Psychological distress in women at risk for hereditary breast cancer: the role of family communication and perceived social support.

BACKGROUND: Hereditary breast cancer has a profound impact on individual family members and on their mutual communication and interactions. The way at-risk women cope with the threat of hereditary breast cancer may depend on the quality of family communication about hereditary breast cancer and on the perceived social support from family and friends. OBJECTIVE: To examine the associations of family communication and social support with long-term psychological distress in a group of women at risk for hereditary breast cancer, who opted either for regular breast surveillance or prophylactic surgery. METHODS: The study cohort consisted of 222 women at risk for hereditary breast cancer, who previously participated in a study on the psychological consequences of either regular breast cancer surveillance or prophylactic surgery. General and breast cancer specific distress, hereditary cancer-related family communication, perceived social support, and demographics were assessed. RESULTS: Using structural equation modelling, we found that open communication about hereditary cancer within the family was associated with less general and breast cancer specific distress. In addition, perceived support from family and friends was indirectly associated with less general and breast cancer-specific distress through open communication within the family. DISCUSSION: These findings indicate that family communication and perceived social support from friends and family are of paramount importance in the long-term adaptation to being at risk for hereditary breast cancer. Attention for these issues needs to be incorporated in the care of women at risk for hereditary breast cancer.

The contribution of self-esteem and self-concept in psychological distress in women at risk of hereditary breast cancer.

OBJECTIVE: Clarification of the role of several aspects of self-concept regarding psychological distress in women at risk of hereditary breast cancer will help to target counselling and psychosocial interventions more appropriately. In this study, we aimed (1) to examine the role of general self-esteem and specific aspects of self-concept (i.e. stigma, vulnerability, and mastery) in psychological distress in women at risk of hereditary breast cancer and (2) to compare the relative importance of these self-concept aspects in psychological distress in women with low versus high self-esteem. METHODS: General and breast-cancer-specific distress, self-esteem, self-concept, and demographics were assessed in 246 women being at risk of hereditary breast cancer, who opted either for regular breast surveillance or prophylactic surgery. RESULTS: In the total study group, self-esteem was negatively associated with general distress. Furthermore, feeling stigmatized was strongly associated with more breast-cancer-specific distress, and to a lesser degree with general distress. In women with low-self esteem, feelings of stigmatization were strongly associated with higher levels of both breast-cancer-specific and general distress, while a sense of mastery was associated with less general distress. For women with high self-esteem, feelings of both stigmatization and vulnerability were associated with more breast-cancer-specific distress, whereas there were no significant associations with general distress. DISCUSSION: Psychosocial interventions or support groups for women at risk of hereditary breast cancer should focus on self-esteem and feelings of stigmatization and isolation, and consequently tailor the interventions on specific items for respective women.

BRCA1-associated breast cancers present differently from BRCA2-associated and familial cases: long-term follow-up of the Dutch MRISC Screening Study.

PURPOSE: The Dutch MRI Screening Study on early detection of hereditary breast cancer started in 1999. We evaluated the long-term results including separate analyses of BRCA1 and BRCA2 mutation carriers and first results on survival. PATIENTS AND METHODS: Women with higher than 15% cumulative lifetime risk (CLTR) of breast cancer were screened with biannual clinical breast examination and annual mammography and magnetic resonance imaging (MRI). Participants were divided into subgroups: carriers of a gene mutation (50% to 85% CLTR) and two familial groups with high (30% to 50% CLTR) or moderate risk (15% to 30% CLTR). RESULTS: Our update contains 2,157 eligible women including 599 mutation carriers (median follow-up of 4.9 years from entry) with 97 primary breast cancers detected (median follow-up of 5.0 years from diagnosis). MRI sensitivity was superior to that of mammography for invasive cancer (77.4% v 35.5%; P<.00005), but not for ductal carcinoma in situ. Results in the BRCA1 group were worse compared to the BRCA2, the high-, and the moderate-risk groups, respectively, for mammography sensitivity (25.0% v 61.5%, 45.5%, 46.7%), tumor size at diagnosis≤1 cm (21.4% v 61.5%, 40.9%, 63.6%), proportion of DCIS (6.5% v 18.8%, 14.8%, 31.3%) and interval cancers (32.3% v 6.3%, 3.7%, 6.3%), and age at diagnosis younger than 30 years (9.7% v 0%). Cumulative distant metastasis-free and overall survival at 6 years in all 42 BRCA1/2 mutation carriers with invasive breast cancer were 83.9% (95% CI, 64.1% to 93.3%) and 92.7% (95% CI, 79.0% to 97.6%), respectively, and 100% in the familial groups (n=43). CONCLUSION: Screening results were somewhat worse in BRCA1 mutation carriers, but 6-year survival was high in all risk groups.

Sensitivity to first-line chemotherapy for metastatic breast cancer in BRCA1 and BRCA2 mutation carriers.

PURPOSE: Preclinical as well as a few small retrospective, neoadjuvant studies suggest that breast cancer (cells) without functional BRCA1 or BRCA2 protein have an increased sensitivity to some chemotherapeutic agents causing double-strand DNA breaks. In this study we assessed the sensitivity to standard first-line chemotherapy of metastatic BRCA1/2-associated breast cancer, compared with sporadic breast cancer patients. PATIENTS AND METHODS: From the Family Cancer Clinic database, we selected 93 BRCA1- and 28 BRCA2-associated breast cancer patients treated with chemotherapy for metastatic disease before January 1, 2007. Objective response (OR), progression-free survival (PFS), and overall survival (OS) after start of first-line chemotherapy were compared with those of sporadic patients, matched for year of birth, age at diagnosis of primary breast cancer, and year of detection of metastatic disease. RESULTS: The chemotherapy regimens most frequently used were anthracycline-based (n = 147) and cyclophosphamide, methotrexate, and fluorouracil (CMF)/CMF like (n = 68). As compared to sporadic patients, BRCA2-associated patients had a significantly higher OR (89% v 50%; P = .001), a longer PFS (hazard ratio multivariate [HR(mult)] 0.64; P = .04) and a prolonged OS (HR(mult), 0.53; P = .005) after start of first-line chemotherapy for metastatic breast cancer. For BRCA1-associated patients, a nonsignificant trend for an increased OR (66% v 50%; P = .07), and a longer PFS (HR(mult), 0.79; P = .14) after first-line chemotherapy for metastatic breast cancer was observed, but not for OS. CONCLUSION: BRCA2-associated breast cancer is more sensitive to standard first-line chemotherapy for metastatic breast cancer in comparison with sporadic breast cancer, especially to anthracyclines. For BRCA1-associated breast cancer no statistically significant higher sensitivity was observed.

Breast cancer screening: evidence for false reassurance?

Tumour stage distribution at repeated mammography screening is, unexpectedly, often not more favourable than stage distribution at first screenings. False reassurance, i.e., delayed symptom presentation due to having participated in earlier screening rounds, might be associated with this, and unfavourably affect prognosis. To assess the role of false reassurance in mammography screening, a consecutive group of 155 breast cancer patients visiting a breast clinic in Rotterdam (The Netherlands) completed a questionnaire on screening history and self-observed breast abnormalities. The length of time between the initial discovery of breast abnormalities and first consultation of a general practitioner ("symptom-GP period") was compared between patients with ("screening group") and without a previous screening history ("control group"), using Kaplan-Meier survival curves and log-rank testing. Of the 155 patients, 84 (54%) had participated in the Dutch screening programme at least once before tumour detection; 32 (38%) of whom had noticed symptoms. They did not significantly differ from control patients (n = 42) in symptom-GP period (symptom-GP period > or = 30 days: 31.2% in the symptomatic screened group, 31.0% in the control group; p = 0.9). Only 2 out of 53 patients (3.8%) with screen-detected cancer had noticed symptoms prior to screening, reporting symptom-GP periods of 2.5 and 4 years. The median period between the first GP- and breast clinic visit was 7.0 days (95% C.I. 5.9-8.1) in symptomatic screened patients and 6.0 days (95% C.I. 4.0-8.0) in control patients. Our results show that false reassurance played, at most, only a minor role in breast cancer screening.

Distant disease-free interval, site of first relapse and post-relapse survival in BRCA1- and BRCA2-associated compared to sporadic breast cancer patients.

BACKGROUND: Data on distant disease-free interval (DDFI) and the localization of the first distant metastasis (DM) in BRCA1- and BRCA2-associated breast cancer (BC) patients are as yet scarcely available. PATIENTS AND METHODS: We identified 57 BRCA1-associated and 31 BRCA2-associated BC patients, diagnosed between 1980 and 2001, and developing DM disease before 2004, July 1. DDFI, the site(s) of first DM and post-relapse survival of these patients were compared with those of 192 sporadic BC patients. RESULTS: As compared to sporadic patients, BRCA1 patients developed less often bone DM (30% vs. 51%; P = 0.005), but tended to develop more often lung DM (26% vs. 16%; P = 0.07), and DM at multiple sites (44% vs. 32%; P = 0.11). In BRCA2-associated compared to sporadic patients, first DM more commonly occurred in lymph nodes (23% vs. 7%; P = 0.007) and at multiple sites (48% vs. 32%; P = 0.08). Adjuvant systemic therapy appeared to be most effective in BRCA2 mutation carriers. Post-relapse survival was worse for BRCA1- and better for BRCA2-associated patients as compared to sporadic patients, but differences disappeared after adjustment for ER-status, site of first DM and DDFI. CONCLUSION: The site of first DM is different between BRCA1- and BRCA2-associated and sporadic BC patients. Differences in post-relapse survival could be explained by differences in site of first DM, in ER-status and in DDFI. Treatment efficacy may differ dependent on genetic status.

Prophylactic mastectomy in BRCA1/2 mutation carriers and women at risk of hereditary breast cancer: long-term experiences at the Rotterdam Family Cancer Clinic.

BACKGROUND: BRCA1/2 mutation carriers and women from a hereditary breast(/ovarian) cancer family have a highly increased risk of developing breast cancer (BC). Prophylactic mastectomy (PM) results in the greatest BC risk reduction. Long-term data on the efficacy and sequels of PM are scarce. METHODS: From 358 high-risk women (including 236 BRCA1/2 carriers) undergoing PM between 1994 and 2004, relevant data on the occurrence of BC in relation to PM, complications in relation to breast reconstruction (BR), mutation status, age at PM and preoperative imaging examination results were extracted from the medical records, and analyzed separately for women without (unaffected, n = 177) and with a BC history (affected, n = 181). RESULTS: No primary BCs occurred after PM (median follow-up 4.5 years). In one previously unaffected woman, metastatic BC was detected almost 4 years after PM (primary BC not found). Median age at PM was younger in unaffected women (P < .001), affected women more frequently were 50% risk carriers (P < .001). Unexpected (pre)malignant changes at PM were found in 3% of the patients (in 5 affected, and 5 unaffected women, respectively). In 49.6% of the women opting for BR one or more complications were registered, totaling 215 complications, leading to 153 surgical interventions (71%). Complications were mainly related to cosmetic outcome (36%) and capsular formation (24%). CONCLUSIONS: The risk of developing a primary BC after PM remains low after longer follow-up. Preoperative imaging and careful histological examination is warranted because of potential unexpected (pre)malignant findings. The high complication rate after breast reconstruction mainly concerns cosmetic issues.

Factors affecting sensitivity and specificity of screening mammography and MRI in women with an inherited risk for breast cancer.

BACKGROUND: The MRISC study is a screening study, in which women with an increased risk of hereditary breast cancer are screened by a yearly mammography and MRI, and half-yearly clinical breast examination. The sensitivity found in this study was 40% for mammography and 71% for MRI and the specificity was 95 and 90%, respectively. In the current subsequent study we investigated whether these results are influenced by age, a BRCA1/2 mutation, menopausal status and breast density. PATIENTS AND METHODS: From November 1999 to October 2003, 1909 eligible women were screened and 50 breast cancers were detected. For the current analysis, data of 4134 screening rounds and 45 detected breast cancers were used. For both imaging modalities, screening parameters, receiver operating characteristic (ROC) curves and uni- and multivariate odds ratios (ORs) were calculated. All analyses were separately performed for age at entry (< 40, 40-49, > or =50), mutation status, menopausal status and breast density. RESULTS: Sensitivity of MRI was decreased in women with high breast density (adjusted OR 0.08). False-positive rates of both mammography (OR(adj) 1.67) and MRI (OR(adj) 1.21) were increased by high breast density, that of MRI by pre-menopausal status (OR(adj) 1.70), young age (OR(adj) 1.58 for women 40-49 years versus women > or =50 years) and decreased in BRCA1/2 mutation carriers (OR(adj) 0.74). In all investigated subgroups the discriminating capacity (measured by the area under the ROC-curve) was higher for MRI than for mammography, with the largest differences for BRCA1/2 mutation carriers (0.237), for women between 40 and 49 years (0.227) and for women with a low breast density (0.237). CONCLUSIONS: This report supports the earlier recommendation that MRI should be a standard screening method for breast cancer in BRCA1/2 mutation carriers.

The impact of having relatives affected with breast cancer on psychological distress in women at increased risk for hereditary breast cancer.

PURPOSE: Being at hereditary risk of breast cancer (BC) may lead to elevated levels of distress because of the impact of the BC-process in relatives. OBJECTIVE: Determine the association between psychological distress and BC in relatives. We studied: kind of kinship with the affected relative(s), degree of involvement with the relative's BC, time elapsed since the BC diagnosis of the relative, and loss of a relative as a consequence of BC. METHODS: The study cohort consisted of women at increased risk of developing BC, adhering to regular surveillance and participating in the Dutch MRISC-study. Two months prior to the surveillance appointment, demographics, general and BC specific distress and experience with BC in the family were assessed. RESULTS: 347 out of 351 participants (mean age 40 1/2) had at least one relative affected with BC. The following variables were significantly, positively related to BC specific distress: having at least one affected sister (n = 105; p < 0.04); close involvement in a sister's BC process (n = 94; p < 0.03); and a recent (less than three years ago) BC diagnosis in a sister (n = 30; p < 0.03). General distress did not show any significant associations with the experience of BC in the family. CONCLUSION: These findings show the impact of a BC diagnosis in a sister, particularly a recent diagnosis, on psychological distress. Women who have experienced BC in their sister may be in need of additional counselling or of more attention during the surveillance process.

Attitudes and distress levels in women at risk to carry a BRCA1/BRCA2 gene mutation who decline genetic testing.

Genetic testing enables women at risk for hereditary breast and/or ovarian cancer to find out whether they have inherited the gene mutation, and if so, to opt for undergoing frequent surveillance and/or prophylactic surgery. However, the option to know about one's genetic status is not always seen as a benefit by women at risk. Motives for declining genetic testing were explored in 13 women at 25% or 50% risk to be a BRCA1/BRCA2 mutation carrier, who participated in a surveillance program for breast/ovarian cancer (the non-tested group). We hypothesized that high anxiety might be an important motive to decline testing. In addition, we investigated whether the non-tested group differed from a reference group of women who did undergo the test (tested group; n = 85) with regard to biographical factors, experience with cancer in relatives, and personality traits. Most non-tested women (10/13) were satisfied with participating in the surveillance program. Four reported to feel emotionally unprepared to cope with the consequences of testing. Compared with the tested group, the non-tested women had similar mean distress levels (which were not high), but a higher education level, they were more often childless, showed more reluctance towards prophylactic surgery, were younger when first confronted with a relative affected with breast/ovarian cancer, and were longer aware of the genetic nature of the disease. This study showed that women were more likely to have thoroughly reflected on their decision not to undergo genetic testing, than to deny the whole issue due to high anxiety. Being confronted at a relatively young age with breast/ovarian cancer in a relative, and being aware of the genetic risk for a many years, may have resulted in the risk for cancer becoming an integrated part of their lives. However, generalization of these results to women who neither underwent the test nor participated in a surveillance program should be considered with caution.

One year follow-up of women opting for presymptomatic testing for BRCA1 and BRCA2: emotional impact of the test outcome and decisions on risk management (surveillance or prophylactic surgery).

Genetic testing enables women at risk for hereditary breast and/or ovarian cancer to find out whether they have inherited the gene mutation (BRCA1/BRCA2), and if so, to opt for frequent surveillance and/or prophylactic surgery (bilateral mastectomy and/or oophorectomy). Here, a follow-up is described for 63 healthy women at 50% risk of being a BRCA1/BRCA2 mutation carrier who underwent genetic testing. The course of distress and problems regarding body image and sexuality up to 1 year after disclosure of the test-outcome were described separately for mutation carriers undergoing mastectomy (n = 14), for mutation carriers opting for surveillance (n = 12) and for non-mutation carriers (n = 37). Furthermore, we analyzed whether women opting for prophylactic mastectomy differed from those opting for close surveillance with respect to biographical characteristics, experiences with cancer in relatives and personality. Women opting for prophylactic mastectomy had significantly higher distress levels than mutation carriers who opted for surveillance, and the non-mutation carriers. This difference in levels of distress was highest at pre- and post-test and had almost disappeared at 1-year follow-up. Besides, mutation carriers opting for prophylactic mastectomy were more often in their thirties, more often had young children and had a longer awareness of the genetic nature of cancer in the family than those opting for regular surveillance. Adverse effects were observed in women who underwent prophylactic mastectomy (mostly in combination with immediate breast reconstruction) regarding the perception of how their breast region looked like and felt, the intimate relationship and physical wellbeing whereas women opting for prophylactic mastectomy reported more distress than the other women in the study, their distress levels had significantly decreased 6 months or longer after surgery, possibly due to the significant risk reduction of developing breast cancer. This might explain, why most women who underwent prophylactic mastectomy were satisfied with this decision, despite a perceived negative impact on body image, the intimate relationship and physical wellbeing.

Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations.

Mutations in BRCA1 and BRCA2 confer a high risk of breast and ovarian cancer, but account for only a small fraction of breast cancer susceptibility. To find additional genes conferring susceptibility to breast cancer, we analyzed CHEK2 (also known as CHK2), which encodes a cell-cycle checkpoint kinase that is implicated in DNA repair processes involving BRCA1 and p53 (refs 3,4,5). We show that CHEK2(*)1100delC, a truncating variant that abrogates the kinase activity, has a frequency of 1.1% in healthy individuals. However, this variant is present in 5.1% of individuals with breast cancer from 718 families that do not carry mutations in BRCA1 or BRCA2 (P = 0.00000003), including 13.5% of individuals from families with male breast cancer (P = 0.00015). We estimate that the CHEK2(*)1100delC variant results in an approximately twofold increase of breast cancer risk in women and a tenfold increase of risk in men. By contrast, the variant confers no increased cancer risk in carriers of BRCA1 or BRCA2 mutations. This suggests that the biological mechanisms underlying the elevated risk of breast cancer in CHEK2 mutation carriers are already subverted in carriers of BRCA1 or BRCA2 mutations, which is consistent with participation of the encoded proteins in the same pathway.