37 research outputs found
Risk-reducing mastectomy in BRCA mutation carriers: survival is one of the issues—author's reply
The impact of menstruation persistence or recovery after chemotherapy on survival in young patients with hormone receptor negative breast cancer
Introduction: Hormone replacement therapy can diminish hormone depletion-related complaints in
postmenopausal women, but is contraindicated for postmenopausal breast cancer (BC) patients. Recovery of menstruation after chemotherapy-induced amenorrhea in young hormone receptor-negative
BC patients however, is accepted. To determine the safety of this strategy, we investigated the effect of
recovery of menstruation on disease-free survival (DFS) and overall survival (OS) in young hormone
receptor-negative BC patients treated with (neo)adjuvant chemotherapy.
Methods: We selected 636 patients from a single-center cohort with early stage hormone receptornegative BC and under the age of 50 years when treated with chemotherapy. Sufficient data on course
of menstruation in medical records was retrospectively found for 397 patients, of whom 299 patients
(75%) had a recovery of menstruation after chemotherapy. We used Cox proportional hazards models to
estimate hazard ratios (HR) for the effect of recovery of menstruation on DFS and OS.
Results: Patients with recovery of menstruation after chemotherapy less frequ
The supplemental value of mammographic screening over breast MRI alone in BRCA2 mutation carriers
Purpose: BRCA2 mutation carriers are offered annual breast screening with MRI and mammography. The aim of this study was to investigate the supplemental value of mammographic screening over MRI screening alone. Methods: In this multicenter study, proven BRCA2 mutation carriers, who developed breast cancer during screening using both digital mammography and state-of-art breast MRI, were identified. Clinical data were reviewed to classify cases in screen-detected and interval cancers. Imaging was reviewed to assess the diagnostic value of mammography and MRI, using the Breast Imaging and Data System (BI-RADS) classification allocated at the time of diagnosis. Results: From January 2003 till March 2019, 62 invasive breast cancers and 23 ductal carcinomas in situ were diagnosed in 83 BRCA2 mutation carriers under surveillance. Overall screening sensitivity was 95.2% (81/85). Four interval cancers occurred (4.7% (4/85)). MRI detected 73 of 85 breast cancers (sensitivity 85.8%) and 42 mammography (sensitivity 49.9%) (p < 0.001). Eight mammography-only lesions occurred. In 1 of 17 women younger than 40 years, a 6-mm grade 3 DCIS, retrospectively visible on MRI, was detected with mammography only in a 38-year-old woman. The other 7 mammography-only breast cancers were diagnosed in women aged 50 years and older, increasing sensitivity in this subgroup from 79.5% (35/44) to 95.5% (42/44) (p ≤ 0.001). Conclusions: In BRCA2 mutation carriers younger than 40 years, the benefit of mammographic screening over MRI was very small. In carriers of 50 years and older, mammographic screening contributed significantly. Hence, we propose to postpone mammographic screening in BRCA2 mutation carriers to at least age 40
Survival and contralateral breast cancer in CHEK2 1100delC breast cancer patients: impact of adjuvant chemotherapy
Sensitivity to systemic therapy for metastatic breast cancer in CHEK2 1100delC mutation carriers
Purpose: The role of CHEK2 in DNA repair by homologous recombination suggests that CHEK2-associated breast cancer (BC) patients might be more sensitive to chemotherapy inducing double-strand DNA breaks, but results hereon are lacking. We compared the sensitivity to first-line chemotherapy and endocrine therapy between CHEK2 1100delC and non-CHEK2 metastatic breast cancer (MBC) patients. Methods: Sixty-two CHEK2 1100delC MBC patients were selected from three cohorts genotyped for CHEK2 1100delC (one non-BRCA1/2 cohort and two sporadic cohorts). Controls were 62 non-CHEK2 MBC patients, matched for age at and year of primary BC diagnosis, and year of metastatic disease. Objective response rate (complete and partial response) to, and progression-free survival (PFS) and overall survival (OS) after start of first-line chemotherapy and endocrine therapy were compared between CHEK2 and non-CHEK2 patients. Results: Median age at BC diagnosis was 46 and 51 years at MBC diagnosis. First-line chemotherapy consisted of anthracycline-based chemotherapy (n = 73), taxanes (n = 16), CMF(-like) chemotherapy (n = 33) and taxane/anthracycline regimens (n = 2). CHEK2 and non-CHEK2 patients had a comparable objective response rate (44 vs. 52 %). Also, PFS and OS after start of chemotherapy were comparable between both patient groups (hazard ratio 0.91; 95 % confidence interval 0.63–1.30 and 1.03; 95 % CI 0.71–1.49, respectively). Thirty-six CHEK2 and 32 non-CHEK2 patients received first-line endocrine therapy (mainly tamoxifen) for MBC. No significant differences were observed in objective response rate to, and PFS and OS after start of endocrine therapy. Conclusion: No differ
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
Recurrent HOXB13 mutations in the Dutch population do not associate with increased breast cancer risk
The HOXB13 p.G84E mutation has been firmly established as a prostate cancer susceptibility allele. Although HOXB13 also plays a role in breast tumor progression, the association of HOXB13 p.G84E with breast cancer risk is less evident. Therefore, we comprehensively interrogated the entire HOXB13 coding sequence for mutations in 1,250 non-BRCA1/2 familial breast cancer cases and 800 controls. We identified two predicted deleterious missense mutations, p.G84E and p.R217C, that were recurrent among breast cancer cases and further evaluated their association with breast cancer risk in a larger study. Taken together, 4,520 familial non-BRCA1/2 breast cancer cases and 3,127 controls were genotyped including the cases and controls of the whole gene screen. The concordance rate for the genotyping assays compared with Sanger sequencing was 100%. The prostate cancer risk allele p.G84E was identified in 18 (0.56%) of 3,187 cases and 16 (0.70%) of 2,300 controls (OR = 0.81, 95% CI = 0.41-1.59, P = 0.54). Additionally, p.R217C was identified in 10 (0.31%) of 3,208 cases and 2 (0.087%) of 2,288 controls (OR = 3.57, 95% CI = 0.76-33.57, P = 0.14). These results imply that none of the recurrent HOXB13 mutations in the Dutch population are associated with breast cancer risk, although it may be worthwhile to evaluate p.R217C in a larger study
Contralateral breast cancer risk in patients with ductal carcinoma in situ and invasive breast cancer
We aimed to assess contralateral breast cancer (CBC) risk in patients with ductal carcinoma in situ (DCIS) compared with invasive
breast cancer (BC). Women diagnosed with DCIS (N = 28,003) or stage I–III BC (N = 275,836) between 1989 and 2017 were identified
from the nationwide Netherlands Cancer Registry. Cumulative incidences were estimated, accounting for competing risks, and
hazard ratios (HRs) for metachronous invasive CBC. To evaluate effects of adjuvant systemic therapy and screening, separate
analyses were performed for stage I BC without adjuvant systemic therapy and by mode of first BC detection. Multivariable models
including clinico-pathological and treatment data were created to assess CBC risk prediction performance in DCIS patients. The 10-
year cumulative incidence of invasive CBC was 4.8% for DCIS patients (CBC = 1334). Invasive CBC risk was higher in DCIS patients
compared with invasive BC overall (HR = 1.10, 95% confidence interval (CI) = 1.04–1.17), and lower compared with stage I BC
without adjuvant systemic therapy (HR = 0.87; 95% CI = 0.82–0.92). In patients diagnosed ≥2011, the HR for invasive CBC was 1.38
(95% CI = 1.35–1.68) after screen-detected DCIS compared with screen-detected invasive BC, and was 2.14 (95% CI = 1.46–3.13)
when not screen-detected. The C-index was 0.52 (95% CI = 0.50–0.54) for invasive CBC prediction in DCIS patients. In conclusion,
CBC risks are low overall. DCIS patients had a slightly higher risk of invasive CBC compared with invasive BC, likely explained by the
risk-reducing effect of (neo)adjuvant systemic therapy among BC patients. For support of clinical decision making more information
is needed to differentiate CBC risks among DCIS patient
Radiation Dose-Response for Risk of Myocardial Infarction in Breast Cancer Survivors
Previous reports suggest that
radiation therapy for breast
cancer can cause ischemic
heart disease, with radiationrelated risk increasing linearly with mean whole heart
dose. This study aimed to
validate these findings and
assesses additional risk factors for radiation-related
myocardial infarction in a
case-control study nested
within a cohort of BC survivors treated 70 years of age
during 1970-2009. The study
confirms a linear relationship
between mean whole heart
dose and myocardial infarction risk after radiation for
breast cancer
A genome-wide association scan on estrogen receptor-negative breast cancer
Introduction: Breast cancer is a heterogeneous disease and may be characterized on the basis of whether estrogen receptors (ER) are expressed in the tumour cells. ER status of breast cancer is important clinically, and is used both as a prognostic indicator and treatment predictor. In this study, we focused on identifying genetic markers associated with ER-negative breast cancer risk.Methods: We conducted a genome-wide association analysis of 285,984 single nucleotide polymorphisms (SNPs) genotyped in 617 ER-negative breast cancer cases and 4,583 controls. We also conducted a genome-wide pathway analysis on the discovery dataset using permutation-based tests on pre-defined pathways. The extent of shared polygenic variation between ER-negative and ER-positive breast cancers was assessed by relating risk scores, derived using ER-positive breast cancer samples, to disease state in independent, ER-negative breast cancer cases.Results: Association with ER-negative breast cancer was not validated for any of the five most strongly associated SNPs followed up in independent studies (1,011 ER-negative breast cancer cases, 7,604 controls). However, an excess of small P-values for SNPs with known regulatory functions in cancer-related pathways was found (global P = 0.052). We found no evidence to suggest that ER-negative breast cancer share