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Molecular Oncology, Markers, Clinical Correlates |
Centro di Senologia [A. Bo., A. Br., S. A., F. C., L. F., P. A.] and Anatomia Patologica Azienda Ospedaliera Istituti Ospitalieri, Cremona, Italy [A. Bers., B. D., G. Bo., E. B., G. Be.], and Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Oncologia Medica, Azienda Ospedaliera San Luigi, 10043 Orbassano, Italy [A. Berr., M. P. B., G. G., L. D.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The tumor-specific action of most anticancer agents has been attributed for decades to their debilitating effects on actively proliferating cells (1) . In recent years, an increasing body of evidence suggests that anticancer agents can induce apoptosis in a manner indistinguishable from that caused in eukaryotic cells by DNA damage and/or depriving cells of growth factors (2 , 3) .
Programmed cell death is an active process and depends on the expression of a specific set of genes (4) . Among them, wild-type p53 can induce apoptosis (5 , 6) , deregulated c-myc can enhance apoptosis in particular conditions (7) , and bcl-2 can inhibit apoptosis (8, 9, 10) .
Because apoptosis requires a genetic program, mutations in apoptotic pathways could produce drug resistant tumors.
In vitro studies have clearly shown that p53 is required for the efficient activation of apoptosis after irradiation or treatment with chemotherapeutic compounds (3 , 11) .
Loss of p53 function has been reported to enhance cellular resistance to chemotherapeutic agents in certain experimental tumor models (2) , as well as in in vivo studies (12) .
Mutation in the p53 tumor suppressor gene frequently occur in a variety of carcinomas, such as lung cancer (13) , colon cancer (14) , and BC3 (15) , that are scarcely or moderately responsive to the cytotoxic treatment. Conversely, it does not occur, or rarely occurs, in neoplasms that are highly responsive to chemotherapy, such as leukemia (5) , lymphomas (16) , and testis cancer (17) . Although wild-type p53 protein has a short half-life, many mutations stabilize the protein, thus making it amenable to detection by immunohistochemistry (18) .
The product of the bcl-2 gene has been shown to protect cells against death induced by a myriad of insults, including most chemotherapeutic drugs (19) . For this reason, it has been hypothesized that bcl-2 overexpression may play a role in the resistance to chemotherapy. High expression of the bcl-2 gene has been found to be associated with chemotherapy resistance in neuroblastoma (20) and acute myeloid leukemia (21) . Unexpectedly, bcl-2 expression in BC patients has been found to be related with a good prognosis (22, 23, 24) and with a better clinical response to tamoxifen (25) .
The administration of PC to BC patients is an elegant model to assess in vivo the chemosensitivity of the tumor. It has been repeatedly demonstrated that PC is able to induce tumor shrinkage (26, 27, 28, 29, 30) in a high percentage of patients, and the occurrence of cCR, observed in about 20%–30% of cases, was found to be significantly associated with a better prognosis (28 , 30) .
In a series of women with operable or locally advanced BC, submitted in the same institution to PC with two different chemotherapeutic regimens, we analyzed in univariate and multivariate analysis the association of bcl-2 expression and p53 inactivation with the clinical complete tumor response.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Treatment.
Chemotherapy was started within 1 or 2 days of diagnosis. The first
consecutive 76 patients received the CMF chemotherapy regimen, which
was given on days 1 and 8 of each treatment cycle. The dose of
cyclophosphamide and 5fluorouracil was 600
mg/m2 of body surface area, and the dose of
methotrexate was 40 mg/m2. The next 81 patients
received epirubicin 60 mg/m2 on days 1 and 2.
Each of the three drugs of the CMF regimen was repeated every 28 days,
whereas epirubicin was administered every 21 days. The first
consecutive 45 patients, with ER+ BC at first biopsy, concomitantly
received tamoxifen (30 mg daily, p.o.). Hormonal treatment was
administered after obtaining the results of the receptor status, about
20 days from the first biopsy, and continued up until surgery. The size
of primary tumor and the size of axillary lymph nodes, when
appreciable, were carefully measured every cycle by palpation by the
same clinician using a caliper. To avoid interference attributable to
postbiopsy edema, tumor shrinkage was evaluated from the second course
onwards. Response was assessed by clinical measurement of the changes
in the product of the two largest diameters recorded at baseline and at
the end of chemotherapy before surgery. According to the WHO criteria
(31)
, tumor progression was defined as an increase of at
least 25%, stable disease as a tumor size increase less than 25% or
reduction less than or equal to 50%, PR as tumor shrinkage greater
than 50%, and complete response as the complete disappearance of all
clinical signs of disease. Surgery was planned after full clinical
reassessment. Quadrantectomy or modified radical mastectomy was
performed when indicated in association with full axillary dissection.
All patients subjected to quadrantectomy underwent irradiation of the
residual breast (60 Gy delivered in 6 weeks).
Preparation of Samples and Assessment of Histopathological Grade
and Immunohistochemistry.
The surgical resection specimens at diagnosis and at mastectomy or
quadrantectomy were examined and cut up fresh. Appropriate tissue
blocks were then taken and fixed in 2.5% phenol formalin before
routine processing and embedding in paraffin wax. In each case, 3-µm
sections were cut and stained with H&E for histological examination.
The degree of malignancy was determined according to the Elston and Ellis (32) grading system, dividing tumors into grade I (well differentiated), grade II (moderately differentiated), and grade III (poorly differentiated).
Immunohistochemistry was performed on paraffin-embedded tissues as follows: sections were cut at 4–6 µm and floated onto slides in a water bath. The sections were then dried at 37°C overnight; paraffin was removed in xylene. Slides were placed in a glass box filled with 10 mM citrate buffer, pH 6.0, and then processed in a microwave oven two times for 5 min each at 750 W. The section were let cool down in the box at room temperature for about 20 min and then rinsed in Tris-buffered saline.
The following primary antibodies were applied according to the manufacturers’ instructions: ER [mouse monoclonal 6F11 (Novocastra Laboratory, Newcastle Upon Tyne, United Kingdom); dilution, 1:50; 1-h incubation at room temperature], PgR [mouse monoclonal 1A6 (Novocastra Laboratory); dilution, 1:20; 1-h incubation at room temperature], Ki67 [mouse monoclonal Mib-1 (Dakopatts, Glostrup, Denmark); dilution, 1:30; 1-h incubation at room temperature], p53 [mouse monoclonal D07 (Novocastra Laboratory); dilution, 1:100; 1-h incubation at room temperature], bcl-2 [mouse monoclonal 124 (DAKO, Glostrup, Denmark); dilution, 1:40; overnight incubation at 4°C], c-erbB2 [mouse monoclonal CB11 (Novocastra Laboratory), overnight incubation at 4°C], and P-glycoprotein [monoclonal MDR/JSB-1 (Novocastra Laboratory); dilution, 1:100; overnight incubation at room temperature].
Biotinylated horse antimouse IgG at a 1:200 dilution and avidin-biotin-peroxidase complex at a 1:100 dilution were added in sequences (Vectastatin ABC kit; Vector Laboratories, Inc., Burlingame, CA). A chromogen substrate solution containing hydrogen peroxide (0.06%, v/v) and diamino-benzidine 4-HCl (0.05, v/v) was added to each specimen for 1–2 min.
Slides were then rinsed in distilled water between applications and finally, were counterstained, dehydrated, cleared, and mounted for examination by light microscope with coverslip.
Immunohistochemical Scoring.
All samples had a negative control slide (no primary antibody) of an
adjacent section to assess the degree of nonspecific staining. Positive
controls included breast carcinomas known to exhibit high levels of
each markers.
All staining was scored by counting the number of positively stained cells and expressed as a percentage of the total tumor cells (at least 1000) counted across several representative fields of the section using a standard light microscope equipped with a 10 x 10 square graticule. Reproducibility of counting was assessed by a second investigator rescoring 10 slides.
The relative intensity of ER and PgR staining was assessed in a semiquantitative fashion as described previously by McCarty et al. (33) , incorporating both the intensity and distribution of specific staining. A value (HSCORE) was derived from the sum of the percentages of positive-stained epithelial cells multiplied by the weighted intensity of staining. Specimens were deemed receptor positive if the HSCORE was greater than 100 (34) . The immunohistochemical evaluation at mastectomy was performed by the same pathologists, who remained blinded as regard as the disease response and the score assessed at first biopsy.
Statistical Analysis.
The association of variables was evaluated by the
2 test or the Fisher’s exact test if
applicable. Ki67 staining was categorized into three classes as shown
in Table 1
. Multivariate analysis to
predict for the complete response was performed by logistic regression.
The regression coefficients were estimated by maximum likelihood
criteria and their significance was tested by Wald’s test. Statistical
analysis was performed on an IBM-compatible personal computer using the
SPSS software (35)
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Treatment Activity.
Patients received a median of three cycles (range, 2–6) of either
CMF ± tamoxifen or epirubicin. At the end of the chemotherapy
administration, 33 patients (23.1%) attained a cDR and 71 patients
attained a clinical PR (49.7%), for an overall response rate (cCR +
clinical PR) of 72.8%. Thirty-seven patients showed stable disease
(25.9%), whereas only two progressed (1.4%). The cCR levels
were higher in patients receiving CMF ± tamoxifen (29.7%) than
in patients submitted to epirubicin (17.7%), although this difference
was not statistically significant.
Overall response was similar dividing patients according to either
bcl-2 or p53 status at various cutoff of positive cells (data
not shown). The distribution of the cCR rates did not show any
difference between bcl-2-positive and -negative tumors, whereas p53
expression was negatively associated with the cCR at the cutoff of 10%
positive cells (Table 2)
. CCR was also
obtained in 7 of 42 (16.7%) and in 26 of 99 (26.3%) gp-170-positive
and -negative BC (P not significant).
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Effect of Chemotherapy on p53 and bcl-2 Immunostaining.
The percentages of cells positive for either p53 or bcl-2 on tumor
specimens obtained at first biopsy and at mastectomy have been
assessed, and a comparison has been performed. An increase >10% in
p53 expression in tumor specimens from matched pairs of untreated and
treated biopsies has been observed in 19 patients (13.3%), whereas
>10% decrease of positive p53 cells has been found in 8 cases
(5.6%). The changes in p53 expression after treatment were mainly
confined to p53-positive tumors at baseline. Primary BC negative for
p53 expression at the first biopsy became p53 positive at mastectomy in
only four cases (2.8%). As far as bcl-2 expression is concerned, more
than 10% increase after treatment has been found in 20 cases (13.9%),
whereas a decrease (>10%) has been observed in 18 patients (12.4%).
Four patients (2.8%) with bcl-2-negative BC at the first biopsy had
the oncogene expressed in their tumor at mastectomy.
Relationship among p53 and bcl-2 Expression and Clinical and
Biological Characteristics of Primary BC.
The relationships among p53, bcl-2, tumor dimension, lymph node
involvement, and other biological indices of aggressiveness, such as
histological grade, ER status, c-erbB2, and Ki67, are depicted on Table 3
. Because the difference in cCR
between p53-positive and -negative primary BC was statistically
significant for p53 stained in more than or equal to 10% cells, this
cutoff was introduced in the statistical analysis; conversely, a cutoff
of 30% positive cells for bcl-2 has been selected according to the
literature (36)
. Neither p53 expression nor bcl-2
expression showed a significant correlation with the node
involvement; bcl-2 but not p53 was inversely related with tumor
staging. A strong inverse relationship was found between p53 and bcl-2
status, and both markers showed opposite patterns when related to the
other biological parameters. bcl-2 was directly correlated with the
steroid hormone receptor status and inversely correlated with c-erbB2,
Ki67, and gp-170 expression. p53 was inversely correlated with the
ER/PgR expression and showed a direct relationship with Ki67
expression, histological grade, c-erb2, and gp-170 positivity. No
statistical differences have been found between bcl-2
expression and histological grade.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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To assess whether the two most studied inhibitors of apoptosis, the bcl-2 gene and the mutant p53 gene, may play a role in modulating response of BC to PC, patients submitted to two different chemotherapy regimens in neoadjuvant setting have been evaluated in the present study.
The relationship in the process of apoptosis between the bcl-2 and p53 genes is not completely clear; however, it has been observed that bcl-2 can inhibit apoptosis triggered by wild-type p53 (37) . Analysis of multiple human BC cell lines with antibodies against p53 and bcl-2 revealed that the expression of the two proteins is in most of the cases reversed (37, 38, 39) . This finding suggests that mutant p53 could determine bcl-2 down-regulation. We confirm that p53 and bcl-2 expressions are reciprocally correlated, and both markers have inverse relationships with respect to the other prognostic factors. Our data are in keeping with the concepts that the bcl-2 expression is related to more indolent and scarcely aggressive tumors (22, 23, 24, 25) , whereas the abrogation of p53 function leads to a more aggressive tumor biology (40 , 41) .
As a whole, bcl-2 expression did not show any relationship with the cCR, whereas mutated p53 was a significant predictor for poor cCR rate. The cCR more frequent in p53-negative primary BC is consistent with previous data, showing that the responsiveness of tumors to cytotoxic therapy in part derives from the tendency of malignant cells to undergo apoptosis in response to DNA damage (2 , 3) . In addition, this study suggests that the poor prognostic role for relapse of the mutated p53 tumor suppressor gene is not only because it is a molecular sign of genomic instability (which increases the likelihood that cells will acquire further mutations; Ref. 42 ) but also because it is a marker of resistance to cytotoxic drugs administered in adjuvant setting.
bcl-2 expression in BC patients has been repeatedly found to be related to a good prognosis (22 , 36) and to a greater chance to obtain response to endocrine therapy (25) . The absence of relationship between bcl-2 expression and cytotoxic drug activity in our series is in agreement with the results of van Slooten et al. (43) , showing that this marker does not predict response to one course of perioperative chemotherapy.
Dividing patients according to the treatment administered, the predictive effect of the p53 status on the cCR was more evident in the subgroup of patients submitted to epirubicin than in the subset of cases submitted to CMF ± tamoxifen, in whom only a trend of lower cCR rate has been observed in p53+ tumors (at a cutoff of 10% positive cells) in comparison to p53– ones. In a multivariate analysis, however, when adjusting for treatment administered and a number of baseline clinical and biological parameters, the p53 status maintained an independent predictive role for cCR.
It is well known that P-glycoprotein encoded by the MDR1 gene is a predictor of chemoresistance of a number of chemotherapeutic drugs, such as anthracyclines and Vinca alkaloids, but not as far as antimetabolites, such as 5-Fluorouracil and Methotrexate, are concerned (44) . The mutant tumor suppressor p53 protein has been shown to activate the MDR1 promoter, whereas the wild-type p53 repressed this activity in cultured cells (45) . Our data are in keeping with these observations, because p53 and gp-170 depicted a strong direct correlation. In addition, gp-170 expression, being reciprocally related to p53 and bcl-2, showed a negative relationship with bcl-2. The cCR obtained in the 8.0% of our gp-170-positive tumors submitted to epirubicin was consistently lower than cCR (22%) in gp-170-negative ones. By contrast, patients submitted to CMF ± tamoxifen did not show any difference in cCR according to the gp-170 status. Because gp-170 is mainly expressed in p53-positive BC, this correlation may be, at least in part, responsible for the difference in activity between the two treatments according to the p53 immunostaining.
Controversial data have been published as regard as the role of p53 in conferring increased resistance to antitumor agents (15) . Lack of unanimity of results may be attributable to differences in technique, study design, or patient population. Our data suggest that the different cytotoxic treatments adopted may have contributed to the variation within the literature in the effect of p53 status upon therapeutic responsiveness.
As an example, the CMF regimen was used in three studies that
failed to find a relationship between p53 status and chemotherapy
efficacy (46, 47, 48)
, whereas an anthracycline-containing
regimen was used in one study (49)
that showed an
association between p53 accumulation and poor treatment response (Table 4)
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To conclude, PC administered to BC patients can provide new insights into mechanisms involved in tumor sensitivity or resistance to cytotoxic agents. An incision biopsy at diagnosis is necessary to obtain adequate tumor samples for biological evaluation before treatment. The status of the p53 gene, which is mutated in a high percentage of breast tumors, is not only a prognostic marker but also a predictive factor for cytotoxic drug activity, particularly as far as anthracyclines are concerned. By contrast, bcl-2 is a good prognostic marker, but fails to be related to chemotherapy activity.
The relatively small sample size may limit the generalization of the results, and the Ps should be interpreted with a correction for multiple comparisons. These limitations notwithstanding, this explorative analysis could offer a valid background for further confirmatory research.
In addition, increasing amounts of data have shown that the assumption that increased p53 staining implies mutant p53 may not be valid in all circumstances. In some cases, increased staining may be attributable to wild type overexpression; likewise, negative cells may not necessarily have normal p53 function (15) . It would be helpful in the future to use molecular techniques in addition to immunostaining to assess the p53 status. Moreover, it is not clear why bcl-2, although it promotes tumor cell survival by blocking programmed cell survival, represents in BC patients a molecular sign of favorable prognosis. Probably, the determination of bcl-2 status alone is not sufficient in assessing the competency of the bcl-2 apoptosis pathway. The assessment of levels of the other member of the bcl-2 family (i.e., bax; Ref. 51 ) may better determine the extent to which apoptosis may occur as well as whether or not dysfunction in this pathway is present.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Presented in part at the XXV
ISOBM meeting (Montreux, Switzerland, 1997), at the XXXIV
American Society of Clinical Oncology meeting (Los Angeles, USA, 1998),
at the 1st International Symposium on Primary Chemotherapy in the
Treatment of Breast Cancer (Cremona, Italy, 1998), and at the XXIII
ESMO meeting (Athens, Greece, 1998). Financial support was
provided by the Association Amici dell’Ospedale di Cremona. 
2 To whom requests for reprints should be
addressed, at Oncologia Medica, Azienda Ospedaliera San Luigi, Regione
Gonzole 10, 10043 Orbassano, Italy. Phone: 0039-11-90-26-512; Fax:
0039-11-90-26-676; E-mail: luigi.dogliotti{at}unito.it
3 The abbreviations used are: BC, breast cancer;
cCR, clinical complete response; CMF, cyclophosphamide, methotrexate,
5-fluorouracil; MDR, multidrug resistance; PC, primary chemotherapy;
PgR, progesterone receptor; PR, partial response.
Received 6/ 3/99; revised 3/15/00; accepted 3/28/00.
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REFERENCES |
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ek B., Barnes D. M., Millis R. R. Problems with p53 immunohistochemical staining: the effect of fixation and variation in the methods of evaluation. Br. J. Cancer, 69: 26-31, 1994.[Medline]
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