C.T.M. Brekelmans

Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1

BACKGROUND Hereditary breast cancer has been associated with mutations in the BRCA1 and BRCA2 genes and has a natural history different from sporadic breast cancer. We investigated disease-free and overall survival for patients with a proven BRCA1 alteration. METHODS We estimated disease-free and overall survival for 49 Dutch patients from 19 consecutive families with a proven specific BRCA1 mutation and one family with strong evidence for linkage to the BRCA1 gene. We compared clinical outcome and data on tumour size, histology, axillary nodal status, contralateral breast cancer, and oestrogen-receptor and progesterone-receptor status with those of 196 patients with sporadic breast cancer, matched for age and year of diagnosis. FINDINGS Disease-free survival for BRCA1 and sporadic patients at 5 years was 49% (95% CI 33-64) and 51% (43-59), respectively (p=0.98). Overall survival at 5 years was 63% (47-76) and 69% (62-76), respectively (p=0.88). Recurrence and death rates did not differ significantly between groups. Hazard ratios for recurrence and death among BRCA1 patients were 1.00 (0.65-1.55) and 1.04 (0.63-1.71) relative to sporadic patients (p=0.88), and these did not differ significantly after adjustment for prognostic factors. Patients with BRCA1-associated breast cancer had twice as many progesterone-receptor-negative tumours (p<0.005) and development of contralateral breast cancer was four to five times as frequent as in the sporadic group (p<0.001). INTERPRETATION We showed that disease-free and overall survival were similar for sporadic and hereditary breast cancer in the presence of different tumour characteristics, which has implications for screening prophylactic therapy, and different treatments of hereditary breast cancer.

SURVIVAL AND TUMOUR CHARACTERISTICS OF BREAST-CANCER PATIENTS WITH GERMLINE MUTATIONS OF BRCA1

Summary Background Hereditary breast cancer has been associated with mutations in the BRCA1 and BRCA2 genes and has a natural history different from sporadic breast cancer. We investigated disease-free and overall survival for patients with a proven BRCA1 alteration. Methods We estimated disease-free and overall survival for 49 Dutch patients from 19 consecutive families with a proven specific BRCA1 mutation and one family with strong evidence for linkage to the BRCA1 gene. We compared clinical outcome and data on tumour size, histology, axillary nodal status, contralateral breast cancer, and oestrogen-receptor and progesterone-receptor status with those of 196 patients with sporadic breast cancer, matched for age and year of diagnosis. Findings Disease-free survival for BRCA1 and sporadic patients at 5 years was 49% (95% CI 33–64) and 51% (43–59), respectively (p=0·98). Overall survival at 5 years was 63% (47–76) and 69% (62–76), respectively (p=0·88). Recurrence and death rates did not differ significantly between groups. Hazard ratios for recurrence and death among BRCA1 patients were 1·00 (0·65–1·55) and 1·04 (0·63–1·71) relative to sporadic patients (p=0·88), and these did not differ significantly after adjustment for prognostic factors. Patients with BRCA1-associated breast cancer had twice as many progesterone-receptor-negative tumours (p<0·005) and development of contralateral

Effectiveness of Breast Cancer Surveillance in BRCA1/2 Gene Mutation Carriers and Women With High Familial Risk

PURPOSE Women with a high breast cancer risk due to a familial predisposition may choose between preventive surgery and regular surveillance. The effectiveness of surveillance in high-risk women and especially BRCA1/2 mutation carriers is unknown. We present first results from a single large family cancer clinic. PATIENTS AND METHODS Women with breast cancer risk over 15% were examined by physical examination every 6 months and mammography every year. Detection rates and screening parameters were calculated for the total group and separately for different age and genetic risk groups. RESULTS At least one examination was performed in 1,198 women: 449 moderate and 621 high-risk women and 128 BRCA1/2 mutation carriers. Within a median follow-up of 3 years, 35 breast cancers were detected (four ductal carcinoma-in-situ; 31 invasive tumors); the average detection rate was 9.7 per 1,000. Detection rates (95% confidence interval) for moderate and high-risk women and BRCA1/2 carriers were 3.3 (1.1 to 8.6), 8.4 (5.4 to 13.2), and 33 (17 to 63) per 1,000 person-years, respectively. The ratio of observed cases versus breast cancers expected in an average-risk population of comparable age was 2.7, 7.0 and 23.7 respectively. Overall, node negativity was 65%; 34% of primary tumors were less than 10 mm; sensitivity was 74%. Results with respect to tumor stage and sensitivity were less favorable in BRCA1/2 carriers and in women under the age of 40. CONCLUSION It is possible to identify young women at high risk for breast cancer. The number of cancers detected was significantly greater than expected in an age-matched average-risk population and related to the risk category. Overall, screening parameters were comparable to population screening data, with less favorable results in the youngest age group (< 40) and BRCA1/2 carriers.

Presymptomatic DNA testing and prophylactic surgery in families with a BRCA1 or BRCA2 mutation

BACKGROUND Germline mutations in the BRCA1 and BRCA2 genes highly predispose to breast and ovarian cancer. In families with BRCA1 or BRCA2 mutations, identification of mutation carriers is clinically relevant in view of the options for surveillance and prevention. METHODS We assessed presymptomatic DNA testing and prophylactic surgery in 53 consecutive families presenting to the Rotterdam Family Cancer Clinic with a known BRCA1 or BRCA2 mutation. We identified predictors for DNA testing and prophylactic surgery with univariate and multivariate analysis. FINDINGS 682 unaffected individuals with a 50% risk (275 women and 271 men) or with a 25% risk (136 women) for carrying a mutation were identified and offered a DNA test. Presymptomatic DNA testing was requested by 48% (198 of 411) of women and 22% (59 of 271) of men (odds ratio for difference between sexes 3.21 [95% CI 2.27-4.51]; p<0.001). In women, DNA testing was significantly more frequent at young age, in the presence of children, and at high pre-test genetic risk for a mutation. Of the unaffected women with an identified mutation who were eligible for prophylactic surgery, 51% (35 of 68) opted for bilateral mastectomy and 64% (29 of 45) for oophorectomy. Parenthood was a predictor for prophylactic mastectomy but not for prophylactic oophorectomy. Age was significantly associated with prophylactic oophorectomy, but not with prophylactic mastectomy, although there was a tendency towards mastectomy at younger ages. INTERPRETATION In a clinical setting, we show a high demand for BRCA1 and BRCA2 testing by unaffected women at risk, and of prophylactic surgery by unaffected women with the mutation. Young women with children especially opt for DNA testing and prophylactic mastectomy.

No efficacy of annual gynaecological screening in BRCA1/2 mutation carriers; an observational follow-up study

BRCA1/2 mutation carriers are offered gynaecological screening with the intention to reduce mortality by detecting ovarian cancer at an early stage. We examined compliance and efficacy of gynaecological screening in BRCA1/2 mutation carriers. In this multicentre, observational, follow-up study we examined medical record data of a consecutive series of 888 BRCA1/2 mutation carriers who started annual screening with transvaginal ultrasonography and serum CA125 between 1993 and 2005. The women were annually screened for 75% of their total period of follow-up. Compliance decreased with longer follow-up. Five of the 10 incident cancers were interval tumours, diagnosed in women with a normal screening result within 3–10 months before diagnosis. No difference in stage distribution between incident screen-detected and interval tumours was found. Eight of the 10 incident cancers were stage III/IV (80%). Cancers diagnosed in unscreened family members had a similar stage distribution (77% in stage III/IV). The observed number of cases detected during screening was not significantly higher than expected (Standardized Incidence Ratio (SIR): 1.5, 95% confidence interval: 0.7–2.8). For the subgroup that was fully compliant to annual screening, a similar SIR was found (1.6, 95% confidence interval: 0.5–3.6). Despite annual gynaecological screening, a high proportion of ovarian cancers in BRCA1/2 carriers are interval cancers and the large majority of all cancers are diagnosed in advanced stages. Therefore, it is unlikely that annual screening will reduce mortality from ovarian cancer in BRCA1/2 mutation carriers.

Tumour characteristics and prognosis of breast cancer patients carrying the germline CHEK2*1100delC variant

Background: The germline CHEK2*1100delC variant has been associated with breast cancer in multiple case families where involvement of BRCA1 and BRCA2 has been excluded. Methods: We have investigated the tumour characteristics and prognosis of carriers of this germline variant by means of a prospective cohort study in an unselected cohort of 1084 consecutive patients with primary breast cancer. Data were collected for 34 patients with a germline CHEK2*1100delC mutation and for 102 patients without this mutation, stratified by age and date of diagnosis of the first primary breast cancer (within 1 year). Results: Carriers developed steroid receptor positive tumours (oestrogen receptor (ER): 91%; progesterone receptor (PR): 81%) more frequently than non-carriers (ER: 69%; PR: 53%; p = 0.04). Mutation carriers more frequently had a female first or second degree relative with breast cancer (p = 0.03), or had any first or second degree relative with breast or ovarian cancer (p = 0.04). Patients with the CHEK2 variant had a more unfavourable prognosis regarding the occurrence of contralateral breast cancer (relative risk (RR) = 5.74; 95% confidence interval (CI) 1.67 to 19.65), distant metastasis-free survival (RR = 2.81; 95% CI 1.20 to 6.58), and disease-free survival (RR = 3.86; 95% CI 1.91 to 7.78). As yet, no difference with respect to overall survival has been found at a median follow up of 3.8 years. Conclusion: We conclude that carrying the CHEK2*1100delC mutation is an adverse prognostic indicator for breast cancer. If independently confirmed by others, intensive surveillance, and possibly preventive measures, should be considered for newly diagnosed breast cancer cases carrying the CHEK2*1100delC variant.

MRI screening for breast cancer in women with familial or genetic predisposition: design of the Dutch National Study (MRISC).

Mammography screening of women aged 50–70 years for breast cancer has proven to be effective in reducing breast cancer mortality. There is no consensus about the value of breast cancer screening in women aged 40–49 years. Five to ten per cent of all breast cancers are hereditary. One of the options to reduce the risk of breast cancer mortality for women with a familial or genetic predisposition is intensive surveillance. However, the effectiveness of mammography screening for breast cancer in these women, who are mainly younger than 50 years, is unproven. MRI might increase the effectiveness of screening in women with a familial or genetic predisposition. This paper describes the design of the Dutch national study for Magnetic Resonance Imaging (MRI) screening in women with a familial or genetic predisposition. The aims of this study are to investigate: the value of regular surveillance in women with a familial or genetic predisposition for breast cancer, the efficacy of MRI as compared to mammography, cost-effectiveness of regular screening and quality of life during surveillance. Included are women with a lifetime risk of familial breast cancer of 15% or more or BRCA1/2 mutation carriers, who visit one of the Dutch family cancer clinics. The aim is to include 2,500 women. The study started on 1 November 1999. On 1 January 2002, more than 1700 women, including 210 proven carriers of a BRCA1 or BRCA2 mutation, were included in the study.

Family History of Breast Cancer and Local Recurrence after Breast-conserving Therapy

The impact of a family history of breast cancer on the local recurrence (LR) risk after breast-conserving therapy (BCT) was performed within the framework of a large, multicentre matched case-control study of risk factors for LR after BCT (BORST study). Family history was assessed for 218 breast cancer patients with LR (cases) and 480 patients without LR (controls). Detailed histological tumour features were determined by review of the primary tumour. The risk of LR for patients with a positive family history was similar to or less than that of non-familial patients (unadjusted odds ratio (ORunadj) 0.66 (95% confidence interval (CI) 0.40-1.08)). Familial patients were older than non-familial patients (P = 0.07) and their tumours had a lower histological grade (P = 0.07). A second primary tumour occurred significantly more often in familial patients (P = 0.02). Adjustment for these factors did not essentially alter the results (ORadj 0.71 (0.38-1.32)). Separate analyses according to age at onset (younger and older than 50 years) and time to LR/site of LR produced similar results. The sole presence of a positive family history of breast cancer does not appear to be a risk factor for local recurrence after BCT. Whilst this might be different for genetically predisposed patients, a positive family history does not appear to be a contra-indication for BCT.

BRCA1- versus non-BRCA1/2-associated breast cancer (BC): Tumor characteristics and impact of prognostic and treatment factors

9557 Background: Genetic testing made it possible to identify persons at high-risk for BC. Most hereditary BC, however, cannot be attributed to mutations in BRCA1/2. The characteristics and the impact of prognostic and treatment factors in non-BRCA1/2- as compared to BRCA1-associated BC are insufficiently known. METHODS From the database of our family cancer clinic, we selected consecutive BC pts. from families with a BRCA1 mutation (n=230) and without an identified BRCA1/2 mutation (non-BRCA1/2) (n=236), diagnosed between 1980 and 2001. Tumorcharacteristics, treatment and follow-up data were extracted from hospital records. Cox proportional hazards modelling was used to investigate the impact of classical prognostic (age, tumorstage, period of diagnosis) and treatment factors (chemotherapy, prophylactic bilateral salpingo-ovariectomy (PBSO) on distant disease free (DDFS) and overall survival (OS). RESULTS Mean age at BC diagnosis was 41yr (24-82) for BRCA1 and 45yr (23-77) for non-BRCA1/2 pts., median follow-up 4.9 and 6.1yrs. Tumorcharacteristics in BRCA1 carriers versus non-BRCA1/2 cases were: T1 in 51/63%; node negative disease in 65/52%; positive estrogen (ER) and progesterone receptor (PR) status in 26/75% and 28/83% respectively. Chemotherapy was given in 44/37%, PBSO performed in 39/7% respectively. Five, 10- and 15-yrs DDFS rates were 72%, 62% and 53% for BRCA1, and 75%, 62%, and 56% for non-BRCA1/2 patients, respectively. For OS this was 76%, 64% and 61% in BRCA1 versus 86%, 71%, and 61% for non-BRCA1/2 cases. In the multivariate analysis, independent prognostic factors for DDFS and OS were tumor stage (TN) (p<0.03), adjuvant chemotherapy (p < 0.01) and PBSO (p<0.001) in BRCA1 carriers, while in non-BRCA1/2-associated BC only TN tumor stage (p<0.02) was significantly determinative. CONCLUSION our data indicate that BRCA1 and non-BRCA1/2-associated BC are different entities. Tumorstage is an independent prognostic factor in both BRCA1- and non-BRCA1/2- associated BC. Further, in BRCA1-BC, adjuvant chemotherapy and PBSO have significant impact on survival. No significant financial relationships to disclose.

Breast Cancer Screening in High-Risk Women

There is circumstantial evidence that population-based screening programmes can reduce breast cancer mortality in women aged 40–70 years old. The value of screening in highrisk groups such as women with a positive family history of breast cancer is unproven. In the meantime a rapidly increasing number of high-risk women seek counselling about strategies to reduce their risk of breast cancer death, such as intensive surveillance. As for ethical reasons no randomized trials can be performed, the effect of screening these women has to be evaluated by means of observational studies. In several specialized centers in the Netherlands, women with a more than 2 times increased risk of breast cancer (BC) (lifetime > 15%) are being screened regularly. In this study the first results of screening highrisk women in the Rotterdam Cancer Center/ University Hospital are described.