Multimodality breast cancer screening in women with a familial or genetic predisposition

Background

Women with a predisposition for breast cancer require a tailored screening program for early cancer detection. We evaluated the performance of mammography (mg), ultrasonography (us), and magnetic resonance imaging (mri) screening in these women.

Patients and Methods

In asymptomatic women either confirmed as BRCA1/2 carriers, or having a greater than 30% probability of being so as estimated by brcapro [Berry D, Parmigiani G. Duke spore (Specialized Program of Research Excellence) in Breast Cancer. 1999], we conducted a prospective comparative trial consisting of annual mri and mg, and biannual us and clinical breast examination. All evaluations were done within 30 days of one another. For each screening round, imaging tests were independently interpreted by three radiologists.

Results

The study enrolled 184 women, and 387 screening rounds were performed, detecting 12 cancers (9 infiltrating, 3 in situ), for an overall cancer yield of 6.5%. At diagnosis, 7 infiltrating cancers were smaller than 2 cm (T1); only 1 woman presented with axillary nodal metastases. All tumours were negative for the human epidermal growth factor receptor 2. Of the 12 cancers, mri detected 10, and mg, 7; us did not identify any additional cancers. The overall recall rate after mri was 21.8%, as compared with 11.4% for us and 16.1% for mg. Recall rates declined with successive screening rounds. In total, 45 biopsies were performed: 21 as a result of an us abnormality; 17, because of an mri lesion; and 7, because of a mg anomaly.

Interpretation

In high-risk women, mri offers the best sensitivity for breast cancer screening. The combination of yearly mri and mg reached a negative predictive value of 100%. The recall rate is greatest with mri, but declines for all modalities with successive screening rounds.     

Differences between first and subsequent rounds of the MRISC breast cancer screening program for women with a familial or genetic predisposition

BACKGROUND: Within the Dutch MRI Screening (MRISC) study, a Dutch multicenter screening study for hereditary breast cancer, the authors investigated whether previously reported increased diagnostic accuracy of magnetic resonance imaging (MRI) compared with mammography would be maintained during subsequent screening rounds. METHODS: From November 1999 to October 2003, 1909 eligible women were included in the study. Screening parameters and tumor characteristics of different rounds were calculated and compared. The authors defined 3 different types of imaging screening rounds: first round in women never screened by imaging before, first round in women screened by imaging (mainly mammography) before, and subsequent rounds. RESULTS: The difference in sensitivity for invasive cancers between mammography and MRI was largest in the first round of women previously screened with mammography (20.0 vs. 93.3%; P=.003), but also in subsequent rounds, there was a significant difference in favor of MRI (29.4 vs. 76.5%; P=.02). The difference in false-positive rate between mammography and MRI was also largest in the first round of women previously screened with mammography (5.5 vs. 14.0%; P<.001), and it remained significant in subsequent rounds (4.6 vs. 8.2%; P<.001). Screen-detected tumors were smaller and more often lymph node negative than symptomatic tumors in age-matched control patients, but no major differences in tumor stage were found between tumors detected at subsequent rounds compared with those in the first round. CONCLUSIONS: In subsequent rounds, a significantly higher sensitivity and better discriminating capacity of MRI compared with mammography was maintained, and a favorable tumor stage compared with age-matched symptomatic controls. As results of these subsequent screening rounds were most predictive for long-term effects, the authors expect that this screening program will contribute to a decrease of breast cancer mortality in these high-risk women.     

MRI screening for breast cancer in women with familial or genetic predisposition: design of the Dutch National Study (MRISC)

Mammography screening of women aged 50–70 years for breast cancer has proven to be effective in reducing breast cancer mortality. There is no consensus about the value of breast cancer screening in women aged 40–49 years. Five to ten per cent of all breast cancers are hereditary. One of the options to reduce the risk of breast cancer mortality for women with a familial or genetic predisposition is intensive surveillance. However, the effectiveness of mammography screening for breast cancer in these women, who are mainly younger than 50 years, is unproven. MRI might increase the effectiveness of screening in women with a familial or genetic predisposition. This paper describes the design of the Dutch national study for Magnetic Resonance Imaging (MRI) screening in women with a familial or genetic predisposition. The aims of this study are to investigate: the value of regular surveillance in women with a familial or genetic predisposition for breast cancer, the efficacy of MRI as compared to mammography, cost-effectiveness of regular screening and quality of life during surveillance. Included are women with a lifetime risk of familial breast cancer of 15% or more or BRCA1/2 mutation carriers, who visit one of the Dutch family cancer clinics. The aim is to include 2,500 women. The study started on 1 November 1999. On 1 January 2002, more than 1700 women, including 210 proven carriers of a BRCA1 or BRCA2 mutation, were included in the study.     

Outcome of a structured surveillance programme in women with a familial predisposition for breast cancer.

We aimed to prospectively evaluate the efficacy of a multi-modal surveillance programme for the early detection of familial breast cancer. Ultrasound, mammography and breast magnetic resonance imaging were evaluated in 413 women who participated in a prospective study with a median follow-up of 2.2 years (range 1-6.75 years). Of these, 49 women carried a BRCA mutation, 203 were at high and 161 at moderate risk. Breast carcinomas diagnosed within the programme were compared with 297 carcinomas previously observed in the risk group and 7894 carcinomas documented in the regional cancer registry within the same time period. Overall, 41 breast carcinomas and no interval carcinoma were detected. The detection rates averaged 107.2/1000 for mutation carriers with highest rates between 20 and 39 years of age, 45.8/1000 for high-risk women with highest rates between 40 and 49 years of age and 23.9/1000 for moderate-risk women with highest rates between 50 and 74 years of age. Overall, 82.8% of the breast carcinomas were node negative and 85.4% pre-invasive or smaller than 2 cm. In comparison, of breast carcinomas detected outside the programme only 47.8% were node negative (P=0.0005) and 43.8% pre-invasive or smaller than 2 cm (P<0.000 01). Of those gathered in the local cancer registry 55.7% were node negative (P=0.004) and 47.6% pre-invasive or smaller than 2 cm (P<0.000 01). Our data indicate that (1) there is a strong correlation between breast cancer detection rates, risk status and age at disease onset and (2) a multi-modal surveillance programme can detect early-stage hereditary breast carcinomas.     

Chromosomal radiosensitivity in breast cancer patients with a known or putative genetic predisposition

The chromosomal radiosensitivity of breast cancer patients with a known or putative genetic predisposition was investigated and compared to a group of healthy women. The chromosomal radiosensitivity was assessed with the G2 and the G0-micronucleus assay. For the G2 assay lymphocytes were irradiated in vitro with a dose of 0.4 Gy (60)Co gamma-rays after 71 h incubation, and chromatid breaks were scored in 50 metaphases. For the micronucleus assay lymphocytes were exposed in vitro to 3.5 Gy (60)Co gamma-rays at a high dose rate or low dose rate. 70 h post-irradiation cultures were arrested and micronuclei were scored in 1000 binucleate cells. The results demonstrated that the group of breast cancer patients with a known or putative genetic predisposition was on the average more radiosensitive than a population of healthy women, and this with the G2 as well as with the high dose rate and low dose rate micronucleus assay. With the G2 assay 43% of the patients were found to be radiosensitive. A higher proportion of the patients were radiosensitive with the micronucleus assay (45% with high dose rate and 61% with low dose rate). No correlation was found between the G2 and the G0-micronucleus chromosomal radiosensitivity. Out of the different subgroups considered, the group of the young breast cancer patients without family history showed the highest percentage of radiosensitive cases in the G2 (50%) as well as in the micronucleus assay (75-78%).     

Local-regional control in breast cancer patients with a possible genetic predisposition

PURPOSE: Local control rates for breast cancer in genetically predisposed women are poorly defined. Because such a small percentage of breast cancer patients have proven germline mutations, surrogates, such as a family history for breast cancer, have been used to examine this issue. The purpose of this study was to evaluate local-regional control following breast conservation therapy (BCT) in patients with bilateral breast cancer and a breast cancer family history. METHODS AND MATERIALS: We retrospectively reviewed records of all 58 patients with bilateral breast cancer and a breast cancer family history treated in our institution between 1959 and 1998. The primary surgical treatment was a breast-conserving procedure in 55 of the 116 breast cancer cases and a mastectomy in 61. The median follow-up was 68 months for the BCT patients and 57 months for the mastectomy-treated patients. RESULTS: Eight local-regional recurrences occurred in the 55 cases treated with BCT, resulting in 5- and 10-year actuarial local-regional control rates of 86% and 76%, respectively. In the nine cases that did not receive radiation as a component of their BCT, four developed local-regional recurrences (5- and 10-year local-regional control rates of BCT without radiation: 49% and 49%). The 5- and 10-year actuarial local-regional control rates for the 46 cases treated with BCT and radiation were 94% and 83%, respectively. In these cases, there were two late local recurrences, developing at 8 years and 9 years, respectively. A log rank comparison of radiation versus no radiation actuarial data was significant at p = 0.009. In the cases treated with BCT, a multivariate analysis of radiation use, patient age, degree of family history, margin status, and stage revealed that only the use of radiation was associated with improved local control (Cox regression analysis p = 0.021). The 10-year actuarial rates of local-regional control following mastectomy with and without radiation were 91% and 89%, respectively. CONCLUSIONS: Patients with a possible genetic predisposition to breast cancer had low 5-year rates of local recurrence when treated with breast conserving surgery and radiation, but the local failure rate exceeded 50% when radiation was omitted. Our data are consistent with the hypothesis that patients with an underlying genetic predisposition develop cancers with radiosensitive phenotypes.     

Evaluation of RAD50 in familial breast cancer predisposition

The genes predisposing to familial breast cancer are largely unknown, but 5 of the 6 known genes are involved in DNA damage repair. RAD50 is part of a highly conserved complex important in recognising, signalling and repairing DNA double-strand breaks. Recently, a truncating mutation in the RAD50 gene, 687delT, was identified in 2 Finnish breast cancer families. To evaluate the contribution of RAD50 to familial breast cancer, we screened the whole coding region for mutations in 435 UK and 46 Finnish familial breast cancer cases. We identified one truncating mutation, Q350X, in one UK family. We screened a further 544 Finnish familial breast cancer cases and 560 controls for the 687delT mutation, which was present in 3 cases (0.5%) and 1 control (0.2%). Neither Q350X nor 687delT segregated with cancer in the families in which they were identified. Functional analyses suggested that RAD50 687delT is a null allele as there was no detectable expression of the mutant protein. However, the wild-type allele was retained and expressed in breast tumors from mutation carriers. The abundance of the full-length RAD50 protein was reduced in carrier lymphoblastoid cells, suggesting a possible haploinsufficiency mechanism. These data indicate that RAD50 mutations are rare in familial breast cancer and either carry no, or a very small, increased risk of cancer. Altogether, these results suggest RAD50 can only be making a very minor contribution to familial breast cancer predisposition in UK and Finland.     

Follow-up of cases with false-negative pathologic sentinel nodes in breast cancer

BACKGROUND: The clinical practice of sentinel lymph node biopsy for breast cancer patients started in 1999 in our hospital, to obviate unnecessary axillary lymph node dissection. The present study examines the pathological false-negative cases on intraoperative sentinel lymph node investigations and evaluates their outcomes. METHODS: The subjects consisted of 183 cases with clinically node-negative breast cancer who had undergone sentinel node biopsy. When the sentinel node was noted to contain malignant cells intraoperatively, a complete axillary lymph node dissection was performed subsequently. The patients with tumor free sentinel nodes underwent no further axillary surgery. The pathological false-negative cases in this series were defined as patients with lymph node involvement which was revealed postoperatively, despite negative intraoperative sentinel node examinations. After these surgeries and/or adjuvant therapies, interval clinical evaluations were performed for all patients. RESULTS: Intraoperative diagnosis of the sentinel node was 96.2% accurate compared with the results of permanent sections. There were six pathological false-negative cases, a false-negative rate of 4.1%, all of which had only micrometastasis. Five cases received systemic adjuvant therapy and have been disease-free, however, one patient who refused further therapy developed infraclavicular lymph node metastasis two years after surgery. CONCLUSIONS: In the management of the patients with postoperatively revealed sentinel node micrometastasis, systemic adjuvant therapies might reduce local relapse without secondary lymph node dissection.     

Predictors associated with MRI surveillance screening in women with a personal history of unilateral breast cancer but without a genetic predisposition for future contralateral breast cancer

Purpose

For women with a personal history of breast cancer (PHBC), no validated mechanisms exist to calculate future contralateral breast cancer (CBC) risk. The Manchester risk stratification guidelines were developed to evaluate CBC risk in women with a PHBC, primarily for surgical decision making. This tool may be informative for the use of MRI screening, as CBC risk is an assumed consideration for high-risk surveillance.

Methods

Three hundred twenty-two women with a PHBC were treated with unilateral surgery within our multidisciplinary breast clinic. We calculated lifetime CBC risk using the Manchester tool, which incorporates age at diagnosis, family history, genetic mutation status, estrogen receptor positivity, and endocrine therapy use. Univariate and multivariate logistic regression analyses (UVA/MVA) were performed, evaluating whether CBC risk predicted MRI surveillance.

Results

For women with invasive disease undergoing MRI surveillance, 66% had low, 23% above-average, and 11% moderate/high risk for CBC. On MVA, previous mammography-occult breast cancer [odds ratio (OR) 18.95, p < 0.0001], endocrine therapy use (OR 3.89, p = 0.009), dense breast tissue (OR 3.69, p = 0.0007), mastectomy versus lumpectomy (OR 3.12, p = 0.0041), and CBC risk (OR 3.17 for every 10% increase, p = 0.0002) were associated with MRI surveillance. No pathologic factors increasing ipsilateral breast cancer recurrence were significant on MVA.

Conclusions

Although CBC risk predicted MRI surveillance, 89% with invasive disease undergoing MRI had <20% calculated CBC risk. Concerns related to future breast cancer detectability (dense breasts and/or previous mammography-occult disease) predominate decision making. Pathologic factors important for determining ipsilateral recurrence risk, aside from age, were not associated with MRI surveillance.

     

Evaluation of Fanconi Anemia genes in familial breast cancer predisposition

Fanconi Anemia (FA) is an autosomal recessive syndrome characterized by congenital abnormalities, progressive bone marrow failure, and susceptibility to cancer. FA has eight known complementation groups and is caused by mutations in at least seven genes. Biallelic BRCA2 mutations were shown recently to cause FA-D1. Monoallelic (heterozygous) BRCA2 mutations confer a high risk of breast cancer and are a major cause of familial breast cancer. To investigate whether heterozygous variants in other FA genes are high penetrance breast cancer susceptibility alleles, we screened germ-line DNA from 88 BRCA1/2-negative families, each with at least three cases of breast cancer, for mutations in FANCA, FANCC, FANCD2, FANCE, FANCF, and FANCG. Sixty-nine sequence variants were identified of which 25 were exonic. None of the exonic variants resulted in translational frameshifts or nonsense codons and 14 were polymorphisms documented previously. Of the remaining 11 exonic variants, 2 resulted in synonymous changes, and 7 were present in controls. Only 2 conservative missense variants, 1 in FANCA and 1 in FANCE, were each found in a single family and were not present in 300 controls. The results indicate that FA gene mutations, other than in BRCA2, are unlikely to be a frequent cause of highly penetrant breast cancer predisposition.     

Psychological distress in women with a familial risk of breast cancer

In the present study women at familial risk for breast cancer (N = 26, risk group) underwent psychological assessments on two occasions: immediately prior to mammography screening and a month after notification of their normal results. Assessments included standardized measures of: acute distress; non-specific distress; intrusive thoughts; and avoidance about breast cancer. Normal risk women not undergoing mammography (N = 27, comparison group) completed the same measures, to provide an indication of concurrent levels of distress in women recruited from the same community. Results revealed that, prior to mammography, the risk group had high levels of acute distress, which were reduced to the level of the comparison group following notification of normal mammography results. On the other hand, despite notification of normal results, the risk group continued to have higher levels of non-specific distress, avoidance and intrusive thoughts about breast cancer. These results confirm and extend previous reports of high levels of non-specific distress and intrusive thoughts in women at familial risk for breast cancer. The findings highlight the need for further studies to determine the sources of this distress and its possible negative consequences for these individuals at risk for cancer.     

Stage of breast cancers found during the surveillance of women with a familial or hereditary risk

Aim

To compare the breast cancer stages found during MG alone surveillance in women at increased risk with those detected in a program where MRI was added.

Methods

Stage results of in a retrospective MG alone study of prospectively followed patients, compared with the pooled stage results of breast cancers MG/MRI surveillance.

Results

One hundred and-fifty-one patients were detected with a first or contralateral breast cancer. Interval cancers were diagnosed in 56% of the BRCA1, 42% of the BRCA2 and 28% of the non-BRCA carriers. A considerable proportion of the breast cancers were detected with breast self-examination alone: 41%, 27% and 31% respectively. Nevertheless the established goals for biennial population screening were reached, except for the BRCA2 carriers, but this group was small. Comparison with pooled data from published MG/MRI surveillance studies did not show significant differences in the stages, except for the BRCA2 carriers.

Conclusion

Breast cancers detected in a MG alone surveillance program for women at increased risk fulfill most goals set for population screening except for the BRCA2 carriers. Breast self-examination appears to be a valuable additional detection method especially for BRCA1 carriers, who are at risk of developing a highly proliferating breast cancer.     

Risk-reducing surgery in women with familial susceptibility for breast and/or ovarian cancer

This multicentre study examined uptake of bilateral risk-reducing mastectomy (BRRM) and bilateral risk-reducing oophorectomy (BRRO) in women at increased risk for breast and/or ovarian cancer who had attended a familial cancer clinic (FCC) between January 1999 and June 2000. Eligible women (N=396), were mailed a questionnaire assessing: BRRM and BRRO details; risk perception; and anxiety. Family history, genetic testing and risk assessment were abstracted from medical records. Surgery was cross-tabulated with demographics, risk perception and anxiety with either Fisher's exact test or the exact form of the Mantel-Haenszel test (for ordinal factors) used to investigate for associations. Ordinal logistic regression was used with continuous-scale covariates. In total, 130 women were lost to follow-up leaving 266; of these 182 (68.4%) responded. Mean follow-up time was 3.73 years. The BRRM rate was 4.4%; with no difference found between moderate and high-risk groups. BRRM was associated with increasing numbers of affected relatives (P=0.025). BRRO was undertaken by 17.3%, more commonly in women older than 40 years of age (P=0.023) and with a BRCA1/2 mutation (P=0.017). Women who underwent BRRM (P=0.052) or BRRO (P<0.001) had a lower post-procedure risk perception than those who did not. During the timeframe of this study, risk-reducing surgery was undertaken by a small percentage of Australian women at increased risk for breast and/or ovarian cancer who attended FCCs. Family cancer history and mutation status were associated with uptake.     

First experiences in screening women at high risk for breast cancer with MR imaging

Women with a genetic predisposition for breast cancer are often advised surveillance with physical examination twice a year and mammography once a year from 25 years onwards. However, the sensitivity of the mammography decreases when breast tissue is dense and this is seen in 40–50% of women under 50 years. We therefore investigated whether magnetic resonance imaging (MRI) in addition to the normal surveillance could detect cancers otherwise missed. In 109 women with over 25% risk of breast cancer, MRI was performed because over 50% dense breast tissue was seen at mammography and no suspect lesion was seen at the previous screening. MRI detected breast cancers in three patients (2.8%) occult at mammography and with no new palpable tumor, twice at stage T1bN0 and T1cN0 once. Two cancers were expected. MRI was false positive in six women, resulting in two benign local excisions because ultrasound or fine needle examination confirmed suspicion. We had no false negative MRI results. MRI proved true benign in four BRCA 1/2 gene mutation carriers at histologic examination. Preoperative wire localization of the malignancies detected at MRI proved necessary as the tumor was not palpable in the lumpectomy specimen nor visible at specimen radiology. The extra cost of breast MRI in addition to mammography and physical examination was uro13.930 per detected cancer. The cost of the detection of one breast cancer patient in our national screening program is uro9000. During follow-up of patients with a familial risk in whom the first breast cancer was detected at MRI, MRI detected two recurrent cancers in stage T1bN0 and T1cN0 and one contralateral cancer T1aNo. Breast MRI is promising in screening young women at high risk for breast cancer, as it can advance the detection of cancers still occult at mammography and physical examination; but the cost may be considerable.     

乳腺癌的遗传易感性

乳腺癌作为全球女性发病率最高的恶性肿瘤,近年来对其发生发展的研究日益增多及深入.众多研究者运用全基因组关联分析(genome-wide association study,GWAS)以及测序技术,发现并鉴定出了多个乳腺癌的易感基因及位点,为乳腺癌发病机制的研究提供了重要的线索.为了发现更多的乳腺癌易感基因及位点,研究者不再局限于单一的研究方法,而是联合运用多种研究方法来进行乳腺癌的遗传易感性研究.本文详细介绍这些研究方法及应用在乳腺癌易感基因研究中的进展.