[Show abstract][Hide abstract] ABSTRACT: Objective: It is unclear if and to what extent family history of breast/ovarian cancer or BRCA1/2-mutation carriership influences breast cancer treatment strategy. We investigated whether treatment differed between patients from BRCA1/2 families and those unselected for family history. Methods: We included 478 BRCA1/2-related patients referred for genetic testing before or after diagnosis. Two references were used: 13,498 population-based and 6896 hospital-based patients. Surgical treatment and adjuvant chemotherapy use was analyzed using logistic regression models, stratified by tumor size, nodal status, age at and period of diagnosis, and estrogen receptor status (ER). Results: BRCA1/2 cases aged 35 - 52 years at diagnosis and/or with tumors < 2 cm were more likely to have undergone a modified radical mastectomy (Odd Ratios (OR) ranging from 2.8 to 5.1) compared to the references. This effect was most pronounced in patients treated after 1995 (OR 5.7 to 10.3). Compared to the reference groups, chemotherapy was more often administered to BRCA1 and ER-negative BRCA1/2-cases irrespective of age and nodal status (OR 1.9 to 24.3). Conclusion: After 1995 treatment of BRCA1/2-associated patients consisted notably of more mastectomies and adjuvant chemotherapy than their population-based counterparts with the same tumor characteristics. There is a need to be aware of such differences in daily practice and interpretation of survival studies on BRCA1/2 mutation carriers.
Advances in Breast Cancer Research 11/2015; 4(04):87-99. DOI:10.4236/abcr.2015.44010
[Show abstract][Hide abstract] ABSTRACT: We studied counselees' expressed understanding of the risk estimate and surveillance recommendation in the final consultation for breast cancer genetic counseling in relation with their risk perception, worry and cancer surveillance adherence 1 year post-counseling. Consecutive counselees were included from 2008 to 2010. Counselees with an indication for diagnostic DNA-testing for themselves or a breast cancer affected relative were requested to complete online questionnaires before and after counseling and one year after counseling (N = 152-124). Self-reported surveillance was compared to surveillance recommendations. Consultations were videotaped. Counselees' reactions to the risks and recommendations were coded. Statements about the risk perception and surveillance intentions of breast cancer unaffected counselees were transcribed. Associations with outcomes were explored. Almost all breast cancer unaffected counselees (>90 %) reacted to their risk estimate with an utterance indicating understanding and this reaction was not significantly associated with their post-visit risk perception alignment. Over one-third (38.6 %) overestimated their risk post-counseling. Few counselees (5.8 %) expressed surveillance intentions. One year after counseling, about three-quarters (74.0 %) of the breast cancer unaffected counselees had adhered to the surveillance recommendation. Almost one-quarter (23.3 %) had performed more mammograms/MRI scans than recommended, which was associated with prior mammography uptake (n = 47; X (2) = 5.2; p = .02). Counselees' post-counseling overestimation of their risk, high levels of worry and high surveillance uptake were not reflected in their reactions to the counselor's information during the final visit.
Journal of Genetic Counseling 09/2015; DOI:10.1007/s10897-015-9869-x · 2.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The p16-Leiden founder mutation in the CDKN2A gene is the most common cause of Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome in the Netherlands. Individuals with this mutation are at increased risk for developing melanoma of the skin, as well as pancreatic cancer. However, there is a notable interfamilial variability in the occurrence of pancreatic cancer among p16-Leiden families. We aimed to test whether previously identified genetic risk factors for pancreatic cancer modify the risk for pancreatic cancer in p16-Leiden germline mutation carriers.
Seven pancreatic cancer-associated SNPs were selected from the literature and were genotyped in a cohort of 185 p16-Leiden germline mutation carriers from 88 families, including 50 cases (median age 55 years) with pancreatic cancer and 135 controls (median age 64 years) without pancreatic cancer. Allelic odds ratios per SNP were calculated.
No significant association with pancreatic cancer was found for any of the seven SNPs.
Since genetic modifiers for developing melanoma have already been identified in CDKN2A mutation carriers, this study does not exclude that genetic modifiers do not play a role in the individual pancreatic cancer risk in this cohort of p16-Leiden germline mutation carriers. The search for these modifiers should therefore continue, because they can potentially facilitate more targeted pancreatic surveillance programs.
BMC Research Notes 06/2015; 8:264. DOI:10.1186/s13104-015-1235-4
[Show abstract][Hide abstract] ABSTRACT: Despite intensive surveillance, a high rate of interval malignancies is still seen in women at increased breast cancer risk. Therefore, novel screening modalities aiming at early detection remain needed. The intraductal approach offers the possibility to directly sample fluid containing cells, DNA and proteins from the mammary ductal system where, in the majority of cases, breast cancer originates. Fluid from the breast can non-invasively be obtained by oxytocin-assisted vacuum aspiration, called nipple fluid aspiration (NFA). The goal of this feasibility study was to evaluate the potential of repeated NFA, which is a critical and essential step to evaluate its possible value as a breast cancer screening method.
In this multicenter, prospective study, we annually collected nipple fluid for up to 5 consecutive years from women at increased breast cancer risk, and performed a questionnaire-based survey regarding discomfort of the aspiration. Endpoints of the current interim analyses were the feasibility and results of 994 NFA procedures in 451 women with total follow-up of 560 person years of observation.
In this large group of women at increased risk of breast cancer, repetitive NFA appeared to be feasible and safe. In 66.4% of aspirated breasts, nipple fluid was successfully obtained. Independent predictive factors for successful NFA were premenopausal status, spontaneous nipple discharge, smaller breast size, bilateral oophorectomy and previous use of hormone replacement therapy or anti-hormonal treatment. The procedure was well tolerated with low discomfort. Drop-out rate was 20%, which was mainly due to repeated unsuccessful aspiration attempts. Only 1.6% of women prematurely declined further participation because of side effects.
Repeated NFA in women at increased breast cancer risk is feasible and safe. Therefore, NFA is a promising method to non-invasively obtain a valuable source of potential breast cancer specific biomarkers.
PLoS ONE 05/2015; 10(5):e0127895. DOI:10.1371/journal.pone.0127895 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Germline CDH1 mutations confer a high lifetime risk of developing diffuse gastric (DGC) and lobular breast cancer (LBC). A multidisciplinary workshop was organised to discuss genetic testing, surgery, surveillance strategies, pathology reporting and the patient's perspective on multiple aspects, including diet post gastrectomy. The updated guidelines include revised CDH1 testing criteria (taking into account first-degree and second-degree relatives): (1) families with two or more patients with gastric cancer at any age, one confirmed DGC; (2) individuals with DGC before the age of 40 and (3) families with diagnoses of both DGC and LBC (one diagnosis before the age of 50). Additionally, CDH1 testing could be considered in patients with bilateral or familial LBC before the age of 50, patients with DGC and cleft lip/palate, and those with precursor lesions for signet ring cell carcinoma. Given the high mortality associated with invasive disease, prophylactic total gastrectomy at a centre of expertise is advised for individuals with pathogenic CDH1 mutations. Breast cancer surveillance with annual breast MRI starting at age 30 for women with a CDH1 mutation is recommended. Standardised endoscopic surveillance in experienced centres is recommended for those opting not to have gastrectomy at the current time, those with CDH1 variants of uncertain significance and those that fulfil hereditary DGC criteria without germline CDH1 mutations. Expert histopathological confirmation of (early) signet ring cell carcinoma is recommended. The impact of gastrectomy and mastectomy should not be underestimated; these can have severe consequences on a psychological, physiological and metabolic level. Nutritional problems should be carefully monitored.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Journal of Medical Genetics 05/2015; 52(6). DOI:10.1136/jmedgenet-2015-103094 · 6.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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).
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.
Journal of the National Cancer Institute 05/2015; 107(5). DOI:10.1093/jnci/djv033 · 12.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Female breast cancer patients carrying a BRCA1/2 mutation have an increased risk of second primary breast cancer. Rapid genetic counseling and testing (RGCT) before surgery may influence choice of primary surgical treatment. In this article, we report on the psychosocial impact of RGCT.
Newly diagnosed breast cancer patients at risk for carrying a BRCA1/2 mutation were randomized to an intervention group (offer of RGCT) or a usual care control group (ratio 2:1). Psychosocial impact and quality of life were assessed with the Impact of Events Scale, Hospital Anxiety and Depression Scale, Cancer Worry Scale, and the EORTC QLQ-C30 and QLQ-BR23. Assessments took place at study entry and at 6- and 12-month follow-up visits.
Between 2008 and 2010, 265 patients were recruited into the study. Completeness of follow-up data was more than 90%. Of the 178 women in the intervention group, 177 had genetic counseling, of whom 71 (40%) had rapid DNA testing and 59 (33%) received test results before surgery. Intention-to-treat and per-protocol analyses showed no statistically significant differences between groups over time in any of the psychosocial outcomes.
In this study, RGCT in newly diagnosed breast cancer patients did not have any measurable adverse psychosocial effects.Genet Med advance online publication 23 April 2015Genetics in Medicine (2015); doi:10.1038/gim.2015.50.
Genetics in medicine: official journal of the American College of Medical Genetics 04/2015; DOI:10.1038/gim.2015.50 · 7.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: IMPORTANCE: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists.
OBJECTIVE:To identify mutation-specific cancer risks for carriers of BRCA1/2.
DESIGN, SETTING, AND PARTICIPANTS:Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk.
EXPOSURES:Mutations of BRCA1 or BRCA2.
MAIN OUTCOMES AND MEASURES: Breast and ovarian cancer risks.
RESULTS:Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers.
CONCLUSIONS AND RELEVANCE: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.
JAMA The Journal of the American Medical Association 04/2015; 313(13):1347-61. DOI:10.1001/jama.2014.5985 · 35.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Familial Cancer 02/2015; 14(3). DOI:10.1007/s10689-015-9788-x · 1.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and non-genetic modifying factors. In this study we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n=3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed p-values of association ranged between 0.005-1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.
[Show abstract][Hide abstract] ABSTRACT: Background:We aimed to quantify previously observed relatively high cancer risks in BRCA2 mutation carriers (BRCA2 carriers) over 60 in the Northern Netherlands, and to analyze whether these could be explained by mutation spectrum or population background risk. Methods:This consecutive cohort study included all known pathogenic BRCA1/2 carriers in the Northern Netherlands (N = 1,050). Carrier and general reference populations were: BRCA1/2 carriers in the rest of the Netherlands (N = 2,013) and the general population in both regions. Regional differences were assessed with hazard ratios (HRs) and odds ratios (ORs). HRs were adjusted for birth year and mutation spectrum. Results:All BRCA1 carriers and BRCA2 carriers under age 60 had a significantly lower breast cancer risk in the Northern Netherlands, HRs were 0.66 and 0.64, respectively. Above age 60, the breast cancer risk in BRCA2 carriers in the Northern Netherlands was higher than in the rest of the Netherlands (HR = 3.99, 95% CI 1.11-14.35). Adjustment for mutational spectrum changed the HRs for BRCA1, BRCA2 <60 and BRCA2 ≥60 years by -3%, +32% and +11% to 0.75, 0.50 and 2.61, respectively. There was no difference in background breast cancer incidence between the two regions (OR = 1.03, 95% CI 0.97-1.09). Conclusions:Differences in mutation spectrum only partly explain the regional differences in breast cancer risk in BRCA2 carriers, and for an even smaller part in BRCA1 carriers. Impact:The increased risk in BRCA2 carriers over 60 may warrant extension of intensive breast screening beyond age 60.
[Show abstract][Hide abstract] ABSTRACT: IntroductionApproximately 70% of counselees undergoing cancer genetic counseling and testing (CGCT) experience some degree of CGCT-related psychosocial problems. We evaluated the efficacy of an intervention designed to increase detection and management of problems four weeks after completion of CGCT.Methods
In this randomized, controlled trial, 118 participants completed a CGCT-related problem questionnaire prior to an -audiotaped- telephone session with their counselor one month after DNA-test disclosure. For those randomized to the intervention group (n = 63), a summary of the questionnaire results was provided to the counselor prior to the telephone session. Primary outcomes were discussion of the problems, counselors’ awareness of problems, and problem management. Secondary outcomes included self-reported distress, cancer worries, CGCT-related problems, and satisfaction.ResultsCounselors who received a summary of the questionnaire were more aware of counselees’ problems in only one psychosocial domain (practical issues). No significant differences in the number of problems discussed, in problem management, or on any of the secondary outcomes were observed. The prevalence of problems was generally low.Conclusions
The telephone session, combined with feedback on psychosocial problems, has minimal impact. The low prevalence of psychosocial problems one month post-CGCT recommends against its use as a routine extension of the CGCT procedure.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
This study evaluated the efficacy of a cancer genetics–specific questionnaire in facilitating communication about, awareness of, and management of psychosocial problems, as well as in lowering distress levels.
Individuals referred to genetic counseling for cancer at two family cancer clinics in The Netherlands were randomly assigned to an intervention or a control group. All participants completed the psychosocial questionnaire before counseling. In the intervention group, the counselors received the results of this questionnaire before the counseling session. All sessions were audiotaped for content analysis. Primary outcomes were the frequency with which psychosocial problems were discussed, the genetic counselors’ awareness of these problems, and their management. Secondary outcomes included cancer worries and psychological distress, duration and dynamics of the counseling, and satisfaction.
The frequency with which psychosocial problems were discussed with 246 participating counselees was significantly higher in the intervention group (n = 127) than in the control group (n =119; P = .004), as was the counselors’ awareness of psychosocial problems regarding hereditary predisposition (P < .001), living with cancer (P = .01), and general emotions (P < .001). Counselors initiated more discussion of psychosocial problems in the intervention group (P < .001), without affecting the length of the counseling session. No significant differences were found on management (P = .19). The intervention group reported significantly lower levels of cancer worries (p = .005) and distress (p = .02) after counseling.
The routine assessment of psychosocial problems by questionnaire facilitates genetic counselors’ recognition and discussion of their clients’ psychosocial problems and reduces clients’ distress levels.
[Show abstract][Hide abstract] ABSTRACT: The purpose of the study was to assess the counselee participation in the follow-up visits, compared to the first visits, for breast cancer genetic counselling and to explore associations with counselees' achievement of their preferred role in decision making, information recall, knowledge, risk perception alignment and perceived personal control. First and follow-up visits for breast cancer genetic counselling of 96 counselees of a Dutch genetics center were videotaped (2008-2010). Counselees completed questionnaires before counselling (T1), after the follow-up visit (T2) and one year after the follow-up visit (T3). Consultations were rated with the Roter Interaction Analysis System (RIAS). Counselee participation was measured as the percentage of counselee utterances, the percentage of counselee questions and the interactivity (number of turns per minute). Follow-up visits had higher levels of counselee participation than first visits as assessed by the percentage of counselee talk, the interactivity and counselee questions. More counselee talk in the follow-up visit was related to higher achievement of the preferred role (T2) and higher perceived personal control (T3). Higher interactivity in the follow-up visit was related to lower achievement of the preferred role in decision making and lower information recall (T2). There were no significant associations with the percentage of questions asked and none of the participation measures was related to knowledge, risk perception alignment and perceived personal control (T2). In line with the interviewing admonishment 'talk less and listen more', the only assessment of counselee participation associated to better outcomes is the percentage of counselee talk. High interactivity might be associated with lower recall in breast cancer genetic counselees who are generally highly educated. However, this study was limited by a small sample size and a heterogeneous group of counselees. Research is needed on the interactions causing interactivity and its relationships with involvement in decision making and recall.
Social Science & Medicine 07/2014; 116C:178-186. DOI:10.1016/j.socscimed.2014.07.012 · 2.89 Impact Factor