Impact of preoperative breast MRI on 10-year survival of patients included in the Swedish randomized multicentre POMB trial.

BACKGROUND: The value of preoperative breast MRI as an adjunct technique regarding its effect on re-excision rates has been a subject of discussion. No survival data regarding preoperative breast MRI are available from randomized studies. METHODS: Ten-year follow-up of the POMB randomized multicentre study was analysed, evaluating MRI and its effect on disease-free survival (DFS) and overall survival (OS). Patients with newly diagnosed breast cancer were randomized to either preoperative MRI or conventional imaging. Kaplan-Meier plots were used to analyse DFS and OS, and Cox regression to estimate hazard ratios (HRs). RESULTS: A total of 440 patients, aged 56 years or less, with newly diagnosed breast cancer were randomized to either preoperative MRI (220) or conventional imaging (220; control). Median follow-up for each group was 10 years. DFS rates were 85.5 and 80.0 per cent for the MRI and control groups respectively (P = 0.099). The risk of relapse or death was 46 per cent higher in the control group (HR 1.46, 95 per cent c.i. 0.93 to 2.29). OS rates after 10 years were 90.9 and 88.6 per cent in the MRI and control groups respectively (P = 0.427). The risk of death was 27 per cent higher in the control group (HR 1.27, 0.71 to 2.29). Locoregional, distant, and contralateral recurrence outcomes combined were increased in the control group (P = 0.048). A subgroup analysis of patients with breast cancer stages I-III showed that preoperative MRI improved DFS compared with conventional imaging, but this did not reach statistical significance (P = 0.057). CONCLUSION: After 10 years of follow-up, preoperative breast MRI as an adjunct to conventional imaging resulted in slightly, but non-significantly, improved DFS and OS. Registration number: NCT01859936 (http://www.clinicaltrials.gov).

Less correspondence between expectations before and cosmetic results after risk-reducing mastectomy in women who are mutation carriers: a prospective study.

PURPOSE: The primary aim was to describe satisfaction with the cosmetic results six months and one year after risk-reducing mastectomy (RRM) with immediate breast reconstruction. Another aim was to ascertain associations between ratings on "correspondence between the overall results and expectations before RRM" and age, mutation carrier status, salpingo-oophorectomy (SOE) before RRM, body image, and with sexual pleasure and discomfort. METHODS: 91/100 women who underwent RRM between 1997 and 2005 were included. Assessments were made six and twelve months after RRM with questionnaires regarding satisfaction with the cosmetic results, sexuality (SAQ), and body image (BIS). RESULTS: At both assessment points, >70% of the women considered the overall results of RRM to correspond to their expectations. Over 80% were satisfied with the size of their breasts, but 49% indicated at the one-year assessment that at least one breast was too hard and 73% indicated that they had no or only minor sensitivity in the breasts. In the univariate analyses, associations between "correspondence between the overall results and expectations before RRM" and mutation carrier status (p = 0.039) and SOE (p = 0.025) were found, but only mutation carrier status remained in the multivariate analysis (0.037). CONCLUSION: The majority of the women reported that the results of RRM corresponded to their expectations, with lower levels of correspondence in mutation carriers than in non-carriers. Overall satisfaction with the cosmetic result was high, but a majority of the women were unsatisfied with the softness of the reconstructed breasts. These results can be useful when informing patients about RRM.

High satisfaction rate ten years after bilateral prophylactic mastectomy - a longitudinal study.

Women from families with an increased risk for breast/ovarian cancer have undergone bilateral prophylactic mastectomy (BPM) since the early 1990s at the Karolinska University Hospital in Sweden. Perceptions of BPM as reported by the first women who underwent the procedure have previously been evaluated on a short-term basis (1-3 years). The present study aims to evaluate the long-term (10 years) physical and psychological consequences of BPM in the same cohort of women. Some of the very first women to undergo BPM participated in the present interview study (n= 13). The semi-structured interviews focused on the women's long-term experiences related to BPM and immediate breast reconstruction. Overall, the women were satisfied with their decision to undergo BPM and perceived a negligible remaining risk of getting breast cancer. For most women, the operation had not resulted in changes in family life or lifestyle (n= 8), although some described that the relationship with their spouse was affected (8/13), either in a negative (n= 5) or positive (n= 3) way. The cosmetic results were mainly positive (n= 10). Recurrent counselling and support during the whole process of decision, treatment and follow up is recommended.

Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA).

BACKGROUND: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. METHODS: We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. RESULTS: We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P = 0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P = 0.5) mutation carriers. CONCLUSION: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.

Preoperative psychological reactions and quality of life among women with an increased risk of breast cancer who are considering a prophylactic mastectomy.

A consecutive sample of 56 women with a familial risk for breast cancer who were considering a prophylactic mastectomy (PM) completed questionnaires preoperatively concerning risk perception, expectations with regard to surgery, anxiety and depressive symptoms (the Hospital Anxiety and Depression Scale (HAD) scale) and quality of life (The Swedish SF-36 Health Survey). 16 had had a previous breast cancer (Group BC) and 40 had not (Group R). They were compared with normative data from an age-matched random sample of the Swedish population and with a reference sample of women with breast cancer. Most women estimated their breast cancer risk accurately. No statistically significant differences were found between Group BC and the normative sample on the HAD scale and SF-36, but Group R reported better physical functioning, emotional role functioning and mental health than the reference sample with breast cancer. Group BC scored closer to them than to the normative sample. Levels of emotional problems and quality of life were comparable to normative values among women considering PM. All women in the present study had previous genetic counselling and our results suggest that their interest in PM was not due to an overestimation of their personal risk.

First BRCA1 and BRCA2 gene testing implemented in the health care system of Stockholm.

The aim of the study was to optimize the criteria for the BRCA1 and BRCA2 gene testing and to improve oncogenetic counseling in the Stockholm region. Screening for inherited breast cancer genes is laborious and a majority of tested samples turn out to be negative. The frequencies of mutations in the BRCA1 and BRCA2 genes differ across populations. Between 1997 and 2000, 160 families with breast and/or ovarian cancer were counseled and screened for mutations in the two genes. Twenty-five BRCA1 and two BRCA2 disease-causing mutations were found. Various factors associated with the probability of finding a BRCA1 mutation in the families were estimated. Age of onset in different generations and other malignancies were also studied. Families from our region in which both breast and ovarian cancer occur were likely to carry a BRCA1 mutation (34%). In breast-only cancer families, mutations were found only in those with very early onset. All breast- only cancer families with a mutation had at least one case of onset before 36 years of age and a young median age of onset (<43 years). Other malignancies than breast and ovarian cancers did not segregate in the BRCA1 families and surveillance for other malignancies is not needed, in general. Decreasing age of onset with successive generations was common and must be taken into account when surveillance options are considered.

Multiple founder effects and geographical clustering of BRCA1 and BRCA2 families in Finland.

In the Finnish breast and ovarian cancer families six BRCA1 and five BRCA2 mutations have been found recurrently. Some of these recurrent mutations have also been seen elsewhere in the world, while others are exclusively of Finnish origin. A haplotype analysis of 26 Finnish families carrying a BRCA1 mutation and 20 families with a BRCA2 mutation indicated that the carriers of each recurrent mutation have common ancestors. The common ancestors were estimated to trace back to 7-36 generations (150-800 years). The time estimates and the geographical clustering of these founder mutations in Finland are in concordance with the population history of this country. Analysis of the cancer phenotypes showed differential ovarian cancer expression in families carrying mutations in the 5' and 3' ends of the BRCA1 gene, and earlier age of ovarian cancer onset in families with BRCA1 mutations compared with families with BRCA2 mutations. The identification of prominent and regional BRCA1 and BRCA2 founder mutations in Finland will have significant impact on diagnostics in Finnish breast and ovarian cancer families. An isolated population with known history and multiple local founder effects in multigenic disease may offer distinct advantages also for mapping novel predisposing genes.

Hereditary breast cancer: a review.

Breast cancer is the most common female malignancy and a major cause of death in middle-aged women. A positive family history of breast cancer is one of the strongest risk factors for the disease. In addition, many afflicted breast cancer families are characterized by early onset and bilateral tumors, and also, in some cases, associated malignancies, most commonly ovarian cancer. It is estimated that 5-10% of all breast cancer cases are due to autosomal dominant genes segregating with the disease. Mutations in the BRCA1 and BRCA2 genes are known to predispose to breast and ovarian cancer in many families. Other genes are only involved in very rare syndromes, and additional genes remain to be disclosed.

BRCA1 screening in patients with a family history of breast or ovarian cancer.

Several studies have shown that the frequency of BRCA1 mutations in high-risk families differs widely between populations. In a recently published study from the Stockholm region, we found BRCA1 mutations in about 35% of the breast/ovarian families, but only in 1% of the families with site-specific breast cancer. To determine the frequency of BRCA1 mutations in families with a less increased risk for breast or ovarian cancer, a second study was performed. A total of 94 families with two and six families with only one affected member were included. Six mutations were found, all localized in exon 11, and five of them were previously known Swedish founder mutations. The mutation frequency was 6%, similar to the finding in families fulfilling the criteria for hereditary breast cancer (7%) that was disclosed in our first study. All families with a mutation had at least one individual with ovarian cancer. Thus, our study further implies that for a woman with breast cancer, a family history of ovarian cancer is far more important than a family history of breast cancer for predicting a BRCA1 mutation. Our results can be used to increase the specificity in selection of families for genetic testing.

BRCA2 germline mutations in Swedish breast cancer families.

Mutations in the breast cancer susceptibility gene (BRCA2) are believed to be responsible for a significant fraction of hereditary breast cancer. To determine the BRCA2 mutation spectrum in a subset of Swedish breast cancer families, 162 families were screened for germline mutations in this gene. A combination of RT-PCR, PTT and direct DNA sequencing was used. Two mutations and one previously reported polymorphic variant resulting in a truncated protein were identified. Our data suggest that only a small proportion of Swedish breast cancer families is attributable to BRCA2 germline mutations. This result, in combination with the low frequency of BRCA1 germline mutations identified in our previous study, suggests additional high penetrant as well as low penetrant breast cancer susceptibility genes are involved in familial breast cancer.

A screening for BRCA1 mutations in breast and breast-ovarian cancer families from the Stockholm region.

To identify BRCA1 germ-line mutations in the breast and breast-ovarian cancer families in the Stockholm region, a total of 127 families were screened. DNA from 174 patients from these families were studied using various mutation screening techniques, followed by direct DNA sequencing. Mutations were identified in 7 of 20 families with breast and ovarian cancer and in one family with ovarian cancer only, whereas only 1 family of 106 with breast cancer showed a mutation. Thus, germ-line mutations in BRCA1 were found in one-third of the families with both breast and ovarian cancer, but in only 1% of the breast cancer families. The low frequency of germ-line mutations in the site-specific breast cancer families means that other genes are likely to segregate in these families.