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Annals of Oncology Advance Access originally published online on December 1, 2005
Annals of Oncology 2006 17(3):391-400; doi:10.1093/annonc/mdj095
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© 2005 European Society for Medical Oncology

Survival and prognostic factors in BRCA1-associated breast cancer

C. T. M. Brekelmans1,*, C. Seynaeve1, M. Menke-Pluymers2, H. T. Brüggenwirth3, M. M. A. Tilanus-Linthorst2, C. C. M. Bartels2, M. Kriege1, A. N. van Geel2, C. M. G. Crepin1, J. C. Blom1, H. Meijers-Heijboer3 and J. G. M. Klijn1

1 Department of Medical Oncology, 2 Department of Surgical Oncology and 3 Department of Clinical Genetics, Family Cancer Clinic, Erasmus MC – Daniel den Hoed Cancer Center, Rotterdam, The Netherlands

* Correspondence to: Dr C. T. M. Brekelmans, Department of Medical Oncology, Erasmus MC – Daniel den Hoed Cancer Center, PO Box 5201, 3008 AE Rotterdam, The Netherlands. Tel: +31-104391633; Fax: +31-104391003; E-mail: c.brekelmans{at}erasmusmc.nl.


   Abstract
Top
 Abstract
introduction
 patients and methods
 results
 discussion
 References
 
Background: Studies comparing survival in BRCA1-associated and sporadic breast cancer (BC) report inconsistent results and frequently concern small sample sizes. Further, the prognostic impact of the classical tumour and treatment factors is unclear in BRCA1-associated BC.

Patients and methods: We selected 223 BC patients diagnosed between 1980 and 2001 within families with a deleterious germline BRCA1-mutation ascertained at the Rotterdam Family Cancer Clinic. To correct for ascertainment bias, the group of index patients undergoing DNA testing more than 2 years after BC diagnosis (n = 53) was separated from the other BRCA1-patients (n = 170). All BRCA1-associated patients were matched in a 1:2 ratio for age and year of diagnosis to sporadic BC patients. We compared the occurrence of ipsi- and contralateral BC (CBC) as well as distant disease-free (DDFS), BC-specific (BCSS) and overall survival (OS). By multivariate modelling, the prognostic impact of tumour and treatment factors was investigated separately in BRCA1-associated and sporadic breast cancers.

Results: For the total group of 669 cases, the median follow-up was 5.1 years, the median age at diagnosis 39 years. We confirmed the existence of the typical BRCA1-associated tumour type and the high CBC incidence. No significant differences between BRCA1-associated and sporadic tumours were found with respect to ipsilateral BC recurrence (HRmult 0.7; P = 0.24), DDFS (HRmult 1.2; P = 0.37) or BC-specific survival (HRmult 1.3; P = 0.23). A trend towards a worse survival was found for BRCA1-associated ductal BC (HRmult 1.5, P = 0.07). Prognostic factors for BRCA1-associated BC were age at diagnosis, tumour size and morphology, and nodal status. Further, survival was non-significantly improved by systemic treatment and a bilateral salpingo-oophorectomy. No effect on survival of a contralateral prophylactic mastectomy was seen.

Conclusions: BRCA1-associated BC is characterised by specific tumour characteristics, a high incidence of CBC and a trend towards a worse survival for the ductal tumour type. Our observation that tumour size and nodal status are also prognostic factors for BRCA1-associated BC implies that the strategy to use these factors as a proxy for ultimate mortality, for instance in BC screening programmes or the consideration of (contralateral) preventive mastectomy, appears to be valid in this specific group of patients.

Key words: BRCA1, hereditary, breast cancer, survival, prognostic factors, histopathology


   introduction
Top
 Abstract
 introduction
patients and methods
 results
 discussion
 References
 
In 1998, we published our initial study into the tumour characteristics and survival of 49 BRCA1-associated and 196 sporadic breast cancer patients [1Go]. Since then, many other studies described the clinical course of BRCA1-associated breast cancer (BC). The typical tumour characteristics of BRCA1-breast cancer are now well known, being a high frequency of the medullary tumour type, a high histological grade and a basal-like phenotype, characterised by ER- and HER2neu-negativity and the expression of basal cytokeratins, such as 5, 6 and 14 [2Go, 3Go]. As many of these tumour characteristics ultimately have an adverse prognostic impact, one might expect a worse survival. However, results with respect to survival in BRCA1-associated BC are inconsistent, with some studies reporting a worse, others an identical survival as compared to age-matched patients with sporadic breast cancer. One of the explanations for this apparent discrepancy is the selection of BRCA1-associated breast cancer patients. Most family-based studies include cases that were tested themselves for germline mutations in BRCA1, and so were alive at the moment of DNA testing, being often many years after the diagnosis of breast cancer. This so-called longevity selection, a form of ascertainment bias, is avoided in population-based studies, where archived tumour material of unselected, incident breast cancer patients is tested for the germline mutation. However, also in the latter type of study, results are inconsistent. While some studies showed a significantly worse survival as compared to sporadic cases [4Go, 5Go], others found a similar or an initially worse survival that became non-significant after multivariate analysis [6Go–8Go].

Apart from selection of patients, studies differ with respect to the degree of correction for confounding factors. Frequently, uncorrected results are presented or only corrected for age, period of diagnosis and, less frequently, tumour stage. Only few authors adjust for or present separate results with respect to other factors, such as the administration of systemic treatment. At least two clinical studies suggest that BRCA1 status is an independent (adverse) prognostic factor only in the subgroup not treated with adjuvant chemotherapy [5Go, 9Go] while another study described an adverse impact of a BRCA1-germline mutation in node-negative patients only [10Go].

To date, the impact on survival of the classical prognostic factors, such as tumour size and nodal status, has not been investigated separately in BRCA1-associated tumours. However, there are indications that this impact might differ as compared to sporadic cases. For instance, Foulkes et al. described the absence of the well-known relation between tumour size and nodal status in BRCA1-associated breast cancer [11Go]. This might imply that, in contrast to sporadic breast cancer, tumour stage does not adequately predict the clinical outcome of BRCA1-associated breast cancer. This has important implications, for instance because tumour stage is used to predict the mortality reduction in breast cancer screening programmes, also in genetically susceptible women.

Therefore, in this study, we assessed the survival of BRCA1-related breast cancer while taking account of the various factors that might influence this survival, such as patient and tumour characteristics and treatment factors. The large number of patients in the current series made it possible to perform subgroup analyses and to investigate whether the prognostic impact of tumour and treatment factors differs between BRCA1-related and sporadic breast cancer patients.


   patients and methods
Top
 Abstract
 introduction
 patients and methods
results
 discussion
 References
 
Included were all female patients with primary, invasive BC and available data on histopathology and follow-up that were diagnosed between 1 January 1980 and 1 January 2001 within a family with an identified deleterious BRCA1-mutation. This selection included thus proven BRCA1-mutation carriers as well as breast cancer cases with unknown BRCA-status within these families. The group was divided into two subgroups: (1) index patients undergoing DNA testing more than 2 years after their BC diagnosis, hereafter called the ‘late-tested index group’ and (2) all other BRCA1-associated breast cancer patients, hereafter called the ‘unselected group’. To investigate the distorting influence of including the remaining index patients in the BRCA1-unselected group, extra analyses were performed leaving out all index patients.

For all families, DNA testing was performed at the Clinical Genetics Department of the Erasmus MC, Rotterdam. The coding parts and exon-flanking intronic regions of the BRCA1 gene (exon 3, 5–10, part of exon 11, and exon 12–23) were screened for the presence of mutations using denaturing gradient gel electrophoresis (DGGE). All aberrant fragments were sequenced; exons 2 and 24 were directly sequenced. Presence of mutations in exon 11 were detected with the protein truncation test (PTT) [12Go]. Additionally, multiplex ligation-dependent probe amplification (MLPA) was performed for detection of large genomic deletions and duplications [13Go].

Each BRCA1-patient was individually matched for age and year of diagnosis (within 5 years) to two cases with sporadic breast cancer, selected from the Erasmus MC – Daniel den Hoed cancer registry. All medical files of potential control patients were checked to exclude a family history suggestive of hereditary breast cancer. Excluded were control patients with at least two additional family members with breast cancer, or one additional family member with breast cancer under age 55 or ovarian cancer (any age). By the matching for age and year of diagnosis we ensured a comparable treatment and follow-up scheme (type and frequency) for the BRCA1 and sporadic group.

The following patient and tumour characteristics were extracted from the medical files: age at diagnosis, axillary lymph node status (negative, positive (1–3 or ≥4 positive nodes) and unknown), tumour diameter, presence of distant metastases at diagnosis, morphology of the tumour, histologic grade (Bloom-Richardson), ER- and PR-status, surgical and adjuvant systemic treatment (hormonal and/or chemotherapy). Further, it was registered if and when women underwent prophylactic contralateral mastectomy and a bilateral (salpingo-) oophorectomy (B(S)O). Further, the reason of the B(S)O was noted (prophylactic, for benign reasons or as treatment for breast or ovarian cancer).

Information on the complete family pedigree, dates of DNA testing/diagnosis and the type of germline mutation were gathered from the department of Clinical Genetics. Endpoints of interest were the occurrence of an ipsilateral recurrence (ILR) after breast-conserving therapy (BCT), contralateral breast cancer (CBC), distant metastases (DM), death (overall or breast-cancer related), loss to follow-up or end of study period (1 July 2004), whichever occurred first.

First, Kaplan–Meier survival curves were constructed for both groups of BRCA1-associated and sporadic breast cancers. Differences between the curves were tested by the log rank test. Second, the influence of traditional prognostic factors on the selected endpoints was examined by the Cox proportional hazard method. The model included all potential confounders, in this case factors associated with the endpoint of interest that differed (P < 0.15) between BRCA1 and sporadic cases. Separate analyses were performed with respect to nodal status (negative and positive), and the administration of adjuvant chemotherapy (yes or no).

The prognostic impact of tumour stage and other variables, including treatment factors, was analyzed separately for BRCA1-related and sporadic breast cancer patients. To investigate the presence of interaction between genetic status and the various tumour and treatment factors, likelihood ratios of models with and without the potential interaction factor were compared and tested by the likelihood ratio test.

All statistical analyses were performed with STATA SE version 8.2.


   results
Top
 Abstract
 introduction
 patients and methods
 results
discussion
 References
 
For this study, 223 breast cancer patients from 149 families with a deleterious BRCA1-germline mutation were selected. The BRCA1-late-tested index group consisted of 53 index patients undergoing DNA testing more than 2 years after their BC diagnosis, the BRCA1-unselected group of the remaining 170 BC patients: 43 index patients affected with breast cancer after or less than 2 years before DNA-testing, 27 patients that were not tested themselves for the deleterious BRCA1-mutation (including 11 obligate carriers) and 100 patients who were tested but not as the first in their family. These cases were matched for age and year of diagnosis to 446 breast cancer cases without a relevant family history (‘sporadic cases’). For the total group of 669 cases, the median follow-up was 5.1 years (range 0.1–21.9 years), the median age at diagnosis 39 (23–82) years.

In Table 1, patient and tumour characteristics are presented for the two groups of BRCA1-related and sporadic breast cancer patients. As expected, tumours in BRCA1-mutation carriers were more often of the medullary type, histologic grade III, and estrogen- and progesterone-receptor negative. Further, lymph node status of both groups of BRCA1-related BC patients was significantly more often negative as compared to sporadic cases. The incidence of contralateral breast cancer and ovarian cancer was significantly increased, whereas no increased incidence of other cancers was found for BRCA1-associated as compared to sporadic cases.


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  		Table 1. Tumour and treatment characteristics of BRCA1-associated and sporadic breast cancers

 
In Table 2, tumour characteristics for BRCA1- and sporadic cases are presented separately for estrogen (ER) receptor-negative and -positive tumours. The higher frequency of grade III-tumours and node-negativity of the BRCA1-associated cases was only visible in the ER-negative subgroup. On the other hand, the higher frequency of the medullary tumour type in BRCA1-associated cases was most outspoken in the ER-positive subgroup (P = 0.001).


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  		Table 2. Tumour stage, morphology and histologic grade of BRCA1-associated and sporadic breast cancers, seperately for estrogen-receptor-negative and -positive tumours

 
The association between tumour size and lymph node status is shown in Figure 1, separately for the BRCA1-unselected and sporadic group. A clear correlation was found for both groups, with a correlation coefficient of 0.33 (P < 0.001) for sporadic and 0.32 (P < 0.001) for BRCA1-unselected cases, respectively. In the BRCA1-late-tested index subgroup no correlation between tumour size and number of positive nodes was found (correlation coefficient –0.08; P = 0.62).


Figure 1
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  		Figure 1. Correlation between tumour size and number of positive lymph nodes, separately for sporadic BC patients (R2 = 0.32) and the BRCA1-unselected group (R2 = 0.33). CI, confidence interval.

 
In Figure 2a–d and Table 3, survival curves and actuarial 5- and 10-year estimates with uni- and multivariate hazard ratios for the endpoints of interest are shown for BRCA1-associated and sporadic breast cancer. All hazard ratios compare the BRCA1-unselected group to sporadic breast cancer patients. In addition to genetic status (BRCA1 versus sporadic), factors included in the multivariate analyses (referred to as HRmult) were tumour stage, administration of adjuvant systemic therapy, tumour morphology, histologic grade, ER-status and B(S)O. These prognostic factors were selected for the current model because a significant difference was found between BRCA1-unselected and sporadic cases (Table 1).


Figure 2
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  		Figure 2. Local recurrence rate (a), incidence of contralateral BC (b), distant disease-free survival (c) and BC-specific survival (d) of BRCA1-associated versus sporadic BC. —— sporadic BC; – – – BRCA1-unselected group; – · – · – BRCA1-late-tested index group. The logrank test in the graph tests the difference between all three groups.

 

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  		Table 3. Actuarial event and survival rates, hazard ratios (HR) and 95% confidence intervals (CI) for five endpoints

 
With respect to the ipsilateral recurrence rate, uni- nor multivariate analyses showed significant differences between the BRCA1-unselected and sporadic group.

The incidence of contralateral breast cancer was significantly higher in both groups of BRCA1-associated breast cancer, with a univariate hazard ratio of the BRCA1-unselected versus the sporadic group of 4.98 (P < 0.001). These results remained essentially the same after correction for the above-mentioned factors.

Univariately, DDFS was significantly more favourable in the BRCA1-unselected as compared to the sporadic group (HR 0.71; P = 0.03). This difference disappeared in the multivariate model (HRmult 1.19; P = 0.37).

For BC-specific survival, no univariate differences were seen between the BRCA1-unselected and sporadic cases (HR 0.89; P = 0.94). After correction for the abovementioned factors, the survival for BRCA1-unselected patients became non-significantly worse (HRmult 1.29; P = 0.23). Tumour stage and morphology, the administration of adjuvant systemic treatment, and ER-negativity all were significant prognostic factors for DDFS and BC-specific survival.

Results remained essentially the same after exclusion of all BRCA1-associated index patients (HRmult 1.31; P = 0.22). Results with overall instead of breast-cancer related survival as endpoint showed a trend towards a worse survival (HRmult 1.47; P = 0.06). The slight difference between BC-specific and overall survival most likely was due to the increased risk of ovarian cancer death in BRCA1-mutation carriers: of the 18 BRCA1-patients (11 from the late-tested index and seven from the unselected group) with ovarian/peritoneal cancer as a second (or third) primary tumour, seven (three from the late-tested index and four from the unselected group) died of the disease during the follow-up of this study.

subgroup analyses (breast-cancer specific survival)
Results with respect to BC-specific survival did not differ when separate uni- and multivariate analyses were performed for node-positive and -negative tumours (HRmult for the BRCA1-unselected versus the sporadic group 1.08 (P = 0.83) for node-negative cases, and 1.43 (P = 0.22) for node-positive cases, respectively).

When we performed analyses separately for patients treated with and without chemotherapy, a tendency was seen towards a better survival for BRCA1-unselected as compared to sporadic patients treated with chemotherapy (HR 0.65; P = 0.12), whereas no different survival was seen between the BRCA1-unselected and sporadic group in patients not receiving adjuvant chemotherapy (HR 1.07; P = 0.76). However, this difference disappeared in the multivariate analyses: the HR for BRCA1-unselected as compared to sporadic patients was 1.39 (P = 0.28) for patients treated with chemotherapy, and 1.04 (P = 0.89) for patients not treated with chemotherapy, respectively.

Further, we performed subgroup analyses for the ductal tumour type only, thus leaving out the special histologic subtypes. A trend towards a worse survival was seen for ductal cancers from the BRCA1-unselected versus the sporadic group (HRmult 1.46, P = 0.07).

In Table 4, uni- and multivariate hazard ratios with respect to breast-cancer specific survival are presented for several prognostic factors, separately for the BRCA1-unselected and sporadic BC groups. As only 13 patients from the BRCA1-unselected group were treated with hormonal therapy, the effect of this factor could not be separately investigated in this subgroup.


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  		Table 4. Prognostic factors for breast-cancer specific survival, separately for the BRCA1-unselected and sporadic group

 
Age at diagnosis, tumour size and nodal status appeared to be prognostic factors in both groups. However, while for sporadic cases a clear trend was seen with increasing number of positive nodes, for BRCA1-patients no significant adverse effect was seen in patients with less than four positive lymph nodes. The administration of chemotherapy (HR 0.36, P = 0.06) and a bilateral (salpingo-)oophorectomy (HR 0.38; P = 0.21) had a non-significantly favourable effect on survival in BRCA1-cases. A contralateral prophylactic mastectomy had no apparent influence on survival.

None of the formal tests for interaction between genetic status (BRCA1-unselected or sporadic) and the various tumour/treatment factors were significant (not shown).


   discussion
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
References
 
In the present paper, we updated and extended our previous publication about tumour characteristics and survival of 49 BRCA1-associated and 196 sporadic breast cancer cases [1Go]. In that paper we found no differences in survival, while a non-significant trend towards a worse survival in BRCA1-associated as compared to sporadic patients was found when excluding the index patients.

To our knowledge, the current update is with 223 BRCA1-associated cases and 446 sporadic BC cases the largest series worldwide from a single family cancer center. With these numbers we were able to detect a difference in 5-year BCSS between BRCA1-associated and sporadic cases of 15%.

We again confirmed the existence of the typical BRCA1-associated tumour type with a high frequency of grade III cancers, a medullary tumour type, and ER/PR-negativity [2Go, 14Go]. Further, BRCA1-associated tumours were more often node negative, a phenomenon already observed by others [11Go, 15Go]. In our series, this might be partly explained by the higher number of tumours in BRCA1-associated patients detected within an (MRI) screening context, especially during the last years [16Go].

The highly increased risk of contralateral breast cancer is in line with our previous results and those of others [1Go, 17Go, 18Go]. The short-term risk of ipsilateral recurrence was not increased. With a median follow-up of 5 years we could not investigate the possible higher risk of late (>5–10 years) ipsilateral recurrences, most likely signifying new primary tumours, that was observed in other studies [19Go, 20Go].

With respect to DDFS and BC-specific survival, we also confirmed our previous results.

Table 5 summarises the experience with respect to studies describing BC-specific or overall survival in BRCA1-associated breast cancer. Only studies describing survival data separately for at least 30 BRCA1-associated cases were selected. Eight of the eleven studies from different centres describe a similar or non-significantly worse survival of patients with BRCA1-associated breast cancer, while four studies found a significantly worse survival. The reasons for this inconsistency have been extensively discussed previously and include small sample sizes, differences in population selection/controlling for longevity bias and confounding factors, or a true biological effect of different germline mutations [14Go, 21Go]. Two of the four studies with a significantly worse survival were performed in unselected populations of Ashkenazi Jewish breast cancer patients [5Go, 9Go]. However, a recent study in this population found no survival difference as compared to sporadic patients [8Go]. While population-based studies circumvent the problem of longevity bias, it is not clear if results from that type of study are applicable to family-based studies. It might be that, identical to penetrance-studies, other genes or environmental factors that cluster within families influence survival in addition to the BRCA1-mutation. Therefore, large family-based studies are still required to estimate survival in families presenting themselves at family cancer clinics.


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  		Table 5. Overview of all studies reporting survival in at least 30 breast cancer cases with a germline mutation in BRCA1

 
Adequate correction for longevity bias is an important aspect of family-based studies, such as ours. Including only tested patients preferentially selects long-living patients. The inclusion of proven BRCA1-carriers as well as patients with unknown BRCA-status is a first step in diminishing this problem. While undoubtedly some phenocopies are included in this way, the amount of dilution is small, as in a previous paper we showed that 95% of tested breast cancer patients in BRCA1-families proved to be carrier of the family-specific germline mutation [22Go]. To further reduce the magnitude of the longevity bias, we separated the index patients undergoing DNA testing more than 2 years after BC diagnosis (the late-tested index group) from the other BRCA1-associated patients. This separation was chosen because the first peak in hazard of recurrence appears at 2 years after BC diagnosis [23Go, 24Go].

For the remaining BRCA1-associated patients, a non-significantly worse BC specific survival was found as compared to the sporadic group. Results remained essentially identical after exclusion of all index patients. One might argue that the exclusion of the index patients, frequently long-surviving women, biases the BRCA1-associated survival towards an unfavourable outcome, and that the unbiased survival of truly unselected BRCA1-patients should lie somewhere between the estimates with and without the index patients. However, it is not possible to simply average the hazard ratios for index and unselected BRCA1-patients, as (nearly) 100% of the index patients but only part of the ‘unselected’ BRCA1-associated patients are included. Even with this bias towards an unfavourable outcome, no significantly worse survival was found for BRCA1-unselected BC in our study.

We did find a trend towards a worse survival when non-ductal tumour types were excluded from the analyses. Most likely this is mainly caused by the exclusion of the medullary tumour type from the group of BRCA1-carriers. It is known that this tumour type has a better survival than the ductal type, and others have already reported that the features of medullary carcinoma, with a favourable prognosis despite unfavourable tumour characteristics such as a high histological grade, a high rate of p53 protein accumulation, are very similar to BRCA1-associated breast cancer [25Go, 26Go].

In our study tumour size as well as nodal status were strong independent prognostic factors, both for BRCA1 and sporadic breast cancer patients (Table 4). This is an important finding, as tumour stage is used as surrogate measure for the prediction of mortality reduction in screening trials, such as the MRISC study [16Go]. Our results indicate that this is a valid approach, also in BRCA1-mutation carriers. The finding that, in contrast to sporadic cases, the prognostic impact of a positive nodal status was only significant for more than four positive nodes might suggest a less strong impact of this factor on prognosis. However, numbers were small in the BRCA1-subgroup of 1–3 positive nodes, and the non-significant HR of 2.1 appears not to be markedly different from the HR of 2.70 for the 1–3 positive nodes category in the sporadic group. Further, we found for both groups a strong and highly significant correlation between tumour size and number of positive nodes (Figure 1), in contrast to Foulkes et al. [11Go]. The complete absence of such a correlation in our BRCA1-late-tested index subgroup might mean that the disruption of the positive correlation in the Foulkes paper could have been partly caused by the inclusion of long-surviving index patients.

Adjuvant chemotherapy was a prognostic factor both in BRCA1-associated and sporadic BC (Table 4). No clear difference between hazard ratios for this factor was found between these groups, while several studies suggest that BRCA1-associated breast cancer might be more chemosensitive than its sporadic counterpart. For instance, Chappuis et al. suggested in a small clinical study that BRCA1-breast cancer better responds to neo-adjuvant chemotherapy than its sporadic counterpart [27Go]. However, it might be that this effect depends on type and duration of chemotherapy. These data are currently being collected for a more extensive investigation of this subject.

The absence of a favourable effect on survival of a contralateral preventive mastectomy is in line with previous findings in BRCA1/2-associated breast cancer patients [28Go, 35Go], Apparently, the prognosis in BRCA1/2-associated BC is largely determined by the characteristics and treatment of the first BC.

We further found that a bilateral (salpingo-)oophorectomy in BRCA1-carriers (non-significantly) improved the BC-specific survival. While the effect was not significant, our study was set up to investigate survival differences between BRCA1 and sporadic patients and not powered to investigate the independent effect of prognostic factors, such as B(S)O, in BRCA1-patients separately. Many patients opted for B(S)O only after the occurrence of the first breast cancer, at a mean age of 47 (range 32–66) years, and therefore the median follow-up after B(S)O was with 3.3 years relatively short. To our knowledge, the effect of a B(S)O on mortality or survival in BRCA1-related BC patients, with a high frequency of ER-negative tumours, has not been assessed before. Longer-term follow-up data from large (retrospective or prospective) cohorts are needed to more definitely assess the effect of B(S)O on survival in BRCA1-associated BC patients.

In conclusion, we confirmed the high incidence of contralateral breast cancer in BRCA1-associated BC. No significant differences between BRCA1-associated and sporadic BC were found with respect to ipsilateral BC recurrence, DDFS and BC-specific survival, while a trend towards a worse survival was found for ductal BRCA1-associated tumours. The classical factors tumour size and nodal status are of prognostic value both for sporadic and BRCA1-associated BC. This implies that, also for BRCA1-associated BC, it is valid to use these factors as a proxy for ultimate mortality, for instance in the evaluation of breast MRI-screening studies, or the counseling of patients considering (contralateral) preventative mastectomy.

The study was supported by grant DDHK 2004–3124 from the Dutch Cancer Society and approved by the local Ethics Committee on July 15, 2004.

Received for publication August 10, 2005. Revision received October 28, 2005. Accepted for publication November 4, 2005.


   References
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 References
 
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