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10.1245/ASO.2004.05.018
Annals of Surgical Oncology 11:157-164 (2004)
© 2004 Society of Surgical Oncology
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ORIGINAL ARTICLES

Survival and Recurrence After Breast Cancer in BRCA1/2 Mutation Carriers

Mahmoud El-Tamer, MD, Donna Russo, MS, Andrea Troxel, DSc, Lourdes P. Bernardino, MD, Robert Mazziotta, MD, Alison Estabrook, MD, Beth-Ann Ditkoff, MD, Freya Schnabel, MD and Mahesh Mansukhani, MD

From the Departments of Breast Surgery (ME-T, B-AD, FS, DR), Pathology (MM, LPB, RM), Biostatistics (AT), and Clinical Surgery (AE), Columbia-Presbyterian Comprehensive Breast Center, New York, New York.

Correspondence: Address correspondence and reprint requests to: Mahmoud El-Tamer, MD, FACS, Columbia-Presbyterian Hospital-Breast Center, Atchley Pavilion, 10th Floor, 161 Fort Washington Ave, New York, NY 10032; Fax: 212-305-0727; E-mail: me180{at}columbia.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Genetic mutation is responsible for approximately 10% of breast cancers. The purpose of this study was to compare breast cancer survival and recurrence rates between BRCA1/2 mutation carriers and noncarriers.

Methods: Using the Columbia Presbyterian breast cancer database, we collected the tissue blocks of all patients younger than 65 years of age and of Jewish descent. The patients were contacted and the data updated. DNA was extracted from the tissue blocks and tested for the common mutations. The results of the genetic mutation and updated database were anonymized and merged. The survival and recurrence rates were compared between mutation carriers and noncarriers.

Results: A total of 739 breast cancer cases in 715 patients were identified. We were able to test 487 patients. We identified 30 BRCA1 and 21 BRCA2 mutation carriers, for an incidence of 10.36%. The median follow-up for the patients tested was 50 months. BRCA1 patients more frequently had estrogen- and progesterone-negative tumors and had a higher incidence of positive nodes. BRCA1 patients received chemotherapy more frequently. The incidence of in situ disease was similar for mutation and non–mutation carriers. BRCA1/2 mutation carriers had a higher incidence of bilateral disease. There was no difference in 5- or 10-year overall and breast cancer–specific survival between mutation and non–mutation carriers.

Conclusions: Breast cancer patients with BRCA1/2 mutations have a similar outcome as non–mutation carriers.

Key Words: Breast cancer • Gene mutation • Survival • Recurrence


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The incidence of BRCA1/2 mutations in breast cancer patients varies with the ethnic background and age of the population under study. Approximately 3.3% of breast cancer patients in the United States carry the BRCA1 mutated gene.1 In patients younger than 35 years of age, however, the incidence increases to 6%.2 The incidence of BRCA1/2 mutation carriers among patients of Ashkenazi Jewish decent is even higher; it ranges from 6.7% to 11.7% for unselected patients3,4 and increases to 29.3% in those younger than 42 years of age.5

The outcome of breast cancer patients associated with BRCA1/2 mutation has been conflicting. Some studies showed improved overall survival,6–8 others showed no significant difference,9–11 and some showed a worse outcome when comparing BRCA1/2-associated breast cancer patients with non–mutation carriers.12–15 The outcome studies had different designs and matching controls. The purpose of this article was to compare the outcome of BRCA1/2 mutation carriers with that of non–mutation carriers by using a retrospective anonymized study in an unselected group of women who were diagnosed and treated at a single institution over a recent period of time.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
We queried the breast cancer database at Columbia University for all breast cancer patients younger than 65 years of age and of Jewish descent. The study period ranged from January 1989 to January 1999. The project was approved by the institutional review board at Columbia University. All patients were given study numbers, and two independent teams conducted the project. Team 1 updated the breast cancer database through hospital and private office charts, as well as letters and phone calls to patients or their relatives. Data collected included age at diagnosis, tumor characteristics, adjuvant treatments, local or systemic recurrences, contralateral disease, cancer status, survival, and cause of death.

Team 2 extracted DNA from archived paraffin blocks. All patients’ identifiers were stripped. By using only study numbers as identifiers, DNA was tested for the three founder mutations in BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT).

DNA Testing
DNA extracted from paraffin blocks was tested for specific mutations of the BRCA1 and BRCA2 genes. The 185delAG mutation of BRCA1 and the 6174delT mutation of BRCA2 were detected by polymerase chain reaction amplification with specific primers, and this was followed by heteroduplex analysis. In normal samples, a single (homoduplex) band was detected, and samples containing mutant DNA yielded three bands (one homoduplex band and two heteroduplex bands). For the 5382insC mutation, an allele-specific polymerase chain reaction assay was performed with two outer primers and an inner, mutant allele–specific primer. Wild-type samples yielded a 399–base pair (bp) product, whereas in individuals with a mutation, both a 399-bp and a 143-bp product were retrieved.

After completion of gene testing and follow-up, the follow-up data were also stripped of all patient identifiers. By using study numbers as identifiers, the two data sets were merged.

Statistical Methods
We assessed the association of many factors with BRCA1/2 mutation status by using {chi}2 or Fisher’s exact tests for discrete variables and t-tests for continuous variables. Throughout, we used two-sided tests and a significance level of .05. We compared the local recurrence, overall survival, and disease-specific survival of BRCA1/2 mutation carriers with those of noncarriers by using Kaplan-Meier curves and log-rank tests. Multivariate Cox regression analysis was preformed to assess the predictors of survival in the entire group.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
A total of 715 patients who declared themselves of Jewish descent and were younger than 65 years of age were treated for 739 breast cancers at our center during the study period. The paraffin blocks of the primary tumors were available for 560 patients. The DNA extraction and testing was successfully completed in 487 patients. These patients constitute the study population. We identified 51 mutation carriers and 436 non–mutation carriers, for an incidence of 10.47%. There were 30 BRCA1 mutation carriers with twenty 185delAG mutations and ten 5382insC mutations, for an incidence of 6.15% BRCA1 mutation carriers. A total of 21 BRCA2 (6174delT) carriers were found.

Table 1 compares tumor characteristics among the three groups. There was no difference in mean size at presentation, grade, ploidy, or percentage in S phase. The incidence in medullary histology was similar in the three groups. The incidence of nodal positivity (P = .067) and stage at presentation (P = .0648; Fig. 1) approached significance but were not statistically significant. BRCA1 patients had a significantly younger mean age at presentation (P = .035) and a higher incidence of negative hormone receptors (P = .0001) when compared with non–mutation carriers.


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  		TABLE 1. Tumor characteristics
 


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  		FIG. 1. Stage at presentation of BRCA1/2 mutation carriers and sporadic breast cancers (11 cases of sporadic breast cancers could not be staged). DCIS, ductal carcinoma- in-situ.

 
Table 2 lists the proportion of patients who underwent breast conservation or mastectomy, as well as the frequency of radiotherapy and chemotherapy. The only significant difference was that BRCA1 patients were more frequently treated with radiotherapy than BRCA2 or non–mutation carriers.


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  		TABLE 2. Treatment
 
The median follow-up for the entire study population was 4.2 years. The median follow-up for BRCA1, BRCA2, and non–mutation carriers was 7.6, 4.99, and 4.01 years, respectively (Table 3). With univariate analysis, the incidence of contralateral cancer in all three groups and the incidence of locoregional recurrence among breast-conservation patients were significantly different between mutation and non–mutation carriers. Local recurrence after mastectomy, systemic recurrence, and mortality were similar among the three study groups.


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  		TABLE 3. Outcome
 
When Kaplan-Meier recurrence and survival estimates were compared by using log-rank tests, there were no differences among locoregional recurrence after breast-conservation therapy, overall survival, and disease-specific survival (Figs. 2–4GoGo). The Kaplan-Meier estimates showed no difference in overall or disease-specific survival when analyzed for patients with invasive disease only (data not shown).



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  		FIG. 2. Locoregional recurrence after breast conservation in BRCA1/2 and non–mutation carriers.

 


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  		FIG. 3. Overall survival of BRCA1/2 and non–mutation carriers.

 


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  		FIG. 4. Death from breast cancer over time for BRCA1/2 and non–mutation carriers.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
To date, conflicting data exist as to whether the prognosis of hereditary breast cancer differs from that of sporadic cancer. Multiple studies comparing disease-free or overall survival in BRCA1-associated and non–BRCA1-associated breast cancer have been performed, with inconsistent results.6–12 There are far fewer data about the outcome of BRCA2-associated breast cancers.9,10,16 This study did not find evidence for a worse prognosis for BRCA1 or BRCA2 mutation carriers as compared with noncarriers in a historical cohort of Ashkenazi Jewish women.

The reasons for these conflicting findings are not clear. In the initial studies of patients with BRCA1-associated breast cancer identified through linkage analysis, an improved survival was suggested.6–8 However, these findings were not confirmed in later studies of patients from familial cancer clinics.9,10 In studies of BRCA1 and BRCA2 mutation carriers with early-onset breast cancer, conflicting results have indicated either similar11 or poorer12 survival. There are several possible sources of selection bias in clinic- or pedigree-based studies, all of which favorably influence prognosis. This is because the biases in linkage or clinic-based studies all result in the preferential inclusion of women who are alive and have consented to undergo genetic testing, as compared with women who died early before undergoing genetic analysis. To eliminate this selection bias, one would need to select incident cases of breast cancer in a population, obtain information on BRCA1 and BRCA2 status and other prognostic factors, and follow these women forward in time to determine survival. However, prospective studies take 10 or more years for follow-up. An alternative method is to use historical cases and archival specimens from ethnic groups with founder mutations, where targeted testing for specific BRCA1/2 mutations can be performed from paraffin-embedded specimens. Two previous large retrospective hospital-based cohort studies of Ashkenazi Jewish women, with designs similar to ours, have been reported by Robson et al.13 and Foulkes et al.14,15 All individuals in the cohorts were tested for the three BRCA1 and BRCA2 recurring mutations in Ashkenazi individuals, and their outcomes were compared after 10 years of follow-up. Robson et al. examined the outcomes of 305 women undergoing breast-conservation therapy for invasive cancer at a single institution. Women with BRCA1/2 mutations had adverse outcomes, including an increased risk for distant recurrence, contralateral breast cancer, and breast cancer–related deaths, when compared with women who were not mutation carriers. However, mutation status was not a statistically significant predictor of outcome in a multivariate analysis that included tumor stage and nodal status. The results suggest that Ashkenazi women with BRCA1/2 mutations may have poorer survival because of presentation at more advanced stage. In another anonymized series of Ashkenazi women with breast cancer, Foulkes et al. studied 287 unselected Ashkenazi women whose cancer was diagnosed when they were younger than 65 years. He reported that BRCA1 mutation status was an independent adverse prognostic factor in women with primary node-negative disease. Taken together, these studies suggest that, among unselected Ashkenazi women, the presence of a germline mutation in BRCA1 (perhaps BRCA2) can adversely affect survival. It is possible that mutations in BRCA1 predispose to early metastasis.

In contrast to these earlier studies, in our series of 487 unselected Ashkenazi women with breast cancer under the age of 65 years, we did not find an adverse effect of BRCA1 or BRCA2 status on outcome at 5 years. We elected to study the BRCA1-associated (n = 30) and BRCA2-associated (n = 21) breast cancers separately because some published reports have shown biologic differences between these tumor populations, as well as some differences in clinical presentation.17–23 We confirmed the very strong associations between BRCA1 mutation carrier status and adverse biologic features of breast cancers that have been described,18,24 such as young age of onset, estrogen receptor–negative status, and progesterone receptor–negative status. Although these characteristics are recognized as being indicators of worse prognosis in breast cancer, women who harbored BRCA1 germline mutations did not have an adverse outcome compared with noncarriers in our series. Not surprisingly, BRCA2-associated breast cancer did not exhibit the same adverse biologic features of breast cancer, in agreement with published reports.9,10,16 BRCA2-associated breast cancer seems more heterogeneous and not clearly different from sporadic forms. BRCA1-associated breast cancers may be biologically distinct from tumors associated with BRCA2, and recognition of these differences may have implications for treatment and possibly for chemoprevention.

As expected, we did observe a significant difference between the groups in the occurrence of second breast cancers. BRCA1 and BRCA2 mutation carriers had a higher percentage of bilateral breast cancer (P = .05) than women who did not carry mutations. Specifically, 7 (23.3%) of 30 BRCA1 carriers had second primary tumors, and 4 (19.0%) of 21 BRCA2 mutation carriers had second breast primary tumors, as compared with 54 (12.4%) of 436 cases of bilateral breast cancer in women without mutations. We were not able to determine risks for contralateral breast cancer because in the vast majority of bilateral disease, the second breast cancer was our index case.

Women with BRCA1 and BRCA2 mutations who underwent breast-conservation therapy had a greater risk of locoregional recurrence (3 [23.0%] of 13 and 1 [12.5%] of 8, respectively) at 5 years than women without BRCA1/2 mutations (13 [5.3%] of 207) in univariate analysis (P = .05), but when assessed over time in a Kaplan-Meier curve, that difference did not remain significant. This is likely due to low power because of the small number of events in the 5-year period. Longer follow-up is necessary. Previous studies comparing the risk of ipsilateral breast tumor recurrence in BRCA1/2 mutation carriers have reported conflicting results, possibly reflecting the mean length of follow-up. Pierce et al.25 reported that there was no evidence of increased radiation sensitivity in BRCA1/2 mutation carriers compared with noncarriers and that the rates of ipsilateral recurrence in the breast were comparable between BRCA1/2 carriers and patients with sporadic cancers at 5 years. In fact, the significant reduction of breast cancer in the irradiated breast compared with the contralateral untreated breast suggests a protective effect of radiotherapy in the development of new breast cancer in the treated breast. However, over a longer time period, this risk reduction may decrease. In a study by Haffty et al.,26 127 women with breast cancer under age 42 who were treated with breast conservation and radiotherapy were followed up for 12 years. The authors reported that the BRCA1/2 group had significantly higher rates of ipsilateral (49% vs. 21%; P = .007) and contralateral (42% vs. 9%; P = .001) events than the group with sporadic cancers. The rate of ipsilateral breast tumor recurrence in the genetic and sporadic group followed a similar course for 5 years and then began to diverge, presumably because of continued development of second tumors in the genetic cohort. Most events were classified as second primary tumors. One explanation for why our study did not see any difference between the hereditary and sporadic groups could be our relatively short follow-up. Therefore, large, long-term prospective studies will be necessary to resolve whether BRCA1 and BRCA2 mutation status independently predicts higher rates of ipsilateral breast cancer for long-term survivors.

The very good survival rate in our cohort of BRCA1- and BRCA2-negative women is in agreement with current trends, and, not surprisingly, most cancers in our hospital-based cohort were detected at an early stage (stages I and II).27 Our results suggest that in Ashkenazi Jewish women, the presence of a BRCA1 or BRCA2 mutation did not adversely affect their overall survival or risks for distant recurrence or breast cancer–related death when compared with women who did not carry mutations. Overall survival among women with BRCA1 and BRCA2 mutations was 90.7% and 94.7%, respectively, at 5 years, compared with 91.2% at 5 years for women without mutations. Breast cancer–specific survival at 5 years in BRCA1 and BRCA2 mutation carriers was 90.7% and 94.7%, respectively, compared with 91.6% at 5 years for women without mutations. Multivariate analysis showed that only tumor size and stage were independent prognostic factors. We also observed that women with BRCA1 and BRCA2 germline mutations, like their noncarrier counterparts, do develop high-risk lesions that can be detected by screening. In our mutation carriers, 4 (14.3%) of 28 BRCA1-associated cancers presented at stage 0 (ductal carcinoma-in-situ; DCIS), whereas 6 (28.6%) of 21 BRCA2-associated cancers presented at this preinvasive stage. A recent study by Hoogerbrugge et al.28 also reports that women with BRCA1/2 mutations are prone to develop high-risk breast lesions. These authors studied prophylactically removed breasts from BRCA1/2 germline mutation carriers and found that 57% had atypical ductal hyperplasia, lobular carcinoma in situ (LCIS), and DCIS. These observations are important for treatment of BRCA1/2 mutation carriers, because it suggests that hereditary breast carcinoma has a preinvasive phase that may be detectable with aggressive surveillance.

An interesting finding was noted in comparing stage and nodal status in mutation carriers and noncarriers. Although BRCA1/2 mutation carriers had similar risks for distant recurrence, contralateral breast cancer, and breast cancer–related deaths when compared with women who were not mutation carriers, we observed a trend toward an increased stage at presentation in BRCA1 mutation carriers as compared with other women. In this regard, BRCA1 mutation carriers were less likely to present with stage I disease than women without BRCA1/2 mutations (28.6% vs. 45.65%) and were more likely to present with stage II disease (57.1% vs. 30.6%; P = .06). Additionally, BRCA1 germline mutation carriers were more likely to have axillary nodal involvement than non-BRCA1/2 carriers (50% vs. 30.9%; P = .067), as previously reported by Robson et al.13 Although these characteristics are recognized as being indicators of worse prognosis in breast cancer, women who harbored BRCA1 germline mutations did not have a poorer outcome compared with BRCA2 mutation carriers or sporadic cases. One possible explanation may be related to our striking finding that the administration of adjuvant systemic treatment was significantly increased in BRCA1 mutation carriers as compared with non-BRCA1/2 mutation carriers (63% vs. 32%; P = .0010). As would be expected, patients were more likely to receive chemotherapy if they presented with a stage II, estrogen receptor–negative cancer, as did >50% of BRCA1 mutation carriers. We do not know whether the use of chemotherapy in BRCA1 mutation carriers lessened the negative effect of mutation status on survival or whether BRCA1-associated cancers are chemosensitive. Limited data exist with respect to BRCA1 mutation status and treatment with chemotherapy. There is some in vitro evidence that BRCA1 mutations confer sensitivity to treatment with doxorubicin and29,30 cisplatin31,32 with subsequent increased levels of apoptosis31–33 and radiation,29 although other studies have shown that cells with BRCA1 mutations are less sensitive to paclitaxel.29,34 There is preliminary evidence for a better clinical response rate to neoadjuvant chemotherapy in BRCA1/2 mutation carriers than noncarriers.35 In addition, a recent 10-year follow-up study by Goffin et al.36 reports a worse prognosis in BRCA1 mutation carriers as compared with noncarriers, but only among women who did not receive adjuvant chemotherapy. As yet, there are no survival studies that have been stratified according to the administration of chemotherapy, and our study cohort was limited by too small of a sample size to investigate this. We could speculate that the poorer survival seen in other retrospective studies compared with our series is partially due to the less frequent use of adjuvant chemotherapy in these earlier studies. Further studies need to address the effect of chemotherapy on prognosis in BRCA1/2 mutation carriers.

There are several potential limitations of a retrospective archival study such as this. Although our study cohort initially comprised 715 breast cancer patients who were selected for inclusion on the basis of their self-declared religious preference, our final study cohort consisted of 487 women. This exclusion was due to difficulty in retrieval of archived samples in 155 patients and failure to obtain DNA results in 75 tumor blocks. Analysis of the patient and tumor characteristics in these groups compared with the final cohort did not reveal any significant differences, suggesting that there was no selection bias introduced into our study design. The study population was followed forward for a mean follow-up of 50 months. Longer follow-up is necessary to address possible differences in outcome that may be obscured by a limited number of events. The relatively small sample size limits the power of this study, and small but significant differences may not have been detected. The small number of cancer recurrences and deaths in the cohort, especially in mutation carriers, can also reduce power. In addition, the inclusion of a substantial number of patients in whom the index case was a second breast cancer may have introduced a survival bias in carriers of BRCA1/2 mutations.

In summary, this study demonstrates comparable rates of recurrence and survival at 5 years between Ashkenazi Jewish carriers of a BRCA1/2 mutation and women treated for sporadic disease. BRCA1 and BRCA2 mutation status was not found to have a statistically significant effect on relapse-free or overall survival, although women with such mutations were more likely to have bilateral disease. We found that a significant proportion of BRCA1/2-associated breast cancers do present as DCIS: 14.3% of BRCA1 mutation carriers and 28.6% of BRCA2 mutation carriers. There was a trend for BRCA1-associated cancers, but not BRCA2-associated cancers, to present with a more advanced stage of disease. Whether the use of chemotherapy in BRCA1 mutation carriers ameliorated the negative effect of mutation status on survival is unknown. Larger, prospective studies will be necessary to expand on this possibility.


   ACKNOWLEDGMENTS
 
The acknowledgments are available online in the fulltext version at www.annalssurgicaloncology.org. They are not available in the PDF version.


   FOOTNOTES
 
Tissue blocks from breast cancer patients younger than 65 years of age and of Jewish descent showed an incidence of 10.36% of BRCA1/2 mutation carriers. The overall and disease-specific survivals of mutation carriers were not different from those of patients with sporadic breast cancer.

Received for publication May 16, 2003. Accepted for publication October 3, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Newman B, Mu H, Butler ML, et al. Frequency of breast cancer attributable to BRCA1 in a population-based series of American women. JAMA 1998; 279: 915–21.[Abstract/Free Full Text]
  2. Malone KE, Daling JR, Neal C, et al. Frequency of BRCA1/BRCA2 mutations in a population based sample of young breast carcinoma cases. Cancer 2000; 88: 1393–402.[CrossRef][Medline]
  3. Fodor F, Weston A, Bleiweiss I, et al. Frequency and carrier risk associated with common BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer patients. Am J Hum Genet 1998; 63: 45–51.[CrossRef][Medline]
  4. Warner E, Foulkes W, Goodwin P, et al. Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer. J Natl Cancer Inst 1999; 91: 1241–7.[Abstract/Free Full Text]
  5. Robson M, Rajan P, Rosen PP, et al. BRCA-associated breast cancer: absence of a characteristic immunophenotype. Cancer Res 1998; 58: 1839–42.[Abstract/Free Full Text]
  6. Marcus JN, Watson P, Page DL, et al. Hereditary breast cancer: pathobiology, prognosis, and BRCA1 and BRCA2 gene linkage. Cancer 1996; 77: 697–709.[CrossRef][Medline]
  7. Porter DE, Dixon M, Smyth E, Steel CM. Breast cancer survival in BRCA1 carriers. Lancet 1993; 341: 184–5.
  8. Porter DE, Cohen BB, Wallace MR, et al. Breast cancer incidence, penetrance and survival in probable carriers of BRCA1 germline mutation in families linked to BRCA1 on chromosome 17q12–21. Br J Surg 1994; 81: 1512–5.[Medline]
  9. Verhoog LC, Brekelmans CT, Seynaeve C, et al. Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1. Lancet 1998; 351: 316–21.[CrossRef][Medline]
  10. Johannsson OT, Ranstam J, Borg A, Olsson H. Survival of BRCA1 breast and ovarian cancer patients: a population-based study from southern Sweden. J Clin Oncol 1998; 16: 397–404.[Abstract]
  11. Robson M, Gilewski T, Haas B, et al. BRCA-associated breast cancer in young women. J Clin Oncol 1998; 16: 1642–9.[Abstract]
  12. Ansquer Y, Gautier C, Fourquet A, Asselain B, Stoppa-Lyonnet D. Survival in early-onset BRCA1 breast-cancer patients. Institut Curie Breast Cancer Group. Lancet 1998; 352: 541.[CrossRef]
  13. Robson M, Levin D, Federici M, et al. Breast conservation therapy for invasive breast cancer in Ashkenazi women with BRCA founder mutations. J Natl Cancer Inst 1999; 91: 2112–7.[Abstract/Free Full Text]
  14. Foulkes WD, Wong N, Brunet JS, et al. Germ-line BRCA1 mutation is an adverse prognostic factor in Ashkenazi Jewish women with breast cancer. Clin Cancer Res 1997; 3: 2465–9.[Abstract/Free Full Text]
  15. Foulkes WD, Chappuis PO, Wong N, et al. Primary node negative breast cancer in BRCA1 mutation carriers has a poor outcome. Ann Oncol 2000; 11: 307–13.[Abstract/Free Full Text]
  16. Karp SE, Tonin PN, Begin LR, et al. Influence of BRCA1 mutations on nuclear grade and receptor status of breast carcinoma in Ashkenazi Jewish women. Cancer 1997; 80: 435–41.[CrossRef][Medline]
  17. Armes JE, Trute L, White D, et al. Distinct molecular pathogenesis of early-onset breast cancers in BRCA1 and BRCA2 mutation carriers: a population based study. Cancer Res 1999; 59: 2011–7.[Abstract/Free Full Text]
  18. Breast Cancer Linkage Consortium. Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 and BRCA2 mutations and sporadic cases. Lancet 1997; 349: 1505–10.[CrossRef][Medline]
  19. Lakhani SR, Jacquemier J, Sloane JP, et al. Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J Natl Cancer Inst 1998; 90: 1138–45.[Abstract/Free Full Text]
  20. Armes JE, Venter DJ. The pathology of inherited breast cancer. Pathology 2002; 34: 309–14.[CrossRef][Medline]
  21. Lakhani SR, van de Vijver MJ, Jacquemier J, et al. The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 2002; 20: 2310–8.[Abstract/Free Full Text]
  22. Levine DA, Federici MG, Reuter VE, Boyd J. Cell proliferation and apoptosis in BRCA-associated hereditary ovarian cancer. Gynecol Oncol 2002; 85: 431–4.[CrossRef][Medline]
  23. Jazaeri AA, Yee CJ, Sotiriou C, et al. Gene expression profiles of BRCA1-linked, BRCA2-linked, and sporadic ovarian cancers. Natl Cancer Inst 2002; 94: 990–1000.[Abstract/Free Full Text]
  24. Eisinger F, Stoppa-Lyonnet D, Londy M, et al. Germ line mutation at BRCA1 affects the histoprognostic grade in hereditary breast cancer. Cancer Res 1996; 56: 471–4.[Abstract/Free Full Text]
  25. Pierce LJ, Strawderman M, Narod SA, et al. Effect of radiotherapy after breast-conserving treatment in women with breast cancer and germline BRCA1/2 mutations. J Clin Oncol 2000; 18: 3360–9.[Abstract/Free Full Text]
  26. Haffty BG, Harrold E, Khan AJ, et al. Outcome of conservatively managed early-onset breast cancer by BRCA1/2 status. Lancet 2002; 359: 1471–7.[CrossRef][Medline]
  27. Early Breast Cancer Trialists’ Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomized trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 1992; 339: 1–15.[Medline]
  28. Hoogerbrugge N, Bult P, de Widt-Levert JM, et al. High prevalence of premalignant lesions in prophylactically removed breasts from women at hereditary risk for breast cancer. J Clin Oncol 2003; 21: 41–5.[Abstract/Free Full Text]
  29. Ren Q, Carbonne C, Potoczek M, et al. Differential response to BRCA1 wild type and BRCA1 mutant breast cancer cells to ionizing radiation and paclitaxel (abstract). Clin Cancer Res 2001; 7 (Suppl): 3723s.
  30. Fan S, Yuan R, Ma YX, et al. Mutant BRCA1 genes antagonize phenotype of wild-type BRCA1. Oncogene 2001; 20: 8215–35.[CrossRef][Medline]
  31. Bhattacharyya A, Ear US, Koller BH, et al. The breast cancer susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA cross-linking agent cisplatin. J Biol Chem 2000; 275: 23899–903.[Abstract/Free Full Text]
  32. Husain A, He G, Venkatraman ES, et al. BRCA1 up-regulation is associated with repair-mediated resistance to cis-diamminedichloroplatinum(II). Cancer Res 1998; 58: 1120–3.[Abstract/Free Full Text]
  33. Abbott DW, Freeman MI, Holt JT. Double-strand repair deficiency and radiation sensitivity in BRCA2 mutant cancer cells. J Natl Cancer Inst 1998; 90: 978–85.[Abstract/Free Full Text]
  34. Freneaux P, Stoppa-Lyonnet D, Mouret E, et al. Low expression of bcl-2 in BRCA1-associated cancers. Br J Cancer 2000; 83: 1318–22.[CrossRef][Medline]
  35. Chappuis PO, Goffin J, Wong N, et al. A significant response to neoadjuvant chemotherapy in BRCA1/2 related breast cancer. J Med Genet 2002; 39: 608–10.[Free Full Text]
  36. Goffin JR, Chappuis PO, Begin LR, et al. Impact of germline BRCA1 mutations and overexpression of p53 on prognosis and response to treatment following breast carcinoma. Cancer 2003; 97: 527–36.[CrossRef][Medline]



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N-(4-Hydroxyphenyl)retinamide is more potent than other phenylretinamides in inhibiting the growth of BRCA1-mutated breast cancer cells
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Advances in Breast Conservation Therapy
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