This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Verhoog, L. C. Articles by Klijn, J.G.M. Search for Related Content PubMed PubMed Citation Articles by Verhoog, L. C. Articles by Klijn, J.G.M. Social Bookmarking                            What's this?

Survival in Hereditary Breast Cancer Associated With Germline Mutations of BRCA2

From the Family Cancer Clinic and Department of Medical Registration, Daniel den Hoed Cancer Center, University Hospital Rotterdam; Department of Clinical Genetics, Erasmus University Rotterdam, Rotterdam; and Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.

Address reprint requests to J.G.M. Klijn, MD, PhD, Family Cancer Clinic, Department of Medical Oncology, Daniel den Hoed Kliniek, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Breast cancer in BRCA1 and BRCA2 gene-mutation carriers may differ from so-called sporadic breast cancer in clinical features and behavior. These potential differences may be of importance for the prevention, screening, and, ultimately, treatment of breast cancer in women with such germline mutations. Thus far, there have been very few studies on the survival of BRCA2-associated breast cancer patients.

PATIENTS AND METHODS: We determined the disease-free and overall survival of 28 breast cancer patients from 14 consecutive families with eight different BRCA2 germline mutations. These patients' survival and tumor characteristics were compared with those of a control group of 112 sporadic breast cancer patients matched to them by age and year of diagnosis.

RESULTS: The 5-year disease-free survival was 52% for each group (P = .91); the overall survival was 74% for BRCA2 carriers and 75% for sporadic cases (P = .50). At the time of diagnosis, tumors from the BRCA2 carriers were borderline significantly larger in comparison to the tumors in sporadic cases (P = .05), but axillary nodal status was not significantly different in the two groups (node-negativity, 63% v 52.8%, respectively; P = .34). With respect to steroid receptor status, BRCA2-associated tumors were more likely to be steroid receptor-positive, especially regarding progesterone receptor status (100% v 76.7% positive, respectively; P = .06). Stage-adjusted recurrence and death rates were nonsignificantly better for BRCA2 cases (hazard ratios of 0.84 and 0.59 [P = .61 and P = .19], respectively). In contrast, after 5 years, the rate of metachronous contralateral breast cancer in BRCA2 patients was 12% (v 2% in controls; P = .02).

CONCLUSION: Patients with hereditary breast cancer due to BRCA2 have a similar prognosis when compared with age-matched sporadic breast cancer patients. Contrary to our previous observation regarding BRCA1-associated breast cancer, BRCA2 tumors tended to be steroid receptor-positive, instead of steroid receptor-negative.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
IN WESTERN COUNTRIES, up to 20% of women diagnosed with breast cancer have at least one relative who is also affected by the disease.¹ Part of this familial clustering shows autosomal dominant inheritance with high penetrance and is due to mutations in the BRCA1 and BRCA2 breast cancer genes.^2,3 Germline mutations in the BRCA1 and BRCA2 genes confer a strongly elevated risk of breast cancer. Women who inherit a mutated copy of the BRCA1 gene have an estimated lifetime risk of breast cancer ranging from 56% to 87%, which is comparable to the lifetime risk for BRCA2 mutation carriers.^4-7 Both genes are known to be involved in the hereditary breast and ovarian cancer syndrome,⁸ although the majority of cases of this syndrome are thought to occur as a result of a mutation in the BRCA1 gene.⁹

A number of other similarities exist in breast cancer associated with either one of these genes.⁷ Familial and proven BRCA1- and BRCA2-associated breast cancers are both characterized by a younger age of onset of the disease, frequent bilateral occurrence,^10-12 and worse histoprognostic features.^13-16 However, it is possible that the higher grade of malignancy of BRCA2-associated tumors is merely determined by reduced tubule formation.¹⁶

A positive family history for breast cancer has been correlated with better, similar, and worse prognoses relative to nonfamilial breast cancer.^17-21 Differences in the definitions of a positive family history for breast cancer and in the ethnic backgrounds of the populations investigated may have resulted in a varied contribution of genetic susceptibility, and this, apart from disparate control groups, might explain the conflicting results regarding prognosis of familial breast cancer.

We and other groups showed in earlier reports that despite the adverse pathobiologic features of BRCA1-related tumors, the prognosis for patients with BRCA1 hereditary breast cancer is not significantly different from that of sporadic controls.^21-27 However, others have found that the presence of a BRCA1 germline mutation is an adverse prognostic factor in breast cancer patients.^28,29

Because little is known about the natural history of BRCA2-associated breast cancer, we investigated disease-free and overall survival in relation to a number of clinical and pathologic characteristics in breast cancer patients from 14 consecutive families with a proven BRCA2 mutation who were counseled at our family cancer clinic. Identifying the potential differences in survival and tumor characteristics could benefit the management of breast cancer in women with a BRCA2 germline mutation and might have implications for screening, chemoprevention, prophylactic surgery, and treatment.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Families and Patients
Families were identified through the Family Cancer Clinic of the Daniel den Hoed cancer center and the Department of Clinical Genetics of Erasmus University Rotterdam. The 14 families eligible for this study (Table 1) consisted of consecutive unselected families with an identified germline mutation in the BRCA2 gene. The presence of a BRCA2 mutation was detected by a protein truncation test,¹² followed by sequence analysis to characterize the precise alteration and by allele-specific oligonucleotide hybridization for distinct mutations as described.²² Each family had to include one or more patients with histologically confirmed breast cancer for whom follow-up data were available through hospital records. This criterion was fulfilled for 28 breast cancer patients from 14 families; 17 of these patients were treated in the Daniel den Hoed Cancer Center. Six of the total group of 28 patients were probands; that is, they were the initial persons counseled in their families.

An overview of the mutation spectrum and number of cases of breast and ovarian cancer per family is listed in Table 1. Seventeen of the total of 45 breast cancer patients from the BRCA2 families were not eligible because of lack of histologic confirmation of the original diagnosis or because no consent was obtained for the extraction of their data from hospital records. Twenty-two of the 28 BRCA2 cases were proved to be carriers of a BRCA2 mutation by direct tests of their blood cells or tumor material or because of their position in the pedigree; for the remaining six BRCA2 patients, it was not possible to confirm carrier status because no blood or tissue samples were available.

The hereditary breast cancer patients were matched for age and date of diagnosis in a 1:4 ratio to a sporadic group of patients selected from the Daniel den Hoed cancer registry. This registry includes data from more than 10,000 breast cancer patients treated in the hospital since 1980. For the majority of cases, matching was performed within 1 year of the age and diagnosis date of the corresponding BRCA2 patient. This was not possible for seven BRCA2-related cases diagnosed before 1980. Patients with a positive family history could generally be excluded from the sporadic group because the registry contains information regarding tumors of the identical type that had occurred in other family members.

We extracted data regarding age at onset of the disease, menopausal status, surgical procedure performed, tumor-node-metastasis system status, histology, contralateral breast cancer, and estrogen/progesterone receptor (ER/PgR) status from hospital records and pathology reports. In the majority of cases, tumor ER and PgR levels were routinely determined with radioligand binding assays as recommended by the European Organization for Research and Treatment of Cancer or with enzyme immunoassays as previously described by our group.³⁰ Values below 10 fmol/mg protein were considered negative.

Breast cancer in the BRCA2-associated patients had been diagnosed between 1960 and 1996; the median year of diagnosis for both groups was 1985 and the mean year of diagnosis was 1983 for the BRCA2 cases and 1985 for the sporadic cases. The mean age at diagnosis was 46 years for both groups (median, 42 years; range, 32 to 85 years). We selected the date of first local or distant recurrence, the occurrence of a second primary breast tumor, and date of death (due to breast cancer or other cause) as the end points of interest. The three eligible BRCA2-associated breast cancer patients with ovarian cancer tumors as second primary tumors were not likely to influence survival because only one woman died as a result of ovarian cancer (33 years after the first diagnosis). From the 17 BRCA2 patients without pathology and/or follow-up data, information about the age at diagnosis and date of death were collected as reported by their family members. This was done to check for possible bias toward longevity of the eligible BRCA2 cases.

Statistical Methods
The comparability of patient and tumor characteristics in the BRCA2-associated and sporadic breast cancer patients was tested by chi-square tests. Kaplan-Meier survival probabilities were computed, and differences were tested using the log-rank test. The simultaneous effect of several prognostic factors on disease-free and overall survival was investigated by use of the Cox proportional hazards regression method. The adequacy of the proportional hazards assumption was tested graphically by examination of logminlogplots.³¹

To exclude any possible biases related to potential differences in treatment, separate analyses were performed for the BRCA2-associated patients diagnosed after 1980. In addition, we performed a separate analysis of the BRCA2 cases that excluded the six probands because these cases might be selected for longevity. All statistical analyses were performed using SPSS-PC version 5 (SPSS Inc, Chicago, IL) and STATA version 5 software (STATA Corporation, College Station, TX), alternately including and excluding the missing variables as a separate group.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient and Tumor Characteristics
The characteristics of patients and of the tumors in cases of BRCA2-associated and sporadic breast cancers are listed in Table 2. By matching for age at onset, we found no significant difference in menopausal status at time of diagnosis. BRCA2-associated tumors were borderline significantly larger in size (P = 0.05) than the sporadic group of tumors, which is possibly related to the lower occurrence of breast-conserving therapy in the former group. Despite their larger size, BRCA2 tumors were slightly more often node-negative (63.0% v 52.8%; P = .34). The histologic type of the BRCA2 tumors did not differ significantly from that of the sporadic tumors (P = .46).

Metachronous contralateral breast cancer occurred in 25% of the BRCA2-associated patients. This was approximately five times more frequent than the occurrence of contralateral breast cancer in the group of sporadic controls (4.5%; P = .002). Of the BRCA2 cases with known receptor status, 14 of 15 tumors were ER⁺ (93.3%) and 12 of 12 tumors (100%) were PgR⁺ (sporadic breast cancer patients: ER⁺, 84.4%, P = .37; PgR⁺, 76.7%, P = .06). In addition, the receptor statuses of three contralateral BRCA2-associated breast tumors was available, and all three tumors were steroid receptor-positive.

Survival Analysis and Multivariate Analysis
Figures 1 and 2 show Kaplan-Meier curves for disease-free and overall survival, respectively, in BRCA2-associated and sporadic breast cancer patients. Disease-free survival at 2 and 5 years (Table 3) was 82% and 52%, respectively, for BRCA2 patients versus 78% and 52%, respectively, for sporadic patients (P_logrank = .91). Overall survival at 2 and 5 years was 93% and 74%, respectively, for the BRCA2 patients versus 92% and 75% for the sporadic patients (P_logrank = .50). The overall clinical outcome of the patients, including the breast cancer–specific death rate, is summarized in Table 3. No significant differences between the BRCA2 and sporadic cases were observed, with the exception of the rate of contralateral breast cancer. After 2 and 5 years of follow-up, metachronous contralateral breast cancer was diagnosed in 4% and 12%, respectively, of the BRCA2-associated breast cancer patients versus 1% and 2%, respectively, in the sporadic breast cancer patients (P_logrank = .02). Kaplan-Meier curves for the occurrence of contralateral breast cancer in BRCA2-associated patients and the matched sporadic controls are shown in Fig 3.

View larger version (11K): [in this window] [in a new window]   Fig 1. Disease-free survival for patients with BRCA2-associated (n = 28; – – – –) or sporadic breast cancer (n = 112; ——) since the time of diagnosis.

View larger version (11K): [in this window] [in a new window]   Fig 2. Overall survival for patients with BRCA2-associated (n = 28; – – – –) or sporadic breast cancer (n = 112; ——) since the time of diagnosis

View larger version (11K): [in this window] [in a new window]   Fig 3. Contralateral breast cancer–free survival for patients with BRCA2-associated (n = 27; – – – –) or sporadic breast cancer (n = 109; ——) since the time of diagnosis (patients with synchronous bilateral breast cancer excluded).

In Table 4, uni- and multivariate hazard ratios and 95% confidence intervals (CIs) of recurrence and all-causes mortality are listed. With sporadic cases as the reference group, the unadjusted hazard ratios for BRCA2-associated cases regarding recurrence and all-causes mortality were 0.92 (95% CI, 0.52 to 1.62) and 0.75 (95% CI, 0.37 to 1.50), respectively. Adjustment for a number of major prognostic factors, including tumor size, nodal status, steroid receptor status, and the occurrence of contralateral breast cancer, did not substantially alter the results. After correction for tumor stage, which is, in general, the most important prognostic factor, the hazard ratios for recurrence and all-causes mortality in the group of BRCA2-associated breast cancer patients were 0.84 (95% CI, 0.44 to 1.63) and 0.59 (95% CI, 0.27 to 1.29) (P = .19).

To further investigate the validity of the control group from the Daniel den Hoed Cancer Registry, we compared our data with the cancer registry data of the southeast Netherlands. In the Southeast, the 5-year survival for patients 15 to 59 years of age who had been diagnosed between 1980 and 1992 was 72%, which is similar to the 5-year survival of our control group (75%).³²

Survival Analysis After Exclusion of Affected Probands
As we discussed previously, ascertainment of BRCA2 families by affected probands might lead to a selection bias of patients who are characterized by longevity.²² Therefore we performed separate analyses that excluded the six probands who were affected by breast cancer and also excluded their matched controls. This did not essentially alter the results: disease-free survival at 2 and 5 years was 77% and 45%, respectively, for BRCA2-associated patients versus 76% and 50%, respectively, for sporadic cases (P_logrank = .78). Overall survival at 2 and 5 years was 91% and 68%, respectively, for BRCA2 cases versus 92% and 72%, respectively, for sporadic breast cancer patients (P_logrank = .79).

We also performed separate analyses for cases diagnosed after 1980 because we were not able to fully match seven BRCA2 cases diagnosed before 1980 with respect to year of diagnosis.

Again, there were no significant differences: disease-free survival at 2 and 5 years was 86% and 45%, respectively, for the BRCA2 group versus 76% and 56%, respectively, for sporadic cases (P_logrank = .72). Overall survival at 2 and 5 years was 95% and 74%, respectively, for BRCA2 patients and 90% and 76% for sporadic patients (P_logrank = .99).

Finally, we estimated the crude overall survival for the entire group of 45 BRCA2-associated breast cancer patients, including the 17 patients without pathology and/or sufficient follow-up. When these patients were included, 2- and 5-year overall survival was 91% and 75%, respectively.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Disease-free and overall survival of 28 breast cancer patients from Dutch families with an identified BRCA2 germline mutation did not significantly differ from the disease-free and overall survival of 112 sporadic patients matched for age of onset of disease and year of diagnosis. Despite some reports on the more adverse histoprognostic characteristics of BRCA2-related breast cancer,^13-16 the clinical outcome for patients with BRCA2-related breast cancer did not appear to be worse. Overall survival of the BRCA2-associated breast cancer patients was even nonsignificantly better when we adjusted for tumor stage. There are currently only a very few studies with which we can compare our findings. Furthermore, the data on the survival of breast cancer patients with a BRCA2 germline mutation are primarily limited to a few mutations that are characteristic for specific populations.^27,33 An overview of those studies that have addressed the issue of survival of BRCA1- and/or BRCA2-associated breast cancer patients is given in Table 5. It must be noted that there are essential differences in the methods used in these studies and therefore also in the way that comparison groups were selected. In part this is reflected by the wide range of values for survival in control patients in the different studies.

One study described the overall survival of 20 breast cancer patients from five BRCA2 families.²⁵ These families were all large families that had previously been used in linkage studies, and a germline mutation had only been identified in three of them. It has been pointed out previously that linkage analysis may have been more conclusive, considering the high number of breast cancer patients still alive at the time of study; therefore selection of these families might have led to a bias toward longevity. Nevertheless, overall survival was similar for BRCA2-associated breast cancer patients and breast cancer patients from a cancer registry who had been matched for age, date of diagnosis, and tumor size.

In the study by Marcus et al,²¹ a poorer prognosis was demonstrated for hereditary breast cancer patients whose disease was not related to the BRCA1 gene. It was suggested that the group of 66 patients in the Marcus et al study predominantly consisted of BRCA2-related cases. However, only seven cases were included from families with evidence for linkage to the BRCA2 gene. At present, it seems unlikely that all of the cases from families not linked to the BRCA1 gene consist of BRCA2 mutation carriers. A worse outcome was also found by Sigurdsson et al,³³ who studied Icelandic breast cancer patients from families with evidence for linkage to the BRCA2 gene. However, in that study, controls were not matched for year of diagnosis, which most likely led to large differences in the treatment of these patients as well as differences in the distribution of the stage of the disease. When controls were matched for year of diagnosis in their study, there was a trend toward a more favorable outcome.¹³ Moreover, as a result of endogamy and the geographic isolation of the Icelandic population, only one single specific mutation is present in the Icelandic breast cancer families linked to the BRCA2 gene.³⁶ The position of this mutation in the gene, as well as its genetic and environmental background, may very well influence tumor and patient characteristics and subsequent survival.³⁷

Robson et al³⁵ described a similar clinical outcome in a combined group of Ashkenazi Jewish breast cancer patients with BRCA1 or BRCA2 germline mutations, compared with cases not associated with BRCA mutations. This study, as well as some other studies, failed to discriminate between BRCA1 and BRCA2 mutations.^27,38-40 In the study presented here, we demonstrated that it may be of interest to differentiate between BRCA1- and BRCA2-associated breast cancers, especially with regard to the endocrine aspects of these tumors.

Earlier, we reported that BRCA1-associated breast cancers are clearly more often steroid receptor-negative, compared with sporadic controls.²² In the study presented here, BRCA2 tumors instead showed a trend toward a higher incidence of steroid receptor positivity, especially with respect to PgRs. At present, few data exist regarding the relationship between steroid receptor status and the presence of a BRCA2 germline mutation. Loman et al⁴¹ found that BRCA2-associated breast cancer was more likely to be ER⁺, compared with BRCA1 cases. In line with our observation, a study of BRCA2-associated tumors with the Icelandic founder mutation 999del5 showed significantly higher ER and PgR levels, compared with a group of tumors from age-matched controls.¹³ Other studies however, that have used immunohistochemical analysis to assess steroid receptor status have not made this observation.^15,42 If confirmed, the higher percentage of steroid receptor-positive tumors in BRCA2 carriers is of special interest in chemoprevention of breast cancer with antiestrogens.⁴³

It has been known for a long time that familial breast cancer is associated with bilateral disease.^10,44 The lifetime risk for contralateral breast cancer in BRCA1 carriers was estimated to be as high as 64%.⁵ We reported the rate of metachronous contralateral disease in BRCA1-associated breast cancer to be 19% after 5 years of follow-up.²² In the study presented here, we found a contralateral breast cancer rate of 12% after 5 years for BRCA2 carriers. In total, bilateral disease was seen in 28.6% of the patients included in our study. Although the high rate of contralateral disease in BRCA2 carriers might support prophylactic contralateral mastectomy as a treatment method, patients with BRCA2 mutations might benefit from adjuvant hormonal therapy with respect to the possible prevention of contralateral disease, considering the high percentage of steroid receptor-positive tumors.

Studying survival in self-ascertained families has been said to lead to selection for longevity of cases because families with more living affected women are more likely to be (self-) referred to a family cancer clinic. In our study, only six probands were women affected with breast cancer. To exclude any possible bias, we performed separate analyses that excluded these six probands; however, this did not essentially alter the results. In two families, which contributed six BRCA2-associated cases, none of the affected family members were alive and a mutation was detected by testing first-degree relatives and then confirming the presence of the mutation in tumor material. In two other families, the diagnosis of breast cancer in the proband was the direct motive to refer a family to the family cancer clinic; therefore, these cases were included in a prospective manner. Finally, estimates for overall survival, including the BRCA2-cases without pathology or follow-up, did not yield significantly different results. For these reasons, we believe that bias is not a major problem in our study.

In conclusion, in this study, we observed that despite the differences in histologic and biochemical characteristics, the disease-free and overall survival of breast cancer patients with germline mutations in the BRCA2 gene are similar to those of sporadic breast cancer patients. One important finding is the significantly increased rate of contralateral breast cancer in our unselected families. In contrast to those in BRCA1-related breast cancer, BRCA2 tumors are not more often ER^- and PgR^- but rather tended to be receptor-positive. For the detection of potential small differences, larger studies are needed.

	ACKNOWLEDGMENTS

 
We thank L.M.C. van den Bosch and C. van Kooten for collecting data and M.F. Niermeijer (clinical geneticist) and C.J. Cornelisse (molecular pathologist) for their advice.

	NOTES

 
This study was supported by grant DDHK 95-953 from the Dutch Cancer Society.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. King MC: Genetic analysis of cancer in families. Cancer Surv9:417-435, 1990[Medline]

2. Miki Y, Swensen J, Shattuck Eidens D, et al: A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science266:66-71, 1994[Abstract/Free Full Text]

3. Wooster R, Bignell G, Lancaster J, et al: Identification of the breast cancer susceptibility gene BRCA2. Nature378:789-792, 1995[Medline]

4. Struewing JP, Hartge P, Wacholder S, et al: Cancer risk with 185delAG and 5382insC mutations of BRCA1 and the 6174delT mutation of BRCA2 among Ashkenazi Jews. N Engl J Med336:1401-1408, 1997[Abstract/Free Full Text]

5. Ford D, Easton DF, Bishop DT, et al: Risks of cancer in BRCA1 mutation carriers. Lancet343:692-695, 1994[Medline]

6. Ford D, Easton DF, Stratton M, et al: Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet62:676-689, 1998[Medline]

7. Blackwood MA, Weber BL: BRCA1 and BRCA2: From molecular genetics to clinical medicine. J Clin Oncol16:1969-1977, 1998[Abstract]

8. Narod S, Ford D, Devilee P, et al: Genetic heterogeneity of breast-ovarian cancer revisited. Am J Hum Genet57:957-958, 1995[Medline]

9. Serova O, Montagna M, Torchard D, et al: A high incidence of BRCA1 mutations in 20 breast-ovarian cancer families. Am J Hum Genet58:42-51, 1996[Medline]

10. Anderson DE: Some characteristics of familial breast cancer. Cancer28:1500-1505, 1971[Medline]

11. Hall JM, Lee MK, Morrow J, et al: Linkage analysis of early onset familial breast cancer to chromosome 17q21. Science250:1684-1689, 1990[Abstract/Free Full Text]

12. Ligtenberg MJL, Hogervorst FBL, Willems HW, et al: Characteristics of small breast and/or ovarian cancer families with germline mutations in BRCA1 and BRCA2. Br J Cancer79:1475-1478, 1999[Medline]

13. Agnarsson BA, Jonasson JG, Björnsdottir IB, et al: Inherited BRCA2 mutation associated with high grade breast cancer. Breast Cancer Res Treat47:121-127, 1998[Medline]

14. Breast Cancer Linkage Consortium: Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Lancet349:1505-1510, 1997[Medline]

15. Lynch BJ, Holden JA, Buys SS, et al: Pathobiological characteristics of hereditary breast cancer. Hum Pathol29:1140-1144, 1998[Medline]

16. 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 Inst90:1138-1145, 1998[Abstract/Free Full Text]

17. Lynch HT, Albano WA, Recabaren JA, et al: Survival in hereditary breast and colon cancer. JAMA246:1197, 1981 (letter) [Abstract/Free Full Text]

18. Wobbes T, van de Wiel MP, van der Sluis RF, et al: The effect of familiality on clinical presentation and survival in mammary carcinoma. Eur J Sur Oncol13:119-121, 1987[Medline]

19. Lees AW, Jenkins HJ, May CL, et al: Risk factors and 10-year breast cancer survival in northern Alberta. Breast Cancer Res Treat13:143-151, 1989[Medline]

20. Malone KE, Daling JR, Weiss NS, et al: Family history and survival of young women with invasive breast carcinoma. Cancer78:1417-1425, 1996[Medline]

21. Marcus JN, Watson P, Page DL, et al: Hereditary breast cancer: Pathobiology, prognosis, and BRCA1 and BRCA2 gene linkage. Cancer77:697-709, 1996[Medline]

22. Verhoog LC, Brekelmans CTM, Seynaeve C, et al: Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1. Lancet351:316-321, 1998[Medline]

23. Watson P, Marcus JN, Lynch HT: Prognosis of BRCA1 hereditary breast cancer. Lancet351:304-305, 1998[Medline]

24. Johannsson OT, Ranstam J, Borg A, et al: Survival of BRCA1 breast and ovarian cancer patients: A population based study from Southern Sweden. J Clin Oncol16:397-404, 1998[Abstract]

25. Gaffney DK, Brohet RM, Lewis CM, et al: Response to radiation therapy and prognosis in breast cancer patients with BRCA1 and BRCA2 mutations. Radiother Oncol47:129-136, 1998[Medline]

26. Wagner TM, Moslinger RA, Muhr D, et al: BRCA1-related breast cancer in Austrian breast and ovarian cancer families: Specific BRCA1 mutations and pathological characteristics. Int J Cancer77:354-360, 1998[Medline]

27. Lee JS, Wacholder S, Struewing JP, et al: Survival after breast cancer in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst91:259-263, 1999[Abstract/Free Full Text]

28. Foulkes WD, Wong N, Brunet J-S, et al: Germ-line BRCA1 mutation is an adverse prognostic factor in Ashkenazi Jewish women with breast cancer. Clin Cancer Res 3:2465-2469,1997

29. Ansquer Y, Gautier C, Fourquet A, et al: Survival in early-onset BRCA1 breast-cancer patients. Lancet352:541, 1998 (letter)

30. Foekens JA, Portengen H, van Putten WL, et al: Prognostic value of estrogen and progesterone receptors measured by enzyme immunoassays in human breast tumor cytosols. Cancer Res49:5823-5828, 1989[Abstract/Free Full Text]

31. Kalbfleisch JD, Prentice RL: The Statistical Analysis of Failure Time Data. New York, NY, John Wiley, 1980

32. Coebergh JWW, van der Heijden LH, Janssen-Heijen MLG (eds): Cancer Incidence and Survival in the Southeast of the Netherlands 1955-1994. Eindhoven, the Netherlands, Comprehensive Cancer Center South, 1995

33. Sigurdsson H, Agnarsson BA, Jonasson JG, et al: Worse survival among breast cancer patients in families carrying the BRCA2 susceptibility gene. Breast Cancer Res Treat367:33, 1996 (abstr 1)

34. Porter DE, Cohen BB, Wallace MR, et al: Breast cancer incidence, penetrance and survival in probable carriers of BRCA1 gene mutation in families linked to BRCA1 on chromosome 17q12-21. Br J Surg81:1512-1515, 1994[Medline]

35. Robson M, Gilewski T, Haas B, et al: BRCA-associated breast cancer in young women. J Clin Oncol16:1642-1649, 1998[Abstract]

36. Thorlacius S, Olafsdottir G, Tryggvadottir L, et al: A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nat Genet13:117-119, 1996[Medline]

37. Neuhausen SL, Godwin AK, Gershoni-Baruch R, et al: Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: Results of an international study. Am J Hum Genet62:1381-1388, 1998[Medline]

38. Osin P, Crook T, Powles T, et al: Hormone status of in-situ cancer in BRCA1 and BRCA2 mutation carriers. Lancet351:1487, 1998 (letter)

39. Robson M, Rajan P, Rosen PP, et al: BRCA-associated breast cancer: Absence of a characteristic immunophenotype. Cancer Res58:1839-1842, 1998[Abstract/Free Full Text]

40. Narod SA, Risch H, Moslehi R, et al: Oral contraceptives and the risk of hereditary ovarian cancer. N Engl J Med229:424-428, 1998

41. Loman N, Johannsson O, Bendahl P-O, et al: Steroid receptors in hereditary breast carcinomas associated with BRCA1 and BRCA2 mutations or unknown susceptibility genes. Cancer83:310-319, 1998[Medline]

42. Osin P, Gusterson BA, Philp E, et al: Predicted anti-oestrogen resistance in BRCA-associated familial breast cancers. Eur J Cancer34:1683-1686, 1998

43. Fisher B, Constantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: Report of the national surgical adjuvant breast and bowel project P-1 study. J Natl Cancer Inst90:1371-1388, 1998[Abstract/Free Full Text]

44. Cady B: Familial bilateral cancer of the breast. Ann Surg172:264-272, 1970[Medline]

Submitted April 12, 1999; accepted July 7, 1999.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				M. Leu, M. Reilly, and K. Czene Evaluation of Bias in Familial Risk Estimates: A Study of Common Cancers Using Swedish Population-based Registers J Natl Cancer Inst, September 17, 2008; 100(18): 1318 - 1325. [Abstract] [Full Text] [PDF]

				J. M. Lee, D. B. Kopans, P. M. McMahon, E. F. Halpern, P. D. Ryan, M. C. Weinstein, and G. S. Gazelle Breast Cancer Screening in BRCA1 Mutation Carriers: Effectiveness of MR Imaging--Markov Monte Carlo Decision Analysis Radiology, March 1, 2008; 246(3): 763 - 771. [Abstract] [Full Text] [PDF]

				B. A. M. Heemskerk-Gerritsen, C. T. M. Brekelmans, M. B. E. Menke-Pluymers, A. N. van Geel, M. M. A. Tilanus-Linthorst, C. C. M. Bartels, M. Tan, H. E. J. Meijers-Heijboer, J. G. M. Klijn, and C. Seynaeve Prophylactic Mastectomy in BRCA1/2 Mutation Carriers and Women at Risk of Hereditary Breast Cancer: Long-Term Experiences at the Rotterdam Family Cancer Clinic Ann. Surg. Oncol., December 1, 2007; 14(12): 3335 - 3344. [Abstract] [Full Text] [PDF]

				P van der Groep, A Bouter, R van der Zanden, I Siccama, F H Menko, J J P Gille, C van Kalken, E van der Wall, R H M Verheijen, and P J van Diest Distinction between hereditary and sporadic breast cancer on the basis of clinicopathological data J. Clin. Pathol., June 1, 2006; 59(6): 611 - 617. [Abstract] [Full Text] [PDF]

				C. E. Jacobi, N. J.D. Nagelkerke, J. C. van Houwelingen, and G. H. de Bock Breast Cancer Screening, Outside the Population-Screening Program, of Women from Breast Cancer Families without Proven BRCA1/BRCA2 Mutations: a Simulation Study. Cancer Epidemiol. Biomarkers Prev., March 1, 2006; 15(3): 429 - 436. [Abstract] [Full Text] [PDF]

				M. H. Frost, J. M. Slezak, N. V. Tran, C. I. Williams, J. L. Johnson, J. E. Woods, P. M. Petty, J. H. Donohue, C. S. Grant, J. A. Sloan, et al. Satisfaction After Contralateral Prophylactic Mastectomy: The Significance of Mastectomy Type, Reconstructive Complications, and Body Appearance J. Clin. Oncol., November 1, 2005; 23(31): 7849 - 7856. [Abstract] [Full Text] [PDF]

				E. Kwiatkowska, M. Teresiak, V. Filas, A. Karczewska, D. Breborowicz, and A. Mackiewicz BRCA2 Mutations and Androgen Receptor Expression as Independent Predictors of Outcome of Male Breast Cancer Patients Clin. Cancer Res., October 1, 2003; 9(12): 4452 - 4459. [Abstract] [Full Text] [PDF]

				H. Meijers-Heijboer, C. T.M. Brekelmans, M. Menke-Pluymers, C. Seynaeve, A. Baalbergen, C. Burger, E. Crepin, A. W.M. van den Ouweland, B. van Geel, and J. G.M. Klijn Use of Genetic Testing and Prophylactic Mastectomy and Oophorectomy in Women With Breast or Ovarian Cancer From Families With a BRCA1 or BRCA2 Mutation J. Clin. Oncol., May 1, 2003; 21(9): 1675 - 1681. [Abstract] [Full Text] [PDF]

				V. G. Vogel, J. P. Costantino, D. L. Wickerham, and W. M. Cronin National Surgical Adjuvant Breast and Bowel Project Update: Prevention Trials and Endocrine Therapy of Ductal Carcinoma in Situ Clin. Cancer Res., January 1, 2003; 9(1): 495S - 501S. [Abstract] [Full Text] [PDF]

				E. L. Goode, A. M. Dunning, B. Kuschel, C. S. Healey, N. E. Day, B. A. J. Ponder, D. F. Easton, and P. P. D. Pharoah Effect of Germ-Line Genetic Variation on Breast Cancer Survival in a Population-based Study Cancer Res., June 1, 2002; 62(11): 3052 - 3057. [Abstract] [Full Text] [PDF]

				M. S. van Roosmalen, L. C.G. Verhoef, P. F.M. Stalmeier, N. Hoogerbrugge, and W. A.J. van Daal Decision Analysis of Prophylactic Surgery or Screening for BRCA1 Mutation Carriers: A More Prominent Role For Oophorectomy J. Clin. Oncol., April 15, 2002; 20(8): 2092 - 2100. [Abstract] [Full Text] [PDF]

				L. Scheuer, N. Kauff, M. Robson, B. Kelly, R. Barakat, J. Satagopan, N. Ellis, M. Hensley, J. Boyd, P. Borgen, et al. Outcome of Preventive Surgery and Screening for Breast and Ovarian Cancer in BRCA Mutation Carriers J. Clin. Oncol., March 1, 2002; 20(5): 1260 - 1268. [Abstract] [Full Text] [PDF]

				S. Narod, K. Offit, M. Robson, D. Schrag, T. Riggs, M. J. Stoutjesdijk, J. O. Barentsz, J. G.M. Klijn, and H. Meijers-Heijboer Prophylactic Mastectomy in Carriers of BRCA Mutations N. Engl. J. Med., November 15, 2001; 345(20): 1498 - 1500. [Full Text] [PDF]

				M.-C. King, S. Wieand, K. Hale, M. Lee, T. Walsh, K. Owens, J. Tait, L. Ford, B. K. Dunn, J. Costantino, et al. Tamoxifen and Breast Cancer Incidence Among Women With Inherited Mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial JAMA, November 14, 2001; 286(18): 2251 - 2256. [Abstract] [Full Text] [PDF]

				S. K. McDonnell, D. J. Schaid, J. L. Myers, C. S. Grant, J. H. Donohue, J. E. Woods, M. H. Frost, J. L. Johnson, D. L. Sitta, J. M. Slezak, et al. Efficacy of Contralateral Prophylactic Mastectomy in Women With a Personal and Family History of Breast Cancer J. Clin. Oncol., October 1, 2001; 19(19): 3938 - 3943. [Abstract] [Full Text]

				H. Meijers-Heijboer, B. van Geel, W. L.J. van Putten, S. C. Henzen-Logmans, C. Seynaeve, M. B.E. Menke-Pluymers, C. C.M. Bartels, L. C. Verhoog, A. M.W. van den Ouweland, M. F. Niermeijer, et al. Breast Cancer after Prophylactic Bilateral Mastectomy in Women with a BRCA1 or BRCA2 Mutation N. Engl. J. Med., July 19, 2001; 345(3): 159 - 164. [Abstract] [Full Text] [PDF]

				C.T.M. Brekelmans, C. Seynaeve, C.C.M. Bartels, M.M.A. Tilanus-Linthorst, E.J. Meijers-Heijboer, C.M.G. Crepin, A.N. van Geel, M. Menke, L.C. Verhoog, A. van den Ouweland, et al. Effectiveness of Breast Cancer Surveillance in BRCA1/2 Gene Mutation Carriers and Women With High Familial Risk J. Clin. Oncol., February 15, 2001; 19(4): 924 - 930. [Abstract] [Full Text] [PDF]

				P. O. Chappuis, L. Kapusta, L. R. Begin, N. Wong, J.-S. Brunet, S. A. Narod, J. Slingerland, and W. D. Foulkes Germline BRCA1/2 Mutations and p27Kip1 Protein Levels Independently Predict Outcome After Breast Cancer J. Clin. Oncol., December 15, 2000; 18(24): 4045 - 4052. [Abstract] [Full Text] [PDF]

				L. C. Verhoog, E. M. J. J. Berns, C. T. M. Brekelmans, C. Seynaeve, E. J. Meijers-Heijboer, and J. G. M. Klijn Prognostic Significance of Germline BRCA2 Mutations in Hereditary Breast Cancer Patients J. Clin. Oncol., November 1, 2000; 18(90001): 119s - 124. [Abstract] [Full Text] [PDF]

				R. T. Penson, M. V. Seiden, K. M. Shannon, M. L. Lubratovich, M. Roche, B. A. Chabner, and T. J. Lynch Jr. Communicating Genetic Risk: Pros, Cons, and Counsel Oncologist, April 1, 2000; 5(2): 152 - 161. [Abstract] [Full Text]

				D. A. Haber Breast Cancer in Carriers of BRCA1 and BRCA2 Mutations: Tackling a Molecular and Clinical Conundrum J. Clin. Oncol., November 1, 1999; 17(11): 3367 - 3370. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Verhoog, L. C. Articles by Klijn, J.G.M. Search for Related Content PubMed PubMed Citation Articles by Verhoog, L. C. Articles by Klijn, J.G.M. Social Bookmarking                            What's this?