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Genomic Loss of 18p Predicts an Adverse Clinical Outcome in Patients with High-Risk Breast Cancer¹

Department of Hematology and Medical Oncology, Hospital Clinico, University of Valencia, Valencia, Spain 46010

	ABSTRACT

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The impact of the genomic imbalances on the clinical outcomeof 34 patients with lymph-node positive high-risk breast cancer (HRBC) was investigated using comparative genomic hybridization. All of the patients were uniformly treated with high-dose chemotherapy and autologous stem cell transplantation. The average number of chromosomal imbalances per tumor was 11 (range, 2–24), including DNA overrepresentation on chromosomes 1q (59%), 17q (38%), 8q and 16p (35% each), 20q (32%), and 19p (26%), and genomic losses involving 9p and 18q (41%), 8p, 11q, and 18p (38%), 17p (32%), 4p and Xq (29%), and 16q (26%). The most significant association among genomic changes and clinical-pathological features was the correlation of the loss of 8p with progesterone receptor positivity (P < 0.005). With a median follow-up time of 74 months, 15 patients (44%) have relapsed. In the univariate analysis, patients with gain/amplification of 17q including the HER-2/neu gene locus had a longer disease-free survival (P = 0.02), whereas those with genomic loss of 18p had a higher probability of relapse (P = 0.003). In multivariate analysis, the loss of 18p was the only parameter correlated with shorter disease-free survival (relative risk, 4.8; 95% confidence interval, 1.57–14.8; P = 0.006). In summary, our data indicate that the tumoral genomic profile may represent a valuable marker for predicting the clinical outcome in HRBC. Furthermore, the genomic loss of 18p may identify a poor prognostic subgroup of patients with HRBC.

	INTRODUCTION

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The presence of axillary lymph nodes affected at diagnosis is the most significant factor in overall survival of breast cancer patients (1) . Adjuvant chemotherapy has been demonstrated to improve outcome of these patients, but it is still controversial whether the use of HDC³ followed by ASCT may be beneficial (2, 3, 4, 5) . Little is known about the impact of the tumor genetic changes on the outcome of patients with lymph node-positive HRBC. Most studies have evaluated single genetic markers that in some cases have been associated with increased risk of relapse (6, 7, 8, 9) . Despite these efforts, based on current knowledge it is not possible to predict the outcome of patients with HRBC after intensive therapy.

Using CGH, tumors can be screened for DNA copy number variation genome-wide (10) . This technique has revealed typical aberrant genomic profiles that include amplification and deletion sites unknown previously in most cancer categories (11 , 12) . In breast carcinomas, distinct patterns of genomic imbalances have been described in the different clinical-pathological subgroups (13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27) . However, the correlation of the CGH data with patient survival has been scarce. Isola et al. (14) reported that genetic aberrations detected by CGH predict outcome in lymph node-negative breast cancer. In a recent report, genomic profiles were valuable prognostic parameters in patients with HRBC (21) . The identification of recurrent genomic changes associated with the outcome of patients with HRBC would reveal novel clinically useful markers.

We report on the CGH analysis of a group of patients with lymph node-positive HRBC treated with a uniform protocol. Our aims were to define the pattern of genomic imbalances in this cohort, to correlate CGH findings with clinical-pathological features, and to identify possible genetic aberrations that might influence in patient outcome.

	MATERIALS AND METHODS

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Tumor Samples.
Breast tumor samples obtained at diagnosis from 34 patients were studied. They were consecutively diagnosed at HRBC stages II or III. Those with >10 lymph nodes affected at diagnosis (n = 24) received six courses of FAC/FEC (5-fluorouracyl 600 mg/m²/day and doxorubicin/epirubicin 50/75 mg/m²/day, respectively, and cyclophosphamide 600 mg/m²/day), whereas patients with 4–10 lymph nodes affected (n = 10) received induction chemotherapy (four courses of FEC 75), followed by breast resection and two additional courses of FEC 75. Subsequently, all of them received pretransplant conditioning chemotherapy regimen (STAMP-V or CEM) followed by ASCT. Median follow-up time after diagnosis was 74 months (range, 18–96). The clinical and pathological characteristics of the patients are shown in Table 1 .

FISH, Western Blot, and IHC Analyses.
These procedures were performed to evaluate gene amplification and/or overexpression of HER-2/neu gene in the tumor samples. FISH methods have been reported previously (29) . The PathVysion HER-2 DNA Probe kit (Vysis) was used on paraffin-fixed tissues following manufacturer’s instructions. IHC studies were performed on paraffin-embedded tissue blocks using the HercepTest (DAKO, Oslo, Norway). For immunoblotting analysis, protein extraction and blotting were performed as reported (30) . The anti-HER-2/neu monoclonal antibody clone CB11 (Biogenex, San Carlos, CA) was used.

Statistical Analyses.
Significant correlation between the genomic imbalances with themselves and with clinical-pathological parameters were analyzed through 2 x 2 contingency tables using Pearson’s ² test unless there was an inadequate number of observations, in which case a Fisher’s exact test was used. All of the resulting Ps were two-tailed. DFS time was calculated according to the Kaplan-Meier survival curves and Ps with the log-rank test. Multivariate analysis using the Cox regression model was performed only on the variables with a P <0.05 in the univariate analyses. Both backward and forward analyses removed the same nonsignificant variables. Finally, the factors were removed one at time, based on the Wald test that was used to determine the level of significance; only statistically significant factors remained (P < 0.05). All of the clinical variables included in statistical analysis were dichotomized, i.e., estrogen and progesterone receptors were considered positive or negative when protein level were higher or lower than 10 fmol/mg, or age that was considered as 50 or >50 years. The statistical analyses were carried out using SPSS 10.0 software for Windows 98.

	RESULTS

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All 34 of the tumors showed genomic changes (Fig. 1) . The average number of chromosomal imbalances per tumor was 11 (range, 2–24), including 5 gains (0–11) and 6 losses (0–15). A variable spectrum of genomic aberrations occurring across the entire genome was observed, including DNA overrepresentation on chromosomes 1q (59%), 17q (38%), 8q (35%), 16p (35%), 20q (32%), 19p (26%), and 11q (24%), and chromosomal losses involving 9p (41%), 18q (41%), 18p (38%), 8p (38%), 11q (38%), 17p (32%), Xq (29%), 4p (29%), 16q (26%), 4q (24%), and 22q (24%). In addition, three amplification events were observed in 6q21-q22, 8q24, and 20q13.

View larger version (35K): [in this window] [in a new window]   Fig. 1. Summary of chromosomal imbalances in 34 patients with HRBC. Lines on the left of the ideograms indicate loss of chromosomal material, lines on the right indicate gain of chromosomal material, and thick bars represent high-level amplified regions. A total of 383 genomic imbalances were found, corresponding to 150 gains, 230 losses, and 3 gene amplification events. Genomic imbalances found in nonrelapsed patients are shown in black, whereas those observed in relapsed patients are shown in gray.

View larger version (10K): [in this window] [in a new window]   Fig. 2. DFS of 34 HRBC patients. The median follow-up time from diagnosis was 74 months.

View larger version (19K): [in this window] [in a new window]   Fig. 3. DFS of HRBC patients according to the pattern of genomic imbalances in the tumors. A, comparison of tumors with 4 genomic losses versus tumors with <4 losses. B, tumors with gain in 17q chromosomal region versus tumors without this genomic gain. C, tumors with 18p genomic loss versus tumors without this genomic loss. D, tumors with genomic gain in 17q and without 18p loss versus the remaining tumors.

	DISCUSSION

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Patients with lymph node-positive breast cancer have markedly different clinical courses and treatment responses from those without. In this cohort, the use of HDC and ASCT is currently being assessed (2, 3, 4, 5, 6) . Within this subgroup, whether genetic changes may have an impact on patient survival is unknown. We report here that the pattern of genomic imbalances may be correlated with different clinical outcome in patients with lymph node-positive HRBC treated with HDC and ASCT. Our results also show that the median number of genomic aberrations per tumor was higher than in other CGH studies of breast tumors (see Table 2 for references). This may reflect the advanced clinical stage and the aggressive histological grade (II and III) of most patients studied herein, with subgroups reported to show more genomic changes than other categories (18 , 21) .

The pattern of genomic aberrations found in our study did not differ significantly from other CGH data reported previously (13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27) . The most common regions of genomic gain were 1q, 17q, 8q, 20q, and 16p. These aberrations occurred in the majority of reports independently from the clinical-pathological features, possibly indicating that these gains occurred at all stages of tumor development. However, the pattern of genomic losses was more variable than in series reported previously. Some of the common deletions observed in our study (9p, 18q, and 18p) were rarely seen in other reports, reflecting that they may develop primarily in patients with advanced or aggressive disease. A summary of the genomic imbalances reported in previous CGH analyses of breast cancer is shown in Table 3 . Despite the few patients in the series, we found some associations among genetic changes and clinical-pathological characteristics. The loss of 8p was correlated with positive progesterone receptors. This association showed a small P (<0.005) in the Fisher’s exact test, therefore supporting that it is not coincidental. Other correlation included the gain of 8q that was frequent in tumors in stage III. This alteration has been associated with tumor progression (14 , 20) and is present not only in the majority of breast tumors but also in other malignancies (11) . On the contrary, gain of 19p was characteristic of tumors in stage II. However, in the associations among the gains of 8q and 19p with tumors in stage III or II, respectively, we cannot exclude a coincidence because of random sampling because of the few patients. The association between 8p loss and 8q gain as a consequence of an isochromosome 8q formation was already known (14 , 21) .

In a univariate analysis, gain in 17q was associated with favorable patient outcome. The long arm of chromosome 17 at 17q12 is the locus of HER-2/neu gene. This oncogene is activated in 20–30% of breast tumors through amplification and overexpression. HER-2/neu positivity is associated with adverse prognostic factors and shorter survival of breast cancer patients (26 , 31) . Nieto et al. (6) reported that HER-2/neu overexpression was an independent negative predictor of relapse in HRBC treated with HDC and ASCT. In contrast, in other reports HER-2/neu overexpression seemed to increase tumor sensitivity to intensive chemotherapy regimens containing doxorubicin or paclitaxel (7, 8, 9 , 32) . In agreement with these studies, we report here that the gain of 17q including the HER-2/neu gene locus is associated with a superior DFS in HRBC treated with intensive chemotherapy including doxorubicin. However, in our series, when HER-2/neu status was evaluated by FISH, Western blotting, or IHC, it did not influence patient outcome. Therefore, according to our data it is the genomic gain of 17q and not the HER-2/neu alteration that the predictive parameter correlated with prolonged survival in HRBC. In 17q, two different regions of amplification have been reported. These loci harbor a number of additional genes that are also amplified in breast tumors and may be critical in the pathogenesis of the disease: RAD51C, S6K, PAT1, and TBX2 in 17q23, and GRB7, MLN64 and TopoII in the HER-2/neu amplicon in 17q12 (33, 34, 35, 36, 37) . TopoII gene amplification is associated frequently with frequently amplification. It has been postulated that the increased gene dosage of TopoII may relate to an increased sensitivity to TopoII inhibitors such as doxorubicin in patients with breast cancer (35, 36, 37) . Whether the amplification of other genes in the 17q12 amplicon, in addition to frequently and TopoII, may be of clinical significance in HRBC is at present unknown.

Despite the results of the univariate analysis, the only parameter correlated with shorter DFS in the multivariate analysis was the loss of 18p, whereas the association of the gain of 17q with superior DFS had a borderline significance. For the multivariate analysis, 10 events per independent variable (in our case, tumor relapses) are required to produce a statistical model of reasonable accuracy (38) . As it was not possible in our series, results of the multivariate analysis should be interpreted carefully. Nevertheless, in our series the status of 18p was the only significant predictive factor for clinical outcome, and it was independent from other genomic changes. Thus, loss of 18p may be an important indicator of adverse outcome in HRBC. The status of 17q was a marginally significant indicator of response to the treatment and seems to show trends to favorable clinical outcome; this is probably related to the few patients included in the series and to the P of 0.02 in the univariate analysis. On the contrary, in the multivariate analysis the 18p loss retained its statistically significance because of the lower P (0.003) observed for this specific correlation in the univariate analysis. Nevertheless, because of the limited number of patients, these results should be confirmed in larger trials.

The deletion of 18p has not been reported as a frequent change in previous CGH studies of breast cancer patients (13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27) , but it was a common event in breast tumor cell lines (39) . Loss of heterozygosity on 18p was detected in patients with breast tumors (40, 41, 42) . In one report, the allelic loss on 18p11.3 occurred early in ductal carcinoma in situ (40) . This genomic loss is also common in other malignancies (12 , 41) . The association of the genomic loss of 18p and shorter DFS has not been reported previously in breast cancer. Our results suggest the presence of one or more tumor suppressor gene(s) on 18p with a role in breast cancer progression.

In summary, using CGH we have identified a subgroup of patients with HRBC with 17q gain or with 18p loss who have a significantly different clinical outcome after HDC and ASCT. The biological importance of these two regions and their definite clinical relevance warrants additional evaluation in a larger series of patients. Our results indicate that HRBC patients with genomic loss of 18p have an adverse clinical outcome and may benefit from more intensive or novel experimental therapies. Future studies using large-scale CGH to microarrays and gene expression profiling will help in the identification of genes at these regions targeted by gene amplification and deletion.

	ACKNOWLEDGMENTS

 
We thank Dra. Maria J. Terol (Department of Hematology, Hospital Clìnìco Universìtarìo, Valencia, Spain) and Prof. Francisco Martinez (Department of Statistics, University of Valencia, Valencia, Spain) for their help with the statistical analysis, and Dr. Samuel Navarro (Department of Pathology, University of Valencia) for IHC analysis. We also thank Dr. Jose Palacios (Centro Nacional de Investìgacìon Oncologìca, Madrid, Spain) for histological evaluation of tumors and Dr. M. J. S. Dyer (Department of Haematology, University of Leicester, UK) for critical reviews of the manuscript.

	FOOTNOTES

 
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.

¹ Supported by grants from Spanish Association Against Cancer (AECC-1999) and Spanish Ministry of Health (FIS 01/0040-01) and Aventis Pharma. M. J. G-B. is supported by a grant from Spanish Ministry of Education (MEC AP99)

² To whom requests for reprints should be addressed, at Department of Hematology and Medical Oncology, Hospital Clínico, University of Valencia, Avda Blasco Ibañez, 17, Valencia, Spain 46010. Phone: 34-96-386-2650; Fax: 34-96-362-2238; E-mail: martinez_jos{at}gva.es

³ The abbreviations used are: HDC, high-dose chemotherapy; ASCT, autologous stem cell transplantation; HRBC, high-risk breast cancer; CGH, comparative genomic hybridization; FISH, fluorescence in situ hybridization; IHC, immunohistochemical; DFS, disease-free survival; RR, relative risk; CI, confidence interval.

Received ; revised ; accepted .

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