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Germline BRCA1/2 Mutations and p27^Kip1 Protein Levels Independently Predict Outcome After Breast Cancer

From the Departments of Medicine, Oncology, Pathology, and Surgery, Sir M.B. Davis-Jewish General Hospital, and Departments of Medicine and Human Genetics, McGill University Health Centre Research Institute, McGill University, Montreal, Quebec; and Departments of Medicine and Pathology and Centre for Research in Women’s Health, Sunnybrook and Women’s College Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.

Address reprint requests to William D. Foulkes, MD, Cancer Prevention Research Unit, Room A-803, Sir M.B. Davis-Jewish General Hospital McGill University, 3755 chemin Côte Ste-Catherine, Montreal, Quebec H3T 1E2, Canada; email MDWF{at}musica .mcgill.ca.

	ABSTRACT

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PURPOSE: Decreased levels of the cyclin-dependent kinase inhibitor p27^Kip1 in breast cancer are associated with a poor outcome. The prognostic significance of BRCA1/2 mutations is less clear, and the relationship between BRCA1/2 mutation status, p27^Kip1 protein levels, and outcome has not been studied.

PATIENTS AND METHODS: Pathology blocks from 202 consecutive Ashkenazi Jewish women with primary invasive breast cancer were studied. Tumor DNA was tested for the three common BRCA1/2 founder mutations present in Ashkenazi Jews, and p27^Kip1 expression was evaluated by immunohistochemistry. The median follow-up was 6.4 years.

RESULTS: Thirty-two tumors (16%) were positive for a BRCA1/2 mutation. Low p27^Kip1 expression was seen in 110 tumors (63%) and was significantly associated with BRCA1/2 mutations (odds ratio, 4.0; 95% confidence interval [CI], 1.4 to 11.1; P = .009). BRCA1/2 mutation carriers had a significantly worse 5-year distant disease-free survival (DDFS) compared with women without BRCA1/2 mutations (58% v 82%; P = .003). Similar results were seen for women whose tumors expressed low levels of p27^Kip1, compared with those with high levels (5-year DDFS, 68% v 93%; P < .0001). In a multivariate analysis, both BRCA1/2 mutation and low p27^Kip1 expression were associated with a shorter DDFS (relative risk [RR], 2.1; 95% CI, 1.0 to 4.3; P = .05; and RR, 3.9; 95% CI, 1.4 to 11.1; P = .01, respectively).

CONCLUSION: In this study, we showed that BRCA1/2 mutations were associated with low levels of p27^Kip1 in breast cancer. Both BRCA1/2 and p27^Kip1 status were identified as independent prognostic factors.

	INTRODUCTION

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BREAST CANCER affects one of every nine women in the Western world, where it is a leading cause of cancer mortality in women. Adjuvant therapy is widely used to prevent relapse, but the heterogeneous nature of the disease makes selection of patients who will benefit from it a major clinical challenge. This is particularly true for node-negative patients, a majority of whom have little or nothing to gain from adjuvant therapy.¹ Besides classical prognostic factors such as tumor size, involvement of axillary lymph nodes, histologic type, and grade, a plethora of new biologic and molecular markers have been proposed as predictors of aggressive clinical behavior or response to adjuvant treatment.² None of them has definitively demonstrated its clinical usefulness in the management of women with breast cancer.³

The putative tumor suppressor gene CDKN1B/p27/Kip1 is a member of the CDKI gene family. Its product, p27^Kip1, inactivates G1 cyclin-Cdk complexes in response to growth inhibitory cytokines, such as transforming growth factor beta (TGF-ß) and interleukin-6 (IL-6).^4,5 Specific mutations in CDKN1B/p27/Kip1 have only rarely been reported in human cancers.⁶ Post-translational control via the ubiquitin-proteasome pathway is thought to be the main process involved in the decrease of p27^Kip1 expression observed in a broad spectrum of cancers.⁷ Other post-transcriptional mechanisms regulate p27^Kip1 abundance, such as translational control, phosphorylation, and subcellular compartmentalization.⁸ Numerous studies showed an association between lesser amounts of p27^Kip1 and worse outcome in various human cancer types, including breast cancer.⁹ Using p27^Kip1 immunohistochemical assays and multivariate analyses, several breast cancer studies have demonstrated that a low level of p27^Kip1 is a significant predictor of reduced survival.^10-15

Families with multiple cases of early-onset breast and ovarian cancer often carry germline mutations in tumor suppressor genes BRCA1 or BRCA2.¹⁶ The pathologic features of hereditary breast cancers, particularly the tumors that occur in BRCA1 mutation carriers, typically are associated with poor prognosis, ie, high grade and proliferation rates, aneuploidy, and lack of estrogen receptor (ER).^17,18 BRCA2-related breast cancers are also higher-grade tumors compared with nonhereditary cases, although less significantly so than BRCA1-associated tumors. BRCA2-related tumors are more frequently of lobular subtype and exhibit substantially less tubule formation compared with sporadic cases.¹⁹ The carcinogenic pathway that links a constitutional BRCA1/2 mutation in histologically normal mammary cells to invasive breast adenocarcinoma harboring particular anatomopathologic characteristics is still unknown. Some indirect data support the hypothesis of a distinct molecular pathway in hereditary breast cancer cases compared with their sporadic counterparts. For example, novel somatic TP53 mutations are seen in BRCA1/2-associated breast cancer.²⁰ Despite the clear evidence for an association between poor prognostic factors and BRCA1/2 mutations, conflicting data exist as to whether the prognosis of familial or hereditary breast cancer differs from that of sporadic cases. So far, a dozen studies comparing the outcome of BRCA1-positive and BRCA1-negative women with breast cancer have been carried out with inconsistent results.^21-24 However, studies that have ascertained breast cancer cases irrespective of vital status have shown a worse outcome in univariate analysis.^23,25 Fewer studies have investigated the outcome of BRCA2-associated breast cancers, and no definitive conclusions can be reached.^26,27

To study the relationship between inherited BRCA1/2 mutations and p27^Kip1 expression and to measure the impact these markers have on survival, we studied 202 unselected Ashkenazi Jewish women with primary invasive breast cancer diagnosed at a single institution between 1986 and 1995. We followed up the patients for local and distant recurrences and death. We chose to study the Ashkenazi Jewish population because the majority of hereditary breast cancer can be attributed to two mutations in BRCA1 (185delAG and 5382insC) and one mutation in BRCA2 (6174delT).²⁸ These three mutations are founder mutations and have attained a high frequency in the Ashkenazi Jewish population.²⁹

	PATIENTS AND METHODS

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Case Identification and Clinicopathologic Review
The study design is an ethnically restricted single hospital–based retrospective cohort study. Study subjects were identified in the medical records department of the Sir Mortimer B. Davis Jewish General Hospital (SMBD-JGH) and included all 202 women who reported themselves as being Ashkenazi Jewish by birth. We used the medical chart to review names at birth and reported religious affiliation, and therefore, it is unlikely that non-Ashkenazi Jewish women would have been included in this study. The study was approved by the Research Ethics Committee of the SMBD-JGH. All women were diagnosed with primary invasive breast cancer between January 1, 1986, and November 1, 1995. We selected the age of 65 years as the upper age limit because, from our clinical experience, we suspected that few breast cancers associated with BRCA1/2 germline mutations would be diagnosed in women older than 65 years. Interestingly, it seems that the likelihood of finding a BRCA1/2 mutation in a woman with breast cancer diagnosed after the age of 65 years is approximately the same as that in the general Ashkenazi Jewish population.³⁰ The routine baseline evaluation of the patients included laboratory analyses, chest radiography, mammography, liver ultrasonography, and bone scanning. One hundred eighty-nine patients (94%) underwent breast conservative treatment, and 13 patients (6%) were treated by total or modified radical mastectomy. Breast cancer blocks were identified from each of these eligible women. Clinicopathologic and follow-up information was obtained from chart review. The median age of patients at the time of diagnosis was 53.3 years (range, 26.5 to 64.9 years). Various regimens of adjuvant chemotherapy were administered to 95 patients (49%). In general, patients at the SMBD-JGH were seen on a regular basis every 6 months for 5 years and yearly thereafter. The follow-up evaluation consisted of a clinical evaluation, a physical examination, radiology, and serum chemistry tests. The median follow-up duration was 6.4 years (range, 0.5 to 13.3 years). The histopathology of all the specimens was reviewed by one pathologist (L.R.B). Tumors were pure histologic variants of invasive breast carcinomas, comprising 80% ductal, 7% lobular, 5% tubular, and 8% other types. The specimens were then coded, and DNA was extracted from the paraffin wax–embedded blocks using standard techniques. Clinical, pathologic, and molecular data from the 202 samples were collected in a mutually blinded fashion. The distant disease-free survival (DDFS) rate was calculated as the number of months from the date of primary surgery until the date of diagnosis of first distant failure. Overall survival (OS) was the time interval between the date of primary surgery and the date of death. At 5 years follow-up, 42 patients (21%) developed distant relapse and 37 (18%) died. Thirteen patients (6%) developed an ipsilateral recurrence and five (2%) a contralateral tumor at 5 years. Ipsilateral recurrences and contralateral breast tumors were not considered in the DDFS evaluation. Three women (1.5%) were lost to follow-up within 3 years of diagnosis. None of these women had had a breast cancer–related event. One of the three women lost to follow-up had a BRCA2 mutation. Information on family history was not available.

Mutation and Immunohistochemical Analysis
Mutation analysis for the recurrent Ashkenazi Jewish BRCA1/2 mutations (BRCA1, 185delAG and 5382insC; BRCA2, 6174delT) was carried out as described previously.²⁵ ER status was determined using standard techniques.³¹ Expression of p27^Kip1 was determined immunohistochemically. Paraffin sections of tumor blocks were deparaffinized with xylene, rehydrated, and microwaved for 3 minutes at full pressure in 10 mmol/L citrate buffer (pH 6.0) using a microwavable pressure cooker. Sections were blocked with 5% hydrogen peroxide in Tris buffer followed by normal goat serum and then incubated 1 hour at room temperature with antip27 monoclonal antibody (Transduction Laboratories, Lexington, KY) diluted 1:1400 (0.18 µg/mL). Slides were then reacted with biotin-labeled antimouse immunoglobulin G and incubated with streptavidin horseradish peroxidase (Zymed Laboratories, San Francisco, CA). Diaminobenzidine substrate (Sigma, St Louis, MO) was then added in the presence of hydrogen peroxide. Sections were counterstained with hematoxylin, dehydrated, and mounted. Negative controls, in which a buffer was substituted for the primary antibody, showed no staining. Strong p27^Kip1 immunostaining in lymphocytes provided an internal positive control. The immunostaining pattern detected with the monoclonal antibody from Transduction Laboratories was similar to that observed with a polyclonal rabbit antibody. The p27^Kip1 stain was abolished by preincubation of the antibody with blocking peptide. The degree of p27^Kip1 staining was scored independently by two pathologists (L.K. and Isabella Morava-Protzner). Between 15 and 20 high-power fields of tumor were scored for the percentage of nuclei showing positive p27^Kip1 staining. Protein levels were classified as low (staining in 50% of cells) and high (staining in > 50% of cells) as previously reported.^11-14

Statistical Analysis
All statistical tests were two-sided. Exact Clopper-Pearson 95% confidence intervals (CIs) were calculated for the proportion of BRCA1/2 mutation carriers in the cohort. P-values were calculated for categorical variables using Fisher’s exact test. For continuous variables, the nonparametric Wilcoxon’s two-sample test was used. Five-year survival rates were estimated using the actuarial method (Kaplan-Meier), and survival rates are also presented for the median follow-up time of 6.4 years. Significance was assessed using the log-rank test. A Cox proportional hazards model was developed for the risk of distant relapse at 5 years follow-up. All the results found to be statistically significant at 5 years were confirmed at the median follow-up time (6.4 years). We noted no significant differences in survival trends or association with p27^Kip1 expression between BRCA1 and BRCA2 mutation carriers, and because the BRCA2-positive subgroup was small, we grouped BRCA1- and BRCA2-related breast cancers together to increase the power of the study. In fact, no difference in outcome has been demonstrated between BRCA1 and BRCA2 mutation carriers.²¹ Patients with missing information regarding p27^Kip1 expression (n = 28; insufficient material to make satisfactory sections or absence of internal positive control staining) were only excluded from the multivariate analysis.

	RESULTS

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Paraffin blocks from 202 breast cancer cases diagnosed among Ashkenazi Jewish women younger than 65 years were analyzed for the presence of two BRCA1 mutations and one BRCA2 mutation. Thirty-two BRCA1/2 mutations were identified (16%; 95% CI, 11% to 22%). Fifteen mutations were 185delAG (BRCA1), nine were 5382insC (BRCA1), and eight were 6174delT (BRCA2). Eighteen of 81 (22%; 95% CI, 14% to 33%) women diagnosed younger than 50 years and 14 of 121 (12%; 95% CI, 7% to 19%) diagnosed between the ages of 50 and 65 years carried a BRCA1 or a BRCA2 mutation. The histologic types of BRCA1/2-related tumors were ductal invasive (n = 28; 90%), medullary (n = 1; 3%), and others (n = 2; 7%). Clinicopathologic characteristics of the studied population and association with BRCA1/2 status are summarized in Table 1. BRCA1/2 mutation carrier status was significantly associated with younger age (P = .05), high nuclear grade (P < .0001), and ER negativity (P < .001), but not with tumor size or axillary nodal status. One hundred seventy-four tumor blocks (86%) were available for p27^Kip1 immunohistochemical studies. Low p27^Kip1 expression (p27^Kip1 staining in less than 50% of tumor nuclei) was seen in 110 (63%) of these breast cancers. The median age of diagnosis did not differ between women with low and high levels of p27^Kip1 expression (P = .19). Among the 27 BRCA1/2 mutation carriers who were studied for p27^Kip1 expression, the frequency of low level of p27^Kip1 expression was 85% (23 of 27), compared with 59% (87 of 147) in noncarriers of BRCA1/2 mutations (odds ratio, 4.0; 95% CI, 1.4 to 11.1; P = .009). When BRCA1- and BRCA2-related breast cancers were analyzed separately, a low p27^Kip1 expression level was present in all of the seven (100%) breast cancers in BRCA2 mutation carriers and in 16 (80%) of 20 breast cancers in BRCA1 mutation carriers. Low p27^Kip1 expression level was also associated with larger tumor size (P = .002), high nuclear grade (P < .0001), and ER negativity (P < .0001), but not with nodal status (P = .24).

View larger version (15K): [in this window] [in a new window]   Fig 1. Kaplan-Meier DDFS curves are shown for BRCA1/2 carriers and BRCA1/2 noncarriers. The curves have been truncated at the median follow-up. At 5 years, there were 12 patients at risk with BRCA1/2 mutations and 107 patients at risk without BRCA1/2 mutations.

View larger version (14K): [in this window] [in a new window]   Fig 2. Kaplan-Meier DDFS curves are shown for tumors with low p27Kip1 and high p27Kip1 expression. At 5 years, there were 53 patients at risk whose tumors expressed low p27Kip1 levels and 48 patients at risk whose tumors had high p27Kip1 levels.

Finally, we evaluated the effect of the BRCA1/2 status combined with the level of p27^Kip1 expression. Among the 60 BRCA1/2-negative women with high p27^Kip1 expression, there were only three relapses, compared with 11 among 23 BRCA1/2-positive women with low p27^Kip1 expression (P < .0001; Fig 3). Of note, the four women who were BRCA1/2-positive and whose breast cancers expressed high levels of p27^Kip1 were all alive at the median follow- up (6.4 years).

View larger version (18K): [in this window] [in a new window]   Fig 3. Kaplan-Meier DDFS curves are shown for combination of BRCA1/2 germline mutation status and p27Kip1 expression. Significant differences (log-rank test) were noted between each survival curve: P value = .001 between the 2 upper curves and P = .006 between the 2 lower curves.

	DISCUSSION

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Numerous factors are associated with an increased risk of distant relapse, but until recently, host factors have not been studied in detail. Our results suggest that, in Ashkenazi Jewish women with primary invasive breast cancer, the presence of a BRCA1/2 germline mutation is an adverse prognostic factor. At 5 years follow-up, 12 (38%) of 32 BRCA1/2 mutation carriers developed metastatic disease, compared with 30 (18%) of 170 BRCA1/2 noncarriers. This difference was highly significant (P = .003). In Cox multivariate analyses, germline BRCA1/2 mutation status had an independent prognostic value for DDFS in the whole cohort and in the node-positive patients. A borderline trend in the node-negative subgroup was noted. Thus, in our study population, we have demonstrated a survival disadvantage for women with germline BRCA1/2 mutations. This study extends our previous observation from a smaller series of patients (n = 112) who are included in this study.²⁵ Several previous survival studies in hereditary breast cancer have indicated that there is no clear survival disadvantage associated with a BRCA1/2 mutation, although a trend was discernible in some articles.^21-24 However, several sources of ascertainment and selection bias may exist in clinic or pedigree-based studies, all of which favorably influence prognosis.^21,22 Using historical cases and archival specimens from an ethnic group with founder mutations and testing all individuals in the cohort irrespective of vital status enabled us to eliminate most of these biases. Robson et al²³ recently reported the results of a similarly designed study with 28 BRCA1/2 mutation carriers among 305 patients with breast cancer of Ashkenazi Jewish descent who underwent conservative treatment. In univariate analysis, the 5- and 10-year DDFS and breast cancer–specific survival were significantly worse among the BRCA1/2 mutation carriers compared with patients with BRCA1/2-negative breast cancers. In multivariate analysis, only tumor stage and nodal status retained prognostic significance, but positive BRCA1/2 mutation status was associated with a statistically nonsignificant trend toward a worse outcome (P = .14). No somatic genetic abnormalities or differential expressions of proteins were described in their study. One prospective study of early-onset breast cancers had shown previously a significantly worse survival for BRCA1 mutation carriers.³⁴ In an extension of this work, Stoppa-Lyonnet et al showed a worse 5-year OS (P = .002) in a series of 40 BRCA1 mutation carriers compared with 143 familial breast cancer cases without germline BRCA1 mutations (this issue, pp 4053-4059).³⁵ BRCA1 status was an independent prognostic factor for both DDFS and OS. In addition, Loman et al reported a worse breast cancer–specific survival (P = .003) among 54 BRCA2 mutation carriers compared with 214 age- and date of diagnosis–matched controls, but this difference did not retain significance in a multivariate analysis when clinical stage was included.³⁶

There is extensive evidence that fine-tuning of the cell cycle is important, and a fortiori, for its deregulation in the carcinogenic process. Deregulation of CDK and CDKI, which normally regulate the progression through the cell cycle, are frequently seen in human cancers. Normally, p27^Kip1 is strongly expressed in nonproliferating cells and plays important roles in the regulation of both quiescence and G1 phase of the cell cycle. p27^Kip1, as a cyclin-dependent kinase inhibitor, is a negative regulator of this delicate balance. Only one study has reported p27^Kip1 expression in the context of hereditary breast cancer.³⁷ Among 58 cases of breast cancer diagnosed in Ashkenazi Jewish women younger than 42 years, no difference in the level of p27^Kip1 expression was detected between 17 BRCA1/2 mutation carriers and the remaining sporadic cases. Of note, in that study,³⁷ the percentage of tumors with a positive immunostaining for p27^Kip1 was higher than that in any other published report, and the p27^Kip1 scoring system was not described. The frequency of low p27^Kip1 expression we observed in this study is in good agreement with results previously reported in unselected breast cancer.^11,14,33

Links between CDK or CDKI and the BRCA1 gene product have been described previously. For example, BRCA1 can transcriptionally induce p21 expression, one of the putative mechanisms of action for growth inhibition of BRCA1.³⁸ There is currently no evidence that BRCA1 or BRCA2 actually directly affect p27^Kip1 regulation. Instead, germline mutations in BRCA1 and BRCA2 could simply set the scene for a lower expression of p27^Kip1 or could favor the selection of clones with decreased levels of p27^Kip1. Interestingly, low p27^Kip1 expression was detected in both in situ and invasive components of breast carcinoma, which suggests that deregulation of p27^Kip1 may be an early event in the carcinogenic process.^11,39 As the tumor suppressor genes BRCA1 and BRCA2 have also been involved in the maintenance of genome integrity, they have also been described as caretakers.⁴⁰ Studies have shown that disruption of BRCA1/2 functions causes genetic instability.^41,42 In this context, the loss of BRCA1/2 function might interfere with the normal regulation of p27^Kip1. Some potential regulators have been identified, such as the cyclin E-Cdk2 complex itself, ras, and c-myc.^4,43 p27^Kip1 haploinsufficiency for tumor suppression has been demonstrated in a murine model, as carcinogen-induced tumors in p27^± mice retain a functional allele.⁴⁴ If this phenomenon is present in human mammary carcinogenesis, one could hypothesize that p27^Kip1 haploinsufficient phenotypes are enhanced by BRCA1/2 mutations. The association between BRCA1/2 mutation status and p27^Kip1 expression described in this work could open a new avenue of investigation for these multifunctional proteins.

Although our study is robust in its design, it has some weaknesses. Despite a long follow-up, the population studied is relatively small. In addition, the study contained a limited number of node-positive patients (38%) and a high proportion of small tumors (57% were smaller than 2 cm). A correlation between tumor size and involvement of axillary lymph nodes is well described.⁴⁵ Therefore, it is perhaps not surprising that lymph node status was not found to be an independent prognostic factor in this series. In fact, only 19 patients (9%) presented with metastasis to four or more axillary lymph nodes. Interestingly, survival, irrespective of the tumor size, is only dramatically different when patients with more than or equal to four nodes are compared with N0 or to patients with one to three nodes, particularly when the follow-up is limited to 5 years.⁴⁵ Thus, the relatively small proportion of lymph node–positive patients and the high proportion of tumors with a small size may have influenced the results. Because samples were rendered anonymous, we were not able to correlate our findings with family history. Nevertheless, this study design has allowed an unbiased ascertainment, which is a crucial issue in evaluating most of the previously reported studies of breast cancer survival in the context of BRCA1 or BRCA2 germline mutation.^21,22,24

Using a historical cohort approach, we have shown here that Ashkenazi Jewish women who carry a BRCA1 or a BRCA2 mutation are likely to develop a breast cancer that has low levels of p27^Kip1 protein. The presence of a BRCA1 or BRCA2 mutation and the low level of p27^Kip1 expression contribute independently to a worse outcome. As of yet, there is no known biologic connection between these proteins, and the relationship is associative, rather than causal. Therefore, experiments are needed to elucidate whether a mechanistic link exists between p27^Kip1 levels and a BRCA1/2 mutation. From the clinical perspective, unlike other prognostic indicators, knowledge of BRCA1/2 status by genetic testing is available before diagnosis; hence, our findings will be of great interest to women and their physicians who are considering management options.

	ACKNOWLEDGMENTS

 
Supported by Quebec Family Cancer Network grant from the Fonds de la Recherche en Santé du Québec, Department of Defense grant no. DAMD17–98-1–8112, and the National Cancer Institute of Canada. P.O.C. is supported by grants from la Ligue Genevoise contre le Cancer and Cancer & Solidarité Fondation, Geneva, Switzerland. W.D.F. is a Chercheur Clinicien Boursier 2 of the Fonds de la Recherche en Santé du Québec.

We particularly thank Isabella Morava-Protzner for reviewing the p27^Kip1 immunostaining and Dominique Stoppa-Lyonnet and Niklas Loman for sharing unpublished data with us. We also thank Florence Rozen, Ann-Josée Paradis, Stephen E. Karp, Michael Pollak, Patricia Tonin, and John Surman for help at various stages of this project.

	NOTES

 
Presented at the American Society of Human Genetics meeting, October 19-23, 1999.

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Submitted February 23, 2000; accepted July 14, 2000.

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