Survival and contralateral breast cancer in CHEK2 1100delC breast cancer patients: impact of adjuvant chemotherapy.

BACKGROUND: We assessed the sensitivity to adjuvant chemotherapy in cell cycle checkpoint kinase 2 (CHEK2) vs non-CHEK2 breast cancer patients by comparing the contralateral breast cancer incidence and distant disease-free and breast cancer-specific survival between both groups, stratified for adjuvant chemotherapy. METHODS: One Dutch hereditary non-BRCA1/2 breast cancer patient cohort (n=1220) and two Dutch cohorts unselected for family history (n=1014 and n=2488, respectively) were genotyped for CHEK2 1100delC. Hazard ratios for contralateral breast cancer, distant disease-free and breast cancer-specific death for mutation carriers vs noncarriers were calculated using the Cox proportional hazard method, stratified for adjuvant chemotherapy. RESULTS: The CHEK2 mutation carriers (n=193) had an increased incidence of contralateral breast cancer (multivariate hazard ratio 3.97, 95% confidence interval 2.59-6.07). Distant disease-free and breast cancer-specific survival were similar in the first 6 years in mutation carriers compared with noncarriers, but diverted as of 6 years after breast cancer diagnosis (multivariate hazard ratios and 95% confidence intervals 2.65 (1.79-3.93) and 2.05 (1.41-2.99), respectively). No significant interaction between CHEK2 and adjuvant chemotherapy was observed. CONCLUSIONS: The CHEK2 1100delC-associated breast cancer is associated with a higher contralateral breast cancer rate as well as worse survival measures beyond 6 years after diagnosis. No differential sensitivity to adjuvant chemotherapy was observed in CHEK2 patients.

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.

The effect of attendance in the Dutch breast cancer screening program on breast tumor characteristics among migrant women.

BACKGROUND: In general, migrant women have a lower breast cancer (BC) incidence rate and higher BC mortality than autochthonous women. Further, migrant women show lower participation in the national BC screening program. To further investigate those aspects, we aimed to determine differences in incidence and tumor characteristics between autochthonous and migrant BC patients in Rotterdam, the Netherlands. METHODS: We selected women diagnosed with BC in Rotterdam during 2012-2015 from the Netherlands Cancer Registry. Incidence rates were calculated by migrant status (i.e., women with or without migration background). Multivariable analyses revealed adjusted odds ratios (OR) and 95% confidence intervals (CI) on the association between migration status and patient and tumor characteristics, additionally stratified by screening attendance (yes/no). RESULTS: In total 1372 autochthonous and 450 migrant BC patients were included for analysis. BC incidence was lower among migrants than among autochthonous women. Overall, migrant women were younger at BC diagnosis (53 vs. 64 years, p < 0.001), and had higher risks of positive lymph nodes (OR 1.76, 95% CI 1.33-2.33) and high grade tumors (OR 1.35, 95% CI 1.04-1.75). Especially non-screened migrant women had higher risk of positive nodes (OR 2.73, 95% CI 1.43-5.21). Among the subgroup of screened women, we observed no significant differences between migrant and autochthonous patients. CONCLUSION: Migrant women have lower BC incidence than autochthonous women, but diagnosis was more often at younger age and with unfavorable tumor characteristics. Attending the screening program strongly reduces the latter. Therefore, promotion of participation in the screening program is recommended.

Chemosensitivity and outcome of BRCA1- and BRCA2-associated ovarian cancer patients after first-line chemotherapy compared with sporadic ovarian cancer patients.

BACKGROUND: Because it is insufficiently clear whether BRCA-associated epithelial ovarian cancer (EOC) is more chemosensitive than sporadic EOC, we examined response to chemotherapy, progression-free survival (PFS) and overall survival (OS) in BRCA1- and BRCA2-associated versus sporadic EOC patients. METHODS: Data about patient characteristics, response to and outcome after primary therapy, including chemotherapy, were collected from 99 BRCA1, 13 BRCA2 and 222 sporadic patients. Analyses were carried out using a chi-square test and Kaplan-Meier and Cox regression methods. RESULTS: Complete response (CR) or no evidence of disease (NED) was observed in 87% of the BRCA1 patients, progressive disease (PD) in 2%, being 71% and 15%, respectively, in sporadic EOC patients (P = 0.002). In BRCA2 patients, 92% had CR/NED, and none PD (P = 0.27). Median PFS in BRCA1, BRCA2 and sporadic patients was 2.1 [95% confidence interval (CI) 1.9-2.5] years (P = 0.006), 5.6 (95% CI 0.0-11.5) years (P = 0.008) and 1.3 (95% CI 1.1-1.5) years, respectively. Median OS in the three groups was 5.9 (95% CI 4.7-7.0) years (P < 0.001), >10 years (P = 0.008), and 2.9 (95% CI 2.2-3.5) years, respectively. A trend for a longer PFS and OS in BRCA2 compared with BRCA1 patients was observed. CONCLUSION: Compared with sporadic EOC patients, both BRCA1- and BRCA2-associated patients have improved outcomes after primary therapy, including chemotherapy.

Timing of risk reducing mastectomy in breast cancer patients carrying a BRCA1/2 mutation: retrospective data from the Dutch HEBON study.

It is expected that rapid genetic counseling and testing (RGCT) will lead to increasing numbers of breast cancer (BC) patients knowing their BRCA1/2 carrier status before primary surgery. Considering the potential impact of knowing one's status on uptake and timing of risk-reducing contralateral mastectomy (RRCM), we aimed to evaluate trends over time in RRCM, and differences between carriers identified either before (predictively) or after (diagnostically) diagnosis. We collected data from female BRCA1/2 mutation carriers diagnosed with BC between 1995 and 2009 from four Dutch university hospitals. We compared the timing of genetic testing and RRCM in relation to diagnosis in 1995-2000 versus 2001-2009 for all patients, and predictively and diagnostically tested patients separately. Of 287 patients, 219 (76%) had a diagnostic BRCA1/2 test. In this cohort, the median time from diagnosis to DNA testing decreased from 28 months for those diagnosed between 1995 and 2000 to 14 months for those diagnosed between 2001 and 2009 (p < 0.001). Similarly, over time women in this cohort underwent RRCM sooner after diagnosis (median of 77 vs. 27 months, p = 0.05). Predictively tested women who subsequently developed BC underwent an immediate RRCM significantly more often than women who had a diagnostic test (21/61, 34%, vs. 13/170, 7.6 %, p < 0.001). Knowledge of carrying a BRCA1/2 mutation when diagnosed with BC influenced decisions concerning primary surgery. Additionally, in more recent years, women who had not undergone predictive testing were more likely to undergo diagnostic DNA testing and RRCM sooner after diagnosis. This suggests the need for RGCT to guide treatment decisions.

Breast cancer risk after salpingo-oophorectomy in healthy BRCA1/2 mutation carriers: revisiting the evidence for risk reduction.

BACKGROUND: Previous studies have reported a breast cancer (BC) risk reduction of approximately 50% after risk-reducing salpingo-oophorectomy (RRSO) in BRCA1/2 mutation carriers, but may have been subject to several types of bias. The purpose of this nationwide cohort study was to assess potential bias in the estimated BC risk reduction after RRSO. METHODS: We selected BRCA1/2 mutation carriers from an ongoing nationwide cohort study on Hereditary Breast and Ovarian Cancer in the Netherlands (HEBON). First, we replicated the analytical methods as previously applied in four major studies on BC risk after RRSO. Cox proportional hazards models were used to calculate hazard ratios and conditional logistic regression to calculate odds ratios. Secondly, we analyzed the data in a revised design in order to further minimize bias using an extended Cox model with RRSO as a time-dependent variable to calculate the hazard ratio. The most important differences between our approach and those of previous studies were the requirement of no history of cancer at the date of DNA diagnosis and the inclusion of person-time preceding RRSO. RESULTS: Applying the four previously described analytical methods and the data of 551 to 934 BRCA1/2 mutation carriers with a median follow-up of 2.7 to 4.6 years, the odds ratio was 0.61 (95% confidence interval [CI] = 0.35 to 1.08), and the hazard ratios were 0.36 (95% CI = 0.25 to 0.53), 0.62 (95% CI = 0.39 to 0.99), and 0.49 (95% CI = 0.33 to 0.71), being similar to earlier findings. For the revised analysis, we included 822 BRCA1/2 mutation carriers. After a median follow-up period of 3.2 years, we obtained a hazard ratio of 1.09 (95% CI = 0.67 to 1.77). CONCLUSION: In previous studies, BC risk reduction after RRSO in BRCA1/2 mutation carriers may have been overestimated because of bias. Using a design that maximally eliminated bias, we found no evidence for a protective effect.

Breast cancer: a study into the value of a historical group as comparative material for new methods of treatment.

A large group of consecutive patients were studied who had been treated for a primary breast carcinoma by a radical mastectomy at the Netherlands Cancer Institute, during the period of 1960-1974. One of the objectives of that retrospective study was to record the results of treatment of a historical group of patients in such a way that they could presumably serve as a reference for new methods of treatment of breast cancer. To verify the validity of this presumption, the present study compares the treatment results of patients from the EORTC trial 10801, which addresses the value of breast conserving procedures, with that of matched controls from the historical group mentioned above. Matching was carried out with respect to the following prognostic factors: age, tumor size, localization, (number of) positive axillary nodes and grade of malignancy. Analysis of the results strongly suggests that the prognosis for the patients from the historical group is worse than for both groups of patients from the trial 10801. Therefore, this study again confirms that a historical group is not suitable as comparative material for new ways of treatment of breast cancer, and that prospective randomized studies are required to test new treatment schedules.

Changing indications for breast conserving therapy: proportion of patients with operable breast cancer suitable for breast conservation.

The changes in indication for breast conserving therapy and the proportion of operable stage-I and stage-II breast cancers suitable for breast conserving therapy were studied in three time periods. The percentage of patients treated with breast conserving therapy gradually increased through the years: 77/199 (39%) in 1980-1981, 122/245 (50%) in 1985-1987, and 168/305 (55%) in 1987-1989. Using the actual selection criteria more patients might have been candidates for breast conserving therapy: 69, 64 and 59 per cent respectively. In the period 1987-1989 almost all patients who were considered good candidates for breast conserving therapy had a breast sparing procedure. Indications widened in relation to age limit (less than or equal to 70 years) and, over the years, more factors became relative contra-indications: very young age, presence of extensive intra-ductal component, data from mammography (multicentricity, size and aspect of the lesion). About 40 per cent of the patients were no appropriate candidates for breast conserving therapy. This percentage would be higher when operable stage-III patients would have been included.