Life Expectancy Gains From Cancer Prevention Strategies for Women With Breast Cancer and &lt;EMPH TYPE="ITAL"&gt;BRCA1&lt;/EMPH&gt; or &lt;EMPH TYPE="ITAL"&gt;BRCA2&lt;/EMPH&gt; Mutations

Schrag, Deborah

doi:10.1001/jama.283.5.617

Cited by 202 publications

(104 citation statements)

References 55 publications

(56 reference statements)

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“…There is some support for a substantial benefit of tamoxifen in prevention of contralateral tumours in mutation-positive breast cancer cases, from a retrospective casecontrol study (Narod et al, 2000). Simulation studies also suggest a secondary preventive effect (Schrag et al, 2000). Our results suggest a modest primary preventive effect, which is stronger in BRCA2 positive women than in BRCA1 positive.…”

supporting

confidence: 54%

Estimates of the likely prophylactic effect of tamoxifen in women with high risk BRCA1 and BRCA2 mutations

Duffy

Nixon

2002

Br J Cancer

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The development of breast cancer control strategies in women at high genetic risk of breast cancer is an important issue. The likely benefit of chemopreventive approaches is of particular interest. Tamoxifen tends to be more effective in both prevention and treatment of oestrogen receptor positive tumours than oestrogen receptor negative. In this study, we combine the oestrogen-receptor specific effects of tamoxifen from randomized preventive or therapeutic trials with the oestrogen receptor status of tumours in BRCA1 and BRCA2 mutation positive women from published tumour surveys to obtain estimates of the likely effect of tamoxifen administration in mutation carriers. We used a simple two-stage procedure to estimate the benefit as a weighted average of the effect on oestrogen receptor positive tumours and oestrogen receptor negative, and using a more complex hierarchical modelling approach. Using the simple procedure and deriving the estimates of benefit from both primary prevention and therapeutic trials, we obtain an estimated reduction in risk of breast cancer from administration of tamoxifen in BRCA1 mutation positive women of 13% (RR=0.87, 95% CI 0.68 -1.11). The corresponding estimated reduction in BRCA2 mutation positive women was 27% (RR=0.73, 95% CI 0.59 -0.90). Using the more complex models gave essentially the same results. Using only the primary prevention trials gave smaller estimates of benefit in BRCA1 carriers but larger estimates in BRCA2, in both cases with wider confidence intervals. The benefit of prophylactic use of tamoxifen in BRCA1 mutation carriers is likely to be modest, and the effect in BRCA2 mutation carriers somewhat greater. In randomized trials, tamoxifen has been shown to be effective in treatment of oestrogen receptor positive (ER+) tumours but not of oestrogen receptor negative (ER7), in terms of prevention of recurrences, new primary tumours and fatality (Early Breast Cancer Trialists' Collaborative Group, 1998). One primary prevention trial in the USA found that tamoxifen substantially reduced incidence of ER+ tumours but had no such effect on ER7 (Fisher et al, 1998). In sporadic breast cancer, the majority of tumours are ER positive (Early Breast Cancer Trialists' Collaborative Group, 1998), whereas the opposite is the case in cancers diagnosed in women with high risk mutations in the BRCA1 and BRCA2 genes (Johannsson et al, 1997;Armes et al, 1999).In this study we synthesize the results on oestrogen receptor (ER) status from tumour series in mutation carriers with subgroup analyses by ER status in primary and secondary prevention trials of long-term tamoxifen use. From this, we derive an estimate of the likely preventive benefit of long-term tamoxifen administration in women with high risk BRCA1 and BRCA2 mutations. MATERIALS AND METHODSFirst, three computerized literature searches augmented with studies brought to our attention by personal communication were performed: (1) To find surveys of ER status in breast cancer patients with a high risk mutation in the BRCA1 or ...

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supporting

confidence: 54%

Estimates of the likely prophylactic effect of tamoxifen in women with high risk BRCA1 and BRCA2 mutations

Duffy

Nixon

2002

Br J Cancer

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“…Data to date from clinical trials are equivocal about the value of tamoxifen for chemoprevention in this population (Narod et al, 2000;Schrag et al, 2000;King et al, 2001;Robson, 2002). An important difference between these trials and the experiments performed here is that in the mouse model full-length Brca1 expression is lost, while in the human studies, the women have loss or mutation of just one allele in the majority of their normal-appearing mammary epithelial cells and loss or mutation of all BRCA1 function only in a subset of these cells or in the carcinomas (Cavalli et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Owing to this, it has been hypothesized that tamoxifen, an SERM, might have a protective role at early stages of cancer progression even if the majority of cancers are ERa negative. Clinical studies published to date demonstrate mixed results (Narod et al, 2000;Schrag et al, 2000;King et al, 2001;Robson, 2002), where one study showed efficacy (Narod et al, 2000) and a second study, albeit with low tumor numbers, showed minor enhancement (King et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Promotion of mammary cancer development by tamoxifen in a mouse model of Brca1-mutation-related breast cancer

Jones

Halama

et al. 2005

Oncogene

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Loss of full-length Brca1 in mammary epithelial cells of the mouse mammary tumor virus (MMTV)-Cre Brca1 conditional exon 11 deletion mouse model results in the development of mammary adenocarcinomas with similar genetic changes to those found in human BRCA1-mutation-related breast cancers. We used this experimental model to evaluate the chemopreventive effect of tamoxifen on the development of mammary preneoplasia and adenocarcinoma. No protective effects of tamoxifen administration on mammary cancer development were found. Instead, tamoxifen treatment significantly increased rates of mammary epithelial cell proliferation and the prevalence of mammary hyperplasia at 6 months of age. Tamoxifen-exposed mice developed adenocarcinomas at younger ages than control mice and a higher percentage of mice developed adenocarcinomas by 12 months of age. Both whole mouse and tissue culture cell models were used to test if loss of full-length Brca1 was associated with a relative increase in the agonist activity of tamoxifen. Tamoxifen induced increased ductal growth in MMTV-Cre Brca1 conditional mice compared to wild type. Estrogen receptor alpha (ERa) expression was downregulated in the tamoxifen-induced hyperplasias. Reducing BRCA1 levels in MCF-7 cells using siRNA resulted in a relative increase in the agonist activity of tamoxifen. Results suggest a model of mammary cancer progression in which loss of full-length Brca1 altered the agonist/antagonist activity of tamoxifen, resulting in tamoxifen-induced mammary epithelial cell proliferation with subsequent loss of ERa expression and development of ERa-negative hyperplasias and adenocarcinomas.

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“…These apparent differences between family-based and population-based studies may have implications for therapeutic decision making. For instance, it has been proposed that the magnitude of life expectancy gains from cancer prevention strategies, including prophylactic contralateral mastectomy, strongly depends on the penetrance of the BRCA mutation (Schrag et al, 2000). Our results suggest that the penetrance with regard to contralateral disease isat least in our hospital-based sample -not necessarily a feature determined only by the nature or location of the BRCA mutation itself, as the mutational types and frequencies were similar in our patients with unilateral and bilateral breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Mutations of the BRCA1 and BRCA2 genes in patients with bilateral breast cancer

et al. 2001

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Summary Mutations of the BRCA1 or BRCA2 genes have been shown to strongly predispose towards the development of contralateral breast cancer in patients from large multi-case families. In order to test the hypothesis that BRCA1 and BRCA2 mutations are more frequent in patients with bilateral breast cancer, we have investigated a hospital-based series of 75 consecutive patients with bilateral breast cancer and a comparison group of 75 patients with unilateral breast cancer, pairwise matched by age and family history, for mutations in the BRCA1 and BRCA2 genes. Five frameshift deletions (517delGT in BRCA1; 4772delA, 5946delCT, 6174delT and 8138del5 in BRCA2) were identified in patients with bilateral disease. No further mutations, apart from polymorphisms and 3 rare unclassified variants, were found after scanning the whole BRCA1 and BRCA2 coding sequence. Three pathogenic BRCA1 mutations (Cys61Gly, 3814del5, 5382insC) were identified in the group of patients with unilateral breast cancer. The frequencies of common BRCA1 and BRCA2 missense variants were not different between the 2 groups. In summary, we did not find a significantly increased prevalence of BRCA1 and BRCA2 mutations in a hospital-based cohort of German patients with bilateral breast cancer. We conclude that bilaterality of breast cancer on its own is not strongly associated with BRCA1 and BRCA2 mutations when adjusted for age and family history. The high frequency of bilateral disease in multi-case breast cancer families may be due to a familial aggregation of additional susceptibility factors modifying the penetrance of BRCA1 and BRCA2 mutations. 850-858 © 2001 Cancer Research Campaign doi: 10.1054/ bjoc.2001.2016 of the patients. After written informed consent had been obtained, blood samples were collected from 1000 participating patients. 75 patients had developed bilateral breast cancer and took part in this study. This proportion of 7.5% of cases with bilateral disease was the same as has been previously reported in another series of over 500 German breast cancer patients (Mose et al, 1995), indicating that our cohort is representative for a hospital-based cancer population in Germany. As a comparison group for mutation frequency determination, we selected 75 patients with unilateral breast cancer from the total cohort who were pairwise matched with respect to age and family history at the time of treatment.Clinical data of the patients with bilateral breast cancer were collected and compared with data of the whole series of 1000 breast cancer patients. In 29 patients, bilateral breast cancer occurred simultaneously. In the other 46 patients, contralateral breast cancer developed with a median time interval of 7.2 years (range 1 to 40 years). A time interval of at least 3 years was observed in 37 patients. The median age at diagnosis of the first breast cancer was 54 years, compared with 57 years in the total cohort. 22 patients (29.3%) were younger than 50 years and 9 patients (12%) younger than 40 years at first diagnosis. Selfreported fam...

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Life Expectancy Gains From Cancer Prevention Strategies for Women With Breast Cancer and <EMPH TYPE="ITAL">BRCA1</EMPH> or <EMPH TYPE="ITAL">BRCA2</EMPH> Mutations

Cited by 202 publications

References 55 publications

Estimates of the likely prophylactic effect of tamoxifen in women with high risk BRCA1 and BRCA2 mutations

Estimates of the likely prophylactic effect of tamoxifen in women with high risk BRCA1 and BRCA2 mutations

Promotion of mammary cancer development by tamoxifen in a mouse model of Brca1-mutation-related breast cancer

Mutations of the BRCA1 and BRCA2 genes in patients with bilateral breast cancer

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