein (Table 2)Citation . This subgroup was considered of particular interest based on previous findings that mutations affecting these domains seem to predict a particularly poor prognosis (4) as well as drug resistance (22 , 24) .


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  		Table 1 Characteristics of mutants found

 
Table 2Citation shows the response to FUMI therapy together with a description of the clinical status in each patient with measurable disease, whereas the distribution of TP53 mutations in the different response categories is given Table 3Citation . Remarkably, seven of nine patients with progressive disease harbored TP53 mutations, all but one affecting the L2/L3 domains. The missense mutation not affecting the L2/L3 domains in the one patient (FU12) with progressive disease is predicted to give a structure clash of the protein and is thus considered a "serious" mutation leading to a nonfunctional protein. The same is the case for the mutations found in patients FU18, FU26, and FU49.


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  		Table 3 Clinical response in relation to different parameters

 
Although there was a trend for TP53 mutations in total to be associated with lack of response (PD), it did not reach statistical significance ({chi}2, P = 0.177; Fisher exact test, P = 0.125). However, when tumors harboring TP53 mutations affecting the L2/L3 DNA-binding domains of the protein were compared with those with wild-type TP53 or TP53 mutations outside the L2/L3 domains, mutations affecting the L2/L3 domains correlated significantly to lack of response ({chi}2, P = 0.006; Fisher exact test, P = 0.004). When the mutations predicted to cause a structure clash with a nonfunctional protein (patients FU12, FU18, FU26, and FU49) were added to the mutations affecting the L2/L3 domains, the statistical significance remained strong ({chi}2, P = 0.007; Fisher exact test, P = 0.004).

LOH for TP53 was significantly correlated to TP53 mutation ({chi}2, P = 0.027; Fisher exact test, P = 0.046) but not to lack of response to therapy. Notably, among the nine patients revealing a PD on therapy, information about LOH status was available for six. The normal TP53 allele was lost in all four of the six PD patients harboring a TP53 mutation and in one without a mutation (patient FU31). In patient FU22, who experienced PD and had no TP53 mutation, the tumor was found to retain both wild-type TP53 alleles.

Although high histological grade and high mitotic count were associated with TP53 mutations (P = 0.064 and 0.009, respectively), none of these parameters was found to predict for chemoresistance.


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Experimental evidence suggests a key role for p53 in apoptosis in response to genotoxic agents (5 , 6) . The conflict among data from in vivo studies evaluating the role of p53 in response to chemotherapy is partially attributable to inadequacy of immunostaining to diagnose mutations correctly (22 , 23 , 37) . Different groups have reported that ~30% of primary breast cancers harboring a TP53 mutation detected by sequencing do not express protein for immunostaining (22 , 23) Whereas Kandioler-Eckersberger et al. (25) found that both TP53 mutation status and p53 immunostaining predict resistance to a regimen containing 5-fluorourcil, epirubicin, and cyclophosphamide in our previous study, we found that most tumors harboring TP53 mutations that progressed on treatment with doxorubicin were negative for protein staining (22 , 24) . Accordingly, in this study we assessed TP53 mutational status only.

In our previous study, we found that mutations affecting the L2/L3 loops of the p53 protein were associated with anthracycline resistance in particular, whereas the authors of other studies found that p53 disturbances in general predict therapy failure in breast cancer (38 , 39) . Although Berns et al. (40) observed a nonsignificant correlation between TP53 mutation and response to combined chemotherapy, they reported a significant correlation between TP53 mutation and lack of response to tamoxifen. Formenti et al. (38) assessed the response to chemotherapy and radiotherapy in concert, whereas Lizard-Nacol et al. (39) combined TP53 gene mutations and LOH in their statistical analysis, stating that "the presence of p53 alterations" predicted chemoresistance.

The novelty of this study is that we evaluated the predictive value of TP53 mutations in relation to a well-defined, non-anthracycline-containing regime consisting of 5-FU and mitomycin. This low-toxicity regimen has provided response rates comparable to those for other treatment regimes in metastatic breast cancer (41 , 42) and is well suited for this purpose, particularly in senior patients. Many patients whose response was recorded as "stable disease" experienced a reduction in tumor volume not filling the criteria of a PR (>50% reduction), substantiating the approach of comparing patients classified as PD versus those classified as PR or SD as a combined group (32) . Mitomycin and 5-FU have different mechanisms of action. 5-FU inhibits thymidylate synthase, a key enzyme for DNA biosynthesis (43) , and it is also incorporated into RNA, thus interfering with normal RNA processing and function (44 , 45) . Mitomycin is an alkylating agent that causes DNA damage in the form of DNA cross-links (46) as well as a variety of DNA monoadducts (47 , 48) . For both drugs, the mechanism(s) of resistance in vivo is unknown. Interestingly, experimental data (49) and clinical studies (50) in head and neck cancers have suggested that 5-FU depends on an intact p53-function to execute its cytotoxic effects. For mitomycin, several mechanisms, such as overexpression of metallothionein, Bcl-x(L), and MDR-1, have each been linked to chemoresistance (51, 52, 53) . Although there is evidence from in vitro studies that the cytotoxic effect of mitomycin also depends on an intact p53 function (54, 55, 56) , we are not aware of any study assessing the role of TP53 to the function of mitomycin in vivo.

The finding of this study that TP53 mutations affecting or disrupting the L2/L3 domains predict resistance to combined treatment with 5-FU and mitomycin are consistent with the hypothesis that p53 is critical for apoptosis with respect to different cytotoxic agents, not only anthracyclines, in breast cancer.

Different TP53 mutations have been shown in experimental systems to be of different biological importance (57, 58, 59) . Our findings here, that mutations of the L2/L3 domains seem to be related to drug resistance in particular, are consistent with our previous results revealing that such mutations are associated with resistance to doxorubicin monotherapy (22) . The structure of p53 is complex, with individual amino acids outside the L2/L3 domains also found to be of critical importance for DNA binding as well as for the overall structure of the protein (60) . When mutations causing a structure clash and a nonfunctional protein were added to those affecting the L2/L3 domains, the association with chemoresistance was as high as for the L2/L3-affecting mutations alone. However, the possibility that other classifications could be more useful underlines the need to report individual mutations to combine the results from different trials for later overviews.

As reported by others (61, 62, 63, 64) , we found a significant association between increased tumor cell proliferation (high mitotic frequency, high histological grade) and mutations in TP53. Defects in the function of p53 might eliminate G1 arrest, which is an important cellular "checkpoint," thereby allowing cells with damaged DNA to enter S-phase. Nevertheless, it remains poorly understood whether TP53 mutations are the primary cause of increased proliferation or whether rapid mitotic activity may facilitate mutations, thus further increasing tumor growth rate. Results reported previously by our group (65) do not support an independent role for proliferation markers in predicting drug resistance.

The finding that some patients with TP53 mutations affecting the L2/L3 domains and concomitant LOH obtained a StbD or PR suggests that redundant mechanisms may be involved in initiating apoptosis in response to chemotherapy in breast cancer (32) . Remarkably, the tissue sample obtained from one of the patients classified as PR revealed a TP53 mutation identical to the one from another patient who experienced a PD (Table 1Citation , patients FU23 and FU05, respectively). Thus, although p53 plays a profound role in regulating the apoptotic response of cancer cells to different classes of chemotherapeutic agents, our results are consistent with the hypothesis that other gene alterations may operate in concert with TP53 in implementing the response to cytotoxic agents.

In conclusion, the data presented here support the hypothesis that p53 plays a critical role in implementing apoptosis in response to treatment with different chemotherapeutics in breast cancer. Further studies are warranted to explore the cause of resistance among those patients expressing a wild-type p53 protein and the "rescue" mechanisms in tumors that respond to therapy despite harboring TP53 mutations that affect the critical L2/L3 loops.


   ACKNOWLEDGMENTS
 
We greatly appreciate the technical assistance of D. Ekse, H. Helle, B. Leirvaag, and B. G. Kolstad. We thank Pierre Hainaut and Magali Olivier at IARC for valuable discussions concerning the function of the different mutations.


   FOOTNOTES
 
Grant support: This study was supported by grants from the Norwegian Cancer Society and the Research Council of Norway.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Requests for reprints: P. E. Lønning, Department of Medicine, Section of Oncology, Haukeland University Hospital, N-5021, Bergen, Norway. Phone: 47-55-972027; Fax: 47-55-972046; E-mail: per.lonning{at}helse-bergen-no

5 The abbreviations used are: LOH, loss of heterozygosity; 5-FU, 5-fluorouracil; FUMI, 5-fluorouracil plus mitomycin; CR, complete remission; PR, partial remission; PD, progressive disease; StbD, stable disease; TTGE, temporal temperature gel electrophoresis. Back

Received 1/ 9/03; revised 4/28/03; accepted 6/17/03.


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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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