M.M.A. Tilanus-Linthorst

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.

Substantial breast cancer risk reduction and potential survival benefit after bilateral mastectomy when compared with surveillance in healthy BRCA1 and BRCA2 mutation carriers: a prospective analysis

BACKGROUND To prospectively assess the efficacy of bilateral risk-reducing mastectomy (BRRM) when compared with surveillance on breast cancer (BC) risk and mortality in healthy BRCA1 and BRCA2 mutation carriers. PATIENTS AND METHODS Five hundred and seventy healthy female mutation carriers (405 BRCA1, 165 BRCA2) were selected from the institutional Family Cancer Clinic database. Eventually, 156 BRCA1 and 56 BRCA2 mutation carriers underwent BRRM. The effect of BRRM versus surveillance was estimated using Cox models. RESULTS During 2037 person-years of observation (PYO), 57 BC cases occurred in the surveillance group versus zero cases during 1379 PYO in the BRRM group (incidence rates, 28 and 0 per 1000 PYO, respectively). In the surveillance group, four women died of BC, while one woman in the BRRM group presented with metastatic BC 3.5 years after BRRM (no primary BC), and died afterward, yielding a HR of 0.29 (95% CI 0.02-2.61) for BC-specific mortality. CONCLUSIONS In healthy BRCA1/2 mutation carriers, BRRM when compared with surveillance reduces BC risk substantially, while longer follow-up is warranted to confirm survival benefits.

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.

Abstract P5-05-05: Lower mitotic activity in BRCA1/2-associated primary breast cancers occurring after risk-reducing salpingo-oophorectomy

Background Bilateral salpingo-oophorectomy reduces breast cancer (BC) risk by about 50% in BRCA1/2 mutation carriers when performed premenopausally. It has been hypothesized that growth activity of BCs originating after risk-reducing salpingo-oophorectomy (RRSO) is lower. We compared tumor characteristics and growth rates of BRCA1/2-associated primary BCs (PBCs) detected after RRSO with those of tumors originating without RRSO. Methods From a cohort of 271 female BRCA1/2-associated patients with screen detected BC, 20 BRCA1/2 mutation carriers with PBC detected ≥12 months after RRSO were selected (RRSO group). Controls were 36 BRCA1/2 mutation carriers with PBC detected without RRSO (non-RRSO group) matched for age at PBC diagnosis (± 2.5 years) and for BRCA1 or BRCA2 mutation (intended matching ratio 1:2). Tumor growth rates, expressed as tumor volume doubling times (DT), were calculated. Pathology samples were revised for histological subtype, tumor differentiation grade, estrogen receptor (ER), progesterone receptor (PR) and HER2 status. Imaging examinations (magnetic resonance imaging (MRI), mammography) before and at BC diagnosis were revised. Results Median age at PBC diagnosis was 52 years (range 35-67). MRI detected more BC than mammography in the RRSO-group as compared to the non-RRSO group (83% vs. 39%, P = 0.02). Tumor size at diagnosis was smaller in the RRSO group (11.0 mm vs. 17.0 mm, P = 0.01). Mitotic activity indexes (MAI) in the RRSO and non-RRSO group were 12 vs. 22 mitotic counts/2 mm 2 (P = 0.02). No significant differences in differentiation grade, ER and HER2 status were found. PR-status was more often positive in the RRSO group without reaching statistical significance (38% vs. 13%, P = 0.07). Median DT in the RRSO group was 124 days (range 89-193) and 93 days (range 54-253) in the non-RRSO group (P = 0.47). Conclusion BC occurring after RRSO in BRCA mutation carriers features a lower MAI, suggesting a less aggressive biological behavior. When confirmed in larger series, this may have consequences for BC screening protocols for BRCA1/2 mutation carriers after RRSO. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-05-05.

Abstract P4-11-05: Optimal age to start preventive measures in women with BRCA1/2 mutations or high familial breast cancer risk

Background: Women from high risk breast cancer families consider preventive measures including screening. Guidelines on screening differ considerably regarding starting age. We investigated whether age at diagnosis in affected family members is predictive for age at diagnosis of a relative. Methods: We analyzed the age of breast cancer detection of 1304 first and second degree relatives of 314 BRCA1, 164 BRCA2 and 244 high-risk participants of the Dutch MRI-SCreening study. The within and between family variance in age at diagnosis was analyzed with a random effect linear regression model. We compared the starting age of screening based on risk-group (25 years for BRCA1, 30 years for BRCA2 and 35 years for familial risk), on family history, and on the model, which combines both. The findings were validated in 63 families from the UK- MARIBS study. Results: Mean age at diagnosis in the family varied between families; 95% range of mean family ages was 35–55 in BRCA1−, 41–57 in BRCA2− and 44–60 in high-risk families.14% of the variance in age at diagnosis was explained by family history, 7% by risk group. Approaches to determining start of screening based on the model and on risk-group were similar in terms of cancers missed and years of screening. The approach based on familial history only, missed more cancers and required more screening years in both the Dutch and UK datasets. Conclusion: Age at breast cancer diagnosis is in part dependent on family history which may assist planning starting age for preventive measures. Keywords: BRCA1, BRCA2, breast cancer, prevention, age at onset Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-11-05.

Abstract P3-02-09: Cost-effectiveness of screening with additional MRI for women with familial risk for breast cancer without a genetic predisposition

Background: To reduce mortality risk, women with a family history of breast cancer are often screened with mammography before 50 years of age. Additional Magnetic Resonance Imaging (MRI) can improve sensitivity. MRI screening is cost-effective for BRCA1/2 mutation carriers. However, for women with a family history of breast cancer without a proven mutation cost-effectiveness is not clear. We evaluated the cost-effectiveness of additional MRI for women with a familial risk in the largest prospective MRI screening study: the Dutch MRI Screening Study (MRISC). Materials & Methods: Between 1999 and 2007 a total of 1597 women (8370 women years at risk) between 25–70 years, with an estimated cumulative lifetime risk of 15–50% for breast cancer participated in the MRISC. Women were screened with clinical breast examination (CBE) every six months and annual mammography and MRI. We calculated the costs per detected breast cancer. In addition, MRISC data were incorporated into a micro simulation screening analysis model: MISCAN. This model simulates screening programs with different screening modalities and time intervals. Different screening schemes were evaluated and the cost per life-year gained (CLYG) estimated. Results: Forty-seven breast cancers, including 9 Ductal Carcinoma in Situ, were detected. Screening with additional MRI leads to a cost per detected breast cancer treated of €101,962. In increasing age-cohorts the cost decreased, probably due to the higher breast cancer incidence. The cost per detected and treated breast cancer in age group 40–50 years doubled in the age group >60 years. We will demonstrate these results more extensively. With MISCAN modeling we predicted that screening with this scheme from age 35 to 60 years reduces breast cancer mortality by 30% at a CLYG of €119,945 (3.5% discounting), compared to 21% estimated mortality reduction at €45,707 CLYG with mammography and CBE alone. Conclusion: Screening with MRI may improve survival for women with familial risk for breast cancer, but is expensive. However, it may be cost-effective for a select group. We will discuss subgroups that may benefit from MRI screening and in which age category MRI was most effective in our study. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-02-09.

Prevention of primary and contralateral breast cancer by risk reducing salpingo-oophorectomy in high risk women with a BRCA1/2 mutation or familial predisposition.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #504 Introduction: Risk reducing salpingo-oophorectomy (RRSO) has become an important preventive option against ovarian/fallopian tube cancer, while it is also risk reducing regarding breast cancer (BC) in women with a BRCA1 or BRCA2 mutation. Recently a difference in efficacy of RRSO concerning the occurrence of BC has been suggested for BRCA1 and BRCA2 mutation carriers, while no data are available on the protective effect of RRSO in women from a hereditary breast/ovarian cancer (HBOC) family without a proven BRCA mutation. Further, it is not known whether the BC risk reduction after RRSO equally applies to primary (PBC) and contralateral BC (CBC). Methods: The occurrence of PBC and CBC was prospectively studied in 639 women ≥ 30 years (330 BRCA1 mutation carriers, 117 BRCA2 mutation carriers, and 192 HBOC women) who were enrolled in a breast/ovarian cancer surveillance program at the Rotterdam Family Cancer Clinic. Women with a history of BC without recurrent disease were eligible if BC treatment did not involve adjuvant systemic therapy. Demographics and follow-up (FU) information up to December 31, 2007, were extracted from the medical records. Ninety-eight BRCA1 mutation carriers, 33 BRCA2 mutation carriers and 15 HBOC women eventually underwent RRSO. Results were analyzed separately for women being at risk for PBC (n=489) and for CBC (n=164). The effect of RRSO on the incidence of BC was analyzed using a Cox proportional hazards model in which RRSO was modeled as a time-dependent covariate. Results: During a mean FU of 5.5 years, RRSO was associated with a reduction in BC risk of 48% (HR=0.52; 95% CI, 0.26-1.02; p=0.058) versus 81% (HR=0.19; 95% CI, 0.02-1.95; p=0.161) in BRCA1 and BRCA2 mutation carriers, respectively. In BRCA1 mutation carriers, PBC was reduced by 74% (HR=0.26; 95% CI, 0.08-0.89; p=0.032), and CBC by 29% (HR=0.71; 95% CI, 0.23-2.16; p=0.544). In BRCA2 mutation carriers no cases of PBC occurred after RRSO (HR=0,00; 95% CI, not estimable), while 1 CBC was diagnosed (HR=0.25; 95% CI, 0.01-5.62; p=0.379). In HBOC women no BC cases were observed after RRSO. Conclusions: RRSO is associated with a BC risk reduction in both BRCA1 and BRCA2 mutation carriers. The risk reductive effect is more pronounced regarding PBC as compared to CBC in BRCA1 mutation carriers. Although a similar trend is suggested for BRCA2 mutation carriers, larger numbers and longer FU are needed to draw firm conclusions. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 504.

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.