OPTIONS & TOOLS
DOI: 10.1200/JCO.2008.19.9430 Journal of Clinical Oncology - published online before print October 26, 2009
Contralateral Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers
Both M.K.G. and C.E. contributed equally to this work.
To estimate the risk for contralateral breast cancer in members of BRCA1- and BRCA2-positive families and to determine predictive risk factors.
A retrospective, multicenter, cohort study was performed from 1996 until 2008 and comprised 2,020 women with unilateral breast cancer (index patients, n = 978; relatives, n = 1.42) from 978 families who had a BRCA1 or BRCA2 mutation. Cox regression analysis was applied to assess the association of age at first breast cancer with time from first to contralateral breast cancer, stratified by the affected BRCA gene.
The cumulative risk for contralateral breast cancer 25 years after first breast cancer was 47.4% (95% CI, 38.8% to 56.0%) for patients from families with BRCA1 or BRCA2 mutations. Members of families with BRCA1 mutations had a 1.6-fold (95% CI, 1.2-fold to 2.3-fold) higher risk of contralateral breast cancer than members of families with BRCA2 mutations. Younger age at first breast cancer was associated with a significantly higher risk of contralateral breast cancer in patients with BRCA1 mutation, and a trend was observed in patients with BRCA2 mutation. After 25 years, 62.9% (95% CI, 50.4% to 75.4%) of patients with BRCA1 mutation who were younger than 40 years of age at first breast cancer developed contralateral breast cancer, compared with only 19.6% (95% CI, 5.3% to 33.9%) of those who were older than 50 years of age at first breast cancer.
Women carrying a deleterious BRCA1 or BRCA2 mutation not only face a strongly increased risk of breast and ovarian cancer but also are at an elevated risk of developing a second breast cancer thereafter.1,2 The majority of second primaries occur in the contralateral breast, though long-term observations in large cohorts are still lacking.3–5 Consequently, after primary therapy, women are faced with a broad spectrum of choices that range from intensive surveillance or antihormonal treatment to prophylactic surgery of the contralateral breast and ovaries. This situation is reflected in a wide range of acceptance rates for prophylactic surgery among patients in western countries, and the range hardly depend on established risk predictors.6 Moreover, several other factors, such as age, type of initial breast cancer surgery, prophylactic bilateral salpingo-oophorectomy, and cultural acceptability, seem to play a role.6
The available evidence suggests that penetrance and organ tropism depend on genetic and nongenetic modifiers; however, the majority of these still remain to be elucidated.7,8 Previous studies have demonstrated that prophylactic bilateral salpingo-oophorectomy and tamoxifen can reduce the risk of contralateral breast cancer.4,5 Moreover, age at first breast cancer may influence the risk of second primaries, although conflicting results persist.3,4,9
Since 1996, the German Consortium for Hereditary Breast and Ovarian Cancer, which comprises 12 university centers, has established a large registry to collect comprehensive genotype and phenotype data on members of families suspected of having hereditary breast cancer. In this article, we sought to estimate contralateral breast cancer risks in a cohort of women who already had developed unilateral breast cancer and who are members of families with a deleterious BRCA mutation.
The German Consortium for Hereditary Breast and Ovarian Cancer comprises 12 university centers. By using standardized clinical criteria, families with clustering or early onset of breast or ovarian cancer are registered and tested for the presence of deleterious germline mutations in BRCA1 and BRCA2. Comprehensive data on familial cancer history, including a detailed pedigree, pathology reports, and results of molecular testing, are documented in a central database by using standardized, electronic, case report forms. Inclusion criteria and methods for genetic testing are described elsewhere.10 Written informed consent was obtained from all patients regarding registration and inspection of their medical records. The registry has been approved by the institutional review boards of each participating center.
From 1996 until November 2008, a total of 1,520 families with a deleterious BRCA1 or BRCA2 germline mutation were registered. For this retrospective analysis, all index occurrences and the first- and second-degree relatives who had a history of breast cancer diagnosed after 1960 were selected (N = 2,615 patients from 1,407 families). All index patients were mutation carriers. Of all relatives, 174 (17%) were proven carriers. For all other relatives, the mutation status was not determined. These relatives were considered putative carriers, because they already had a breast cancer. Thirty-three relatives who tested negative for the known mutation in the family were excluded. Individuals were selected only from that branch of the family in which the pathogenic mutation was detected or in which familial clustering of cancers was observed. Patients with synchronous bilateral or noninvasive breast cancer were excluded (n = 536 patients from 408 families). An additional 59 patients (2.8%) from 21 families were excluded because of insufficient information regarding age at cancer events or bilateral mastectomy. In summary, 2,020 women with unilateral breast cancer were included in this analysis, which comprised 978 index patients and 1,042 relatives. Medical and pathologic records could be obtained from 81% of the index patients and from 45% of the relatives. For all other individuals, anamnestic information was obtained by a structured interview. Index patients had a considerably higher risk for contralateral breast cancer than their relatives (Fig 1), which reflected the positive selection of the index patients on the basis of clinical criteria. That is, DNA testing was preferentially performed in those patients with clinical phenotypes that were more indicative of a BRCA mutation (eg, younger age of onset, presence of bilateral cancer). Thus, to avoid overestimation of contralateral breast cancer risks, index patients were excluded.
BRCA1- and BRCA2-positive families were analyzed separately. Cumulative risks for developing contralateral breast cancer after the first unilateral breast cancer were calculated by using the Kaplan-Meier product-limit method and were compared between groups by using the log-rank test. Cox proportional hazards regression was used to calculate hazard ratios (HRs) and their 95% CIs. Observations were censored at the time of second unilateral breast cancer, ovarian cancer, bilateral mastectomy, or death, whichever occurred first. The remaining patients without contralateral breast cancer were censored at the time of last observation. All reported P values were two sided. P values less than .05 were considered statistically significant. SPSS 188.8.131.52 (SPSS, Chicago, IL) was used for all data analyses.
A total of 2,020 women with unilateral breast cancer who were members of families with a deleterious mutation in either the BRCA1 or BRCA2 gene were included in this analysis (index patients, n = 978; relatives, n = 1,042). Basic characteristics for index patients and their relatives are listed in Table 1. Patients from families with BRCA1 mutation were younger at first breast cancer than patients from families with BRCA2 mutation. Index patients had a younger median age at first unilateral breast cancer than their relatives.
|Characteristic||Relatives of Index Patients||Index Patients|
|Total No. of patients||1,042||978|
|No. of patients with mutation|
|BRCA1 pathogenic mutation||117||645|
|BRCA2 pathogenic mutation||57||333|
|Not tested, BRCA1 family||558||—|
|Not tested, BRCA2 family||310||—|
|No. of patients with contralateral breast cancer|
|From BRCA1 families||101||197|
|From BRCA2 families||34||49|
|Year of birth|
|From BRCA1 families|
|From BRCA2 families|
|Age at first breast cancer, years|
|From BRCA1 families|
|From BRCA2 families|
Abbreviation: IQR, interquartile range.
In relatives of index patients, 135 contralateral breast cancers were observed. The total observation time from first breast cancer until contralateral breast cancer or censoring was 7,211 person-years. Figure 2A shows the distribution of age at first breast cancer for relatives from families with BRCA1 and BRCA2 mutations. Relatives from families with BRCA1 mutations were significantly younger at their first breast cancers than those from families with BRCA2 mutations (P < .001). Likewise, the age at contralateral breast cancer also was significantly lower in the BRCA1 group compared with the BRCA2 group (Fig 2B; P < .001). The cumulative risk of having contralateral breast cancer up to the age of 75 years was 30.4% (95% CI, 23.9% to 36.9%) in the BRCA1 group and was 20.1% (95% CI, 12.1% to 28.1%) in the BRCA2 group. If the time difference between first and contralateral breast cancer was analyzed, the contralateral breast cancer risk was still higher in women from families with BRCA1 mutations than from families with BRCA2 mutations (Fig 2C; P = .02), and the HR was 1.58 (95% CI, 1.07 to 2.33). The 10-year cumulative risks of contralateral breast cancer after first breast cancer were 18.5% (95% CI, 14.2% to 22.8%) and 13.2% (95% CI, 7.9% to 18.5%) for relatives from families with BRCA1 and BRCA2 mutations, respectively (Table 2). Twenty-five years after the first breast cancer, the contralateral breast cancer risks reached 48.1% (95% CI, 38.3% to 57.9%) and 47.1% (95% CI, 28.9% to 65.3%) for the BRCA1 and BRCA2 groups, respectively. Importantly, there was no indication that contralateral breast cancer risk levels off within 25 years after first breast cancer.
|Evaluation Time After First Breast Cancer According to Age||Risk by Mutation Group|
|BRCA1 (n = 675) ||BRCA2 (n = 367) ||Total (N = 1,042)|
|Cumulative Risk||95% CI||Cumulative Risk||95% CI||Cumulative Risk||95% CI|
|Age at first breast cancer, years|
|< 40||n = 282||n = 97||n = 379|
|5 years||14.2||9.1 to 19.3||3.8||0.0 to 8.9||11.7||7.6 to 15.8|
|10 years||30.7||22.7 to 38.7||20.7||6.4 to 35.0||28.3||21.2 to 35.4|
|15 years||42.6||32.4 to 52.8||20.7||6.4 to 35.0||37.8||29.0 to 46.6|
|25 years||62.9||50.4 to 75.4||63.0||32.8 to 93.2||62.5||50.5 to 74.5|
|40-50||n = 216||n = 122||n = 338|
|5 years||7.3||3.0 to 11.6||7.9||2.2 to 13.6||7.5||4.2 to 10.8|
|10 years||10.6||5.1 to 16.1||12.8||5.2 to 20.4||11.5||7.0 to 16.0|
|15 years||17.7||9.3 to 26.1||18.9||8.1 to 29.7||18.2||11.5 to 24.9|
|25 years||43.7||24.9 to 62.5||48.8||22.7 to 74.9||45.4||30.1 to 60.7|
|> 50||n = 177||n = 148||n = 325|
|5 years||7.9||2.8 to 13.0||3.1||0.0 to 6.6||5.5||2.4 to 8.6|
|10 years||7.9||2.8 to 13.0||9.2||1.8 to 16.6||8.4||4.1 to 12.7|
|15 years||13.4||4.6 to 22.2||16.7||1.0 to 32.4||14.5||6.5 to 22.5|
|25 years||19.6||5.3 to 33.9||16.7||1.0 to 32.4||19.5||7.3 to 31.7|
|5 years||10.3||7.4 to 13.2||4.9||2.2 to 7.6||8.4||6.2 to 10.6|
|10 years||18.5||14.2 to 22.8||13.2||7.9 to 18.5||16.6||13.3 to 19.9|
|15 years||27.3||21.4 to 33.2||17.7||10.4 to 25.0||24.0||19.5 to 28.5|
|25 years||48.1||38.3 to 57.9||47.1||28.9 to 65.3||47.4||38.8 to 56.0|
For patients from BRCA1 families, contralateral breast cancer risk was significantly associated with age at first breast cancer. Patients who were younger at their first breast cancer had a higher risk for contralateral breast cancer (Fig 3A; P < .001). After 25 years, patients from BRCA1 families with age at first breast cancer younger than 40 years developed contralateral breast cancer in 62.9% (95% CI, 50.4% to 75.4%) compared with 43.7% (95% CI, 24.9% to 62.5%) and 19.6% (95% CI, 5.3% to 33.9%) of those whose first breast cancer occurred between 41 and 50 years of age or at age older than 50 years, respectively. For patients from BRCA2 families, contralateral breast cancer risk also was lower in patients who were older at their first unilateral breast cancers, although this difference was not statistically significant (Fig 3B; P = .223). Table 2 shows cumulative, contralateral breast cancer risk estimates for 5, 10, 15, and 25 years after first breast cancer depending on the affected BRCA gene and age at first breast cancer.
Ipsilateral breast cancer before contralateral breast cancer or last observation occurred in 42 patients. The cumulative risks of ipsilateral breast cancer were 4.1% (95% CI, 2.7% to 5.5%) after 5 years and 6.2% (95% CI, 4.0% to 8.4%) after 10 years. The mode of surgery of the first breast cancer (ie, breast-conserving surgery v mastectomy) could not be taken into account, because this information was largely not available. However, ipsilateral breast cancer risks were considerably lower than the corresponding cumulative risks of contralateral breast cancer after 5 years (ie, 8.4%; 95% CI, 6.2% to 10.6%) and 10 years (ie, 16.6%; 95% CI, 13.3% to 19.9%). There were no significant differences in ipsilateral breast cancer risks between families with BRCA1 and BRCA2 mutations (P = .357).
This study aimed to estimate the risk for contralateral breast cancer in members of BRCA1- and BRCA2-positive families. These estimates of the risk of contralateral breast cancer in members of families with BRCA1 and BRCA2 mutations are lower than previously reported. We excluded index patients from the analysis, because they had been selected by early age of onset or presence of bilateral breast cancer and, thus, caused a strong ascertainment bias in analysis of contralateral breast cancer risk. In relatives, the 10-year cumulative risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers was 16.6% (95% CI, 13.3% to 19.9%). Metcalfe et al5 estimated the 10-year contralateral breast cancer risk to be higher, at 29.5% (95% CI, 20.6% to 38.3%), for mutation carriers in a cohort of 491 patients. Also, Pierce et al4 estimated the 10-year contralateral breast cancer rate in the same range, at 26.0% (95% CI, 22.0% to 30.0%), in a cohort of 71 BRCA1 and BRCA2 carriers. Although most studies analyzed solely index patients, Metcalfe et al5 included affected family members as well.3,4 However, the family members accounted for only 154 of the 491 occurrences, which might explain why the results of these studies are similar. As the mean age at first breast cancer was similar in our cohort (ie, 43.4 years) and the cohort of Metcalfe (ie, 42.1 years), age distribution does not explain the observed difference. Only Pierce et al4 reported a follow-up time of 15 years, after which they observed a contralateral breast cancer risk of 39% (95% CI, 31.0% to 47.0%) compared with only 24% (95% CI, 19.5% to 28.5%) in our cohort. Our observation period comprised 25 years, at which time the contralateral breast cancer risk reached 47.4% (95% CI, 38.8% to 56.0%). Although there is an increasing uncertainty of the point estimates with increasing observation time, our data indicate that contralateral breast cancer risk is relevant even a long time after diagnosis of first breast cancer.
To our knowledge, this study is the first to show that patients from families with BRCA1 mutations face a significantly higher contralateral breast cancer risk compared with patients from families with BRCA2 mutations. This was already suggested by Metcalfe et al,5 who reported a higher risk for BRCA1 than BRCA2 mutation carriers, although this difference was not statistically significant. They estimated the 10-year contralateral breast cancer risks at 32.0% for BRCA1 mutation carriers and 24.5% for BRCA2 mutation carriers in a cohort of 491 patients. Other studies did not reveal differences, probably because of their small sample sizes.3,11
Importantly, our study revealed that patients from families with BRCA1 mutations who had higher ages at first breast cancer onset had lower risks for contralateral breast cancer. Among women with breast cancer diagnosed after age 40 years, the risk was lower than reported from other studies, although it was still high for women diagnosed before they were 40 years of age. We could not detect such an association for members of families with BRCA2 mutations because of the lower sample size, although a certain trend could be observed (Fig 2B). In line with our results, Verhoog et al9 reported a significantly lower risk of contralateral breast cancer in 40 BRCA1 mutation carriers who contracted first breast cancer at age 50 years or older versus 124 patients who contracted first breast cancer at younger than 50 years of age. Although Robson et al12 observed no age-dependent effect in a small cohort of 62 BRCA1 carriers and 25 BRCA2 carriers, Metcalfe et al5 described a trend for a lower risk of contralateral breast cancer in 336 BRCA carriers diagnosed after age 50 years. As the subgroups were rather small, no stratification of the affected gene was performed. One might speculate that the association between contralateral breast cancer risk and age at first breast cancer is an artifact caused by differences in the distribution of censoring events among the three age groups. However, we could not find evidence for such a biased censoring process in our data. Moreover, patients who had earlier ages at their first breast cancers were likely to be at higher cancer risks than patients who had later ages of onset. Therefore, it seems plausible that contralateral breast cancer also manifests itself earlier in this group.
The risk of ipsilateral breast cancer was low in our study cohort. Two other case-control studies reported significantly higher rates of ipsilateral breast cancer in BRCA1/2 mutation carriers compared with sporadic controls.13,14 However, both studies included fewer than 30 mutation carriers. Our data are supported by Robson et al,3 who did not find an increased risk of ipsilateral breast cancer in 87 BRCA1/2 mutation carriers when compared with women who had sporadic breast cancer. They provided evidence for a protective effect of adjuvant radiation therapy. This finding was supported additionally by Metcalfe et al,5 who demonstrated a significant ipsilateral breast cancer risk reduction in patients receiving radiation therapy compared with those who were not receiving radiation therapy. We censored at ipsilateral breast cancer to take into account the possibility that adjuvant therapy, especially antihormonal therapy, could also have an effect on contralateral breast cancer risk by eradicating early lesions or by preventing new lesions in the contralateral breast. Indeed, Metcalfe et al5 provided evidence of risk reduction for contralateral breast cancer by oophorectomy and by tamoxifen; the former was significant in univariate and multivariate analysis, and the latter was significant in univariate analysis only.
Some limitations have to be considered in this study. First, we can not rule out that phenocopies might be included in our analysis, because only 17% of the relatives were proven mutation carriers, and because other relatives were not tested. Patients who were diagnosed at late ages were more likely to have sporadic disease than patients who had younger ages at diagnoses. Because women with sporadic cancer have a low risk for contralateral cancer, this age-dependent imbalance in the proportion of sporadic cancers may contribute to some extent to the age effect observed in our analysis. However, the proportion of cancers observed after age 60 years was only 4.4%, which indicated that the potential influence should be small. Moreover, in only 4.5% of the tested relatives, a mutation was excluded. This is in agreement with Meijers-Heijboer et al15 who calculated a phenocopy rate of 5% to 6%, which should not derogate our results. Second, to avoid a survivorship bias, we excluded index patients and only considered affected relatives, including deceased patients. This procedure is supported by Brekelmans et al11,16 and Tilanus-Linthorst et al,17 who provided convincing evidence that index patients undergoing genetic testing for more than 2 years after initial breast cancer diagnosis account for a significant longevity bias in BRCA1/2-positive as well as BRCA1/2-negative, high-risk families. Third, this is a retrospective analysis that needs confirmation from prospective data. A prospective, breast cancer–surveillance study currently is underway in our consortium, and this study may be used for validation purposes. Because of the retrospective approach, medical records could only be obtained from 45% of the patients. This potentially could have led to an incomplete ascertainment of contralateral breast cancer in relatives because of incomplete reporting.
In conclusion, patients from high-risk families increasingly are seeking genetic counseling and testing before or at the time of breast cancer diagnosis to decide on treatment modalities. This trend is being promoted additionally by the expansion of neoadjuvant treatment regimes, which allow sufficient time for genetic testing, and by the availability of intensive surveillance programs, which result in diagnosis of early-stage breast cancer with favorable prognosis. Therefore, more accurate measures of contralateral breast cancer risk are needed to allow patients more individualized, informed decision making on the extension of surgical treatment. The estimated absolute risks are considerably lower than in other studies, which may be of particular clinical relevance for women trying to decide whether to undergo contralateral prophylactic mastectomy at the time of breast cancer diagnosis.
Our retrospective study provides such risk estimates in the largest cohort reported so far. While data from prospective studies are lacking, we consider these risk estimates an appropriate approximation of the true risks for contralateral breast cancer during up to 20 years of follow-up.
See accompanying editorial on page 5862
Written on behalf of the German Consortium for Hereditary Breast and Ovarian Cancer.
Supported by the German Cancer Aid (Deutsche Krebshilfe) Grant No. 107054.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
The author(s) indicated no potential conflicts of interest.
Conception and design: Monika K. Graeser, Christoph Engel, Rita Schmutzler
Provision of study materials or patients: Rita K. Schmutzler
Collection and assembly of data: Christoph Engel
Data analysis and interpretation: Christoph Engel, Markus Loeffler
Manuscript writing: Monika K. Graeser, Christoph Engel, Rita Schmutzler
Final approval of manuscript: Monika K. Graeser, Christoph Engel, Kerstin Rhiem, Dorothea Gadzicki, Ulrich Bick, Karin Kast, Ursula G. Froster, Bettina Schlehe, Astrid Bechtold, Norbert Arnold, Sabine Preisler-Adams, Carolin Nestle-Kraemling, Mohammad Zaino, Marion Kiechle, Alfons Meindl, Dominic Varga, Rita K. Schmutzler
|1.||D Ford, DF Easton, M Stratton , etal: Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families: The Breast Cancer Linkage Consortium Am J Hum Genet 62: 676– 689,1998 Crossref, Medline, Google Scholar|
|2.||A Antoniou, PD Pharoah, S Narod , etal: Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: A combined analysis of 22 studies Am J Hum Genet 72: 1117– 1130,2003 Crossref, Medline, Google Scholar|
|3.||ME Robson, PO Chappuis, J Satagopan , etal: A combined analysis of outcome following breast cancer: Differences in survival based on BRCA1/BRCA2 mutation status and administration of adjuvant treatment Breast Cancer Res 6: R8– R17,2004 Crossref, Medline, Google Scholar|
|4.||LJ Pierce, AM Levin, TR Rebbeck , etal: Ten-year multi-institutional results of breast-conserving surgery and radiotherapy in BRCA1/2-associated stage I/II breast cancer J Clin Oncol 24: 2437– 2443,2006 Link, Google Scholar|
|5.||K Metcalfe, HT Lynch, P Ghadirian , etal: Contra-lateral breast cancer in BRCA1 and BRCA2 mutation carriers J Clin Oncol 22: 2328– 2335,2004 Link, Google Scholar|
|6.||KA Metcalfe, J Lubinski, P Ghadirian , etal: Predictors of contra-lateral prophylactic mastectomy in women with a BRCA1 or BRCA2 mutation: The Hereditary Breast Cancer Clinical Study Group J Clin Oncol 26: 1093– 1097,2008 Link, Google Scholar|
|7.||MC King, JH Marks, JB Mandell: Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2 Science 302: 643– 646,2003 Crossref, Medline, Google Scholar|
|8.||AC Antoniou, AB Spurdle, OM Sinilnikova , etal: Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers Am J Hum Genet 82: 937– 948,2008 Crossref, Medline, Google Scholar|
|9.||LC Verhoog, CT Brekelmans, C Seynaeve , etal: Contra-lateral breast cancer risk is influenced by the age at onset in BRCA1-associated breast cancer Br J Cancer 83: 384– 386,2000 Crossref, Medline, Google Scholar|
|10.||A Meindl: Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population Int J Cancer 97: 472– 480,2002 Crossref, Medline, Google Scholar|
|11.||CT Brekelmans, MM Tilanus-Linthorst, C Seynaeve , etal: Tumour characteristics, survival and prognostic factors of hereditary breast cancer from BRCA2-, BRCA1- and non-BRCA1/2 families as compared to sporadic breast cancer cases Eur J Cancer 43: 867– 876,2007 Crossref, Medline, Google Scholar|
|12.||M Robson, T Svahn, B McCormick , etal: Appropriateness of breast-conserving treatment of breast carcinoma in women with germline mutations in BRCA1 or BRCA2: A clinic-based series Cancer 103: 44– 51,2005 Crossref, Medline, Google Scholar|
|13.||BG Haffty, E Harrold, AJ Khan , etal: Outcome of conservatively managed early-onset breast cancer by BRCA1/2 status Lancet 359: 1471– 1477,2002 Crossref, Medline, Google Scholar|
|14.||C Seynaeve, LC Verhoog, LM van de Bosch , etal: Ipsilateral breast tumour recurrence in hereditary breast cancer following breast-conserving therapy Eur J Cancer 40: 1150– 1158,2004 Crossref, Medline, Google Scholar|
|15.||H Meijers-Heijboer, CT Brekelmans, M Menke-Pluymers , etal: 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 21: 1675– 1681,2003 Link, Google Scholar|
|16.||CT Brekelmans, C Seynaeve, M Menke-Pluymers , etal: Survival and prognostic factors in BRCA1-associated breast cancer Ann Oncol 17: 391– 400,2006 Crossref, Medline, Google Scholar|
|17.||MM Tilanus-Linthorst, KC Bartels, C Alves , etal: Selection bias influences reported contra-lateral breast cancer incidence and survival in high risk non-BRCA1/2 patients Breast Cancer Res Treat 95: 117– 123,2006 Crossref, Medline, Google Scholar|
We thank the following medical data assistants for their competence in meticulously maintaining and updating the database: Melanie Bednarski, Berlin; Claudia Jung-Hildebrand, Dresden; Edith Nothof, Düsseldorf; Kirsten Mischke, Hannover; Ursula Major, Heidelberg; Manuela Arnold, Kiel; Petra Wihler, Köln; Claudia Fischer and Ute Enders, Leipzig; Manuela Jähnig, München; Ariane König, München; Anne Sturm and Yvonne Böckenfeld, Münster; Ute Zemmler, Ulm; and Katharina Höhn, Würzburg. In memoriam of Iris Mallmann, a BRCA1 mutation carrier who never gave up her zest for life.