Contralateral Breast Cancer In Women Research Articles

Tamoxifen and the risk of breast cancer in women with a BRCA1 or BRCA2 mutation.

Chemoprevention with a selective estrogen receptor modulator (tamoxifen or raloxifene) is a non-surgical option offered to high-risk women to reduce the risk of breast cancer. The evidence for tamoxifen benefit is based on trials conducted among predominantly postmenopausal women from the general population and on studies of contralateral breast cancer in women with a pathogenic variant (mutation hereafter) in BRCA1 or BRCA2. Tamoxifen has not been assessed as a primary prevention agent in women with an inherited BRCA mutation. We conducted a prospective analysis of tamoxifen chemoprevention and the risk of breast cancer in women with a BRCA1 or BRCA2 mutation. Data on tamoxifen (and raloxifene) use was collected by questionnaire and updated biennially. Information on incident cancers was collected by self-report and was confirmed by medical record review. In a matched analysis, we estimated the hazard ratio (HR) and 95% confidence intervals (CI) for developing a first primary breast cancer associated with tamoxifen or raloxifene use, using Cox proportional hazards analysis. There were 4578 unaffected women in the cohort, of whom 137 reported tamoxifen use (3%), 83 reported raloxifene use (2%) and 12 used both drugs (0.3%). Women who used tamoxifen or raloxifene were matched 1:3 with women who used neither drug on year of birth, country of residence, year of study entry and gene (BRCA1 or BRCA2). We generated 202 matched pairs. After a mean follow-up of 6.8years, there were 22 incident breast cancers diagnosed among tamoxifen/raloxifene users (10.9% of users) and 71 cases diagnosed among non-users (14.3% of non-users; HR = 0.64; 95% CI 0.40-1.03; P = 0.07). Chemoprevention may be an effective risk-reduction option for BRCA mutation carriers, but further studies with longer follow-up are necessary.

Countercurrents: DCIS or Cancer? Why All the Confusion?

At present, women with ductal carcinoma in situ are counseled that they have a pre-malignant condition which carries the possibility of progression to a fully malignant breast cancer. However, in most cases, the treatment of DCIS resembles that of a small invasive breast cancer and this is a source of confusion to many. In order to properly evaluate the benefit of radiotherapy, mastectomy and contralateral mastectomy, it is necessary to consider the risks of ipsilateral invasive cancer and of contralateral breast cancer in women with DCIS and with small invasive breast cancer. Several registry-based studies indicate that the risks of ipsilateral and contralateral cancer are similar in the two conditions and therefore a similar approach to treatment is rational.

Surgical Management and Contralateral Breast Cancer Risk in Women with History of Radiation Therapy for Hodgkin Lymphoma: Results from a Population-Based Cohort.

Women with history of chest irradiation for Hodgkin lymphoma are at increased risk of developing bilateral breast cancer, although contralateral breast cancer risk estimates in this population remain undefined. We queried the SEER database for women treated with radiation therapy for Hodgkin lymphoma prior to age 30 years and were diagnosed with a subsequent breast cancer between 1990-2016. Trends in surgical management and the 5- and 10-year cumulative incidence of contralateral breast cancer were evaluated. The cohort included 295 women with a median age of 22 years (range 8-30 years) at Hodgkin lymphoma diagnosis, and 42 years (range 22-65 years) at breast cancer diagnosis. Overall, 263 (89.2%) presented with unilateral breast cancer, while 32 (10.8%) presented with synchronous bilateral breast cancer. Breast-conserving surgery was performed in 17.3% of patients, while mastectomy was performed in 82.7%. In 263 patients presenting with unilateral breast cancer, 50 (19.0%) underwent breast-conserving surgery and 213 (81.0%) underwent mastectomy. Subgroup analysis of mastectomy patients demonstrated a 40.5% bilateral mastectomy rate. The 5-year incidence of contralateral breast cancer in women who underwent unilateral surgery was 9.4% [95% confidence interval (CI), 5.6-15.4%], increasing to 20.2% (95% CI, 13.7-29.2%) at 10-year and 29.9% (95% CI, 20.8-41.9%) at 15-year follow-up. Women with a history of prior chest radiation for Hodgkin lymphoma with a diagnosis of breast cancer have a 10-year contralateral breast cancer risk of 20%. These findings support consideration of contralateral prophylactic mastectomy during surgical decision-making for management of this high-risk patient population.

Abstract PD7-07: Surgical management and contralateral breast cancer risk in women with a history of radiation therapy for Hodgkin lymphoma: Results from a population-based cohort

Abstract Background: Women with a history of chest radiation for Hodgkin lymphoma are at an increased risk of developing breast cancer. Although mastectomy has historically been recommended for surgical treatment of breast cancers in women with prior radiation exposure, surgical management trends and contralateral breast cancer risk in this population remain undefined. Methods: We performed a population-based retrospective study using the Surveillance, Epidemiology, and End Results (SEER) database from 1990-2016. Our cohort included women who received radiation for Hodgkin lymphoma prior to 30 years old and were diagnosed with a subsequent breast cancer. We evaluated trends in local therapy including rates of breast conserving surgery (BCS) and mastectomy. In those undergoing unilateral surgery, the Kaplan-Meier method was used to estimate the 5- and 10-year cumulative incidence of contralateral breast cancer. Results: Our final cohort included 295 women with a median age of 22 years (range, 8-30 years) at Hodgkin lymphoma diagnosis, and 42 years (range, 22-65 years) at breast cancer diagnosis. Of these patients, 263 (89.2%) presented with unilateral breast cancer, while 32 (10.8%) presented with synchronous bilateral breast cancer. Overall, BCS was performed in 17.3% of patients and mastectomy was performed in 82.7%. In the 263 patients presenting with unilateral breast cancer, 50 (19.0%) underwent BCS and 213 (81.0%) underwent mastectomy. Subgroup analysis of mastectomy patients with surgical laterality information available demonstrated a 40.5% bilateral mastectomy rate. In the entire cohort, the 5-year incidence of contralateral breast cancer in women who underwent unilateral surgery was 9.4% (95% CI, 5.6-15.4), increasing to 20.2% (95% CI, 13.7-29.2) at 10-years of follow up. Hormone receptor status of the index breast cancer was not associated with significant differences in the incidence of contralateral breast cancer (p=0.13). Conclusions: Women with a history of prior chest radiation for Hodgkin Lymphoma with a diagnosis with breast cancer have a 10-year contralateral breast cancer risk of 20%. These findings support consideration of contralateral prophylactic mastectomy during surgical decision-making in this high-risk patient population. Citation Format: Elisheva R Eisenberg, Anna Weiss, Ipshita Prakash, Sonia Skamene, Mark Basik, Jean Francois Boileau, Lissa Ajjamada, Michael Pollak, Stephanie M Wong. Surgical management and contralateral breast cancer risk in women with a history of radiation therapy for Hodgkin lymphoma: Results from a population-based cohort [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD7-07.

Contralateral breast cancer after curative-intent treatment for ductal carcinoma in situ: Rate and associated clinicopathological and imaging risk factors

PurposePatients who have ductal carcinoma in situ (DCIS) are undergoing bilateral mastectomy at increasing rates. One of the reasons is to minimize contralateral breast cancer (CBC) risk. The purpose of this study is to determine the rate of and risk factors associated with CBC in women treated for DCIS. MethodsA retrospective study was performed of women with DCIS at surgery from 2007 to 2014 who had at least five-year follow-up. Patient attributes, imaging findings, histopathology results, and surgical and long-term outcomes were collected. Features associated with a CBC were assessed with multivariable logistic regression models. Results613 women (mean 56 years, range 30–87) with DCIS underwent breast-conserving surgery (BCS) (n = 426), unilateral mastectomy (n = 101), or bilateral mastectomy (n = 86), with mean follow-up of 7.9 years. Of the 527 women who had BCS or unilateral mastectomy, 7.4% (n = 39) developed a CBC (DCIS in 12 and invasive cancer in 27). 4.1% (5/122) of women treated with adjuvant endocrine therapy developed a CBC, compared to 8.4% (34/405) who were not treated (p = .11). Features associated with CBC risk were younger age at menarche (adjusted odds ratio [aOR] of 0.76, p = .03) and low nuclear grade of DCIS (aOR of 5.43 for grade 1 versus 3, p = .01). ConclusionIn women treated for DCIS, the overall rate of CBC was low at 7.4%. Younger age at menarche and low nuclear grade of DCIS had significant associations with higher CBC risk.

Contralateral Risk-Reducing Mastectomy in Breast Cancer Patients Who Undergo Multigene Panel Testing.

An increasing number of breast cancer patients are undergoing expanded genetic testing and are being identified as germline mutation carriers. We sought to determine rates of contralateral risk-reducing mastectomy (CRRM) in patients with various germline mutations. All women ≥ 18years of age with unilateral breast cancer who underwent multigene panel testing between January 1, 2014 and August 1, 2019 at our academic institution were identified. Demographic, tumor, and treatment variables were identified from the medical record. Multivariable analyses were performed to compare factors associated with performance of CRRM. We identified 1613 patients, of whom 28.1% had a pathogenic variant and 40.1% had variants of uncertain significance (VUS). Overall, 420 patients (26.0%) underwent a CRRM. On multivariable analysis, factors associated with CRRM included age < 50years (OR 3.8, 95% CI 3.0, 5.0), race (OR 0.5, 95% CI 0.3, 0.7 and OR 0.4, 95% CI 0.2, 0.7 for Black and Asian women, respectively, versus White women), and the presence of any germline mutation or VUS (OR 13.2, 95% CI 8.7, 20.2 for BRCA1/2; OR 3.9, 95% CI 2.7, 5.8 for non-BRCA germline mutation; and OR 1.8, 95% CI 1.3, 2.6 for VUS). In breast cancer patients who undergo multigene panel testing, a sizeable number of women with pathogenic non-BRCA germline findings are opting for CRRM. Given that the risk of contralateral breast cancer in women with most pathogenic mutations other than BRCA1/2 remains poorly characterized, these data have implications for risk counseling and for ascertaining the true risks of contralateral breast cancer in this population.

Abstract P5-07-12: Prediction and clinical utility of a contralateral breast cancer risk model

Abstract Background: Breast cancer survivors are at risk for contralateral breast cancer (CBC), with the consequent burden of further treatment and potentially less favorable prognosis. We aimed to develop and validate a CBC risk prediction model, and evaluate its applicability for clinical decision-making. Methods: We included data of 132,756 invasive non-metastatic breast cancer patients from 20 studies with 4,682 CBC events and a median follow-up of 8.8 years. We developed a multivariable Fine and Gray prediction model (PredictCBC-1A) including patient, primary tumor, and treatment characteristics, and BRCA1/2 germline mutation status, accounting for the competing risks of death and distant metastasis. We also developed a model without BRCA1/2 mutation status (PredictCBC-1B). Prediction performance was evaluated using calibration and discrimination, calculated by a time-dependent Area-Under-the-Curve (AUC) at 5 and 10 years after diagnosis of primary breast cancer, and an internal-external cross-validation procedure. Decision curve analysis was performed to evaluate the net benefit of the model to quantify clinical utility. Results: In the multivariable model, BRCA1/2 germline mutation status, family history and systemic adjuvant treatment showed the strongest associations with CBC risk. The AUC of PredictCBC-1A was 0.63 (95% prediction interval (PI) at 5 years: 0.52–0.74; at 10 years: 0.53–0.72). Calibration in-the-large was -0.13 (95%PI: -1.62–1.37) and the calibration slope was 0.90 (95%PI: 0.73–1.08). The AUC of Predict-1B at 10 years was 0.59 (95% PI: 0.52–0.66); calibration was slightly lower. Decision curve analysis for preventive contralateral mastectomy showed potential clinical utility of PredictCBC-1A between thresholds of 4-10% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. Conclusions: We developed a reasonably calibrated model to predict the risk of CBC in women of European-descent, however, prediction accuracy was moderate. Our model shows potential for improved risk counseling, but decision regarding contralateral preventive mastectomy, especially in the general breast cancer population, remains challenging. Citation Format: Daniele Giardiello, Ewout W Steyerberg, Michael Hauptmann, Muriel A Adank, Agnes Jager, Hester OA Oldenburg, Maartje J Hooning, Marjanka K Schmidt, Breast Cancer Association Consortium. Prediction and clinical utility of a contralateral breast cancer risk model [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-07-12.

Risk of Contralateral Breast Cancer in Women with and without Pathogenic Variants in BRCA1, BRCA2, and TP53 Genes in Women with Very Early-Onset (&lt;36 Years) Breast Cancer

Early age at diagnosis of breast cancer is a known risk factor for hereditary predisposition and some studies show a high risk of contralateral breast cancer in BRCA1 carriers diagnosed at very young ages. However, little is published on the risk of TP53 carriers. 397 women with breast cancer diagnosed <36 years of age were obtained from three sources: (i) a population-based study of 283 women diagnosed sequentially from 1980–1997 in North-West England, (ii) referrals to the Genomic Medicine Department at St Mary’s Hospital from 1990–2018, and (iii) individuals from (i) and the Family History Clinic at Wythenshawe Hospital South Manchester who tested negative for pathogenic variants (PV) in all three genes. Sequencing of BRCA1, BRCA2, and TP53 genes was carried out alongside tests for copy number for PV on all referred women. Rates of contralateral breast cancer were censored at death, last assessment, or risk-reducing mastectomy. In total, 47 TP53, 218 BRCA1, and 132 BRCA2 PV carriers were identified with breast cancer diagnosed aged 35 years and under, as well as a representative sample of 261 not known to carry a PV in BRCA1, BRCA2, and TP53. Annual rates of contralateral breast cancer (and percentage of synchronous breast cancers) were TP53: 7.03% (4.3%), BRCA1: 3.57% (1.8%), and BRCA2: 2.63% (1.5%). In non-PV carriers, contralateral rates in isolated presumed/tested non-carrier cases with no family history were 0.56%, and for those with a family history, 0.69%. Contralateral breast cancer rates are substantial in TP53, BRCA1, and BRCA2 PV carriers diagnosed with breast cancer aged 35 and under. Women need to be advised to help make informed decisions on contralateral mastectomy, guided by life expectancy from their index tumor.

Prediction and clinical utility of a contralateral breast cancer risk model

BackgroundBreast cancer survivors are at risk for contralateral breast cancer (CBC), with the consequent burden of further treatment and potentially less favorable prognosis. We aimed to develop and validate a CBC risk prediction model and evaluate its applicability for clinical decision-making.MethodsWe included data of 132,756 invasive non-metastatic breast cancer patients from 20 studies with 4682 CBC events and a median follow-up of 8.8 years. We developed a multivariable Fine and Gray prediction model (PredictCBC-1A) including patient, primary tumor, and treatment characteristics and BRCA1/2 germline mutation status, accounting for the competing risks of death and distant metastasis. We also developed a model without BRCA1/2 mutation status (PredictCBC-1B) since this information was available for only 6% of patients and is routinely unavailable in the general breast cancer population. Prediction performance was evaluated using calibration and discrimination, calculated by a time-dependent area under the curve (AUC) at 5 and 10 years after diagnosis of primary breast cancer, and an internal-external cross-validation procedure. Decision curve analysis was performed to evaluate the net benefit of the model to quantify clinical utility.ResultsIn the multivariable model, BRCA1/2 germline mutation status, family history, and systemic adjuvant treatment showed the strongest associations with CBC risk. The AUC of PredictCBC-1A was 0.63 (95% prediction interval (PI) at 5 years, 0.52–0.74; at 10 years, 0.53–0.72). Calibration-in-the-large was -0.13 (95% PI: -1.62–1.37), and the calibration slope was 0.90 (95% PI: 0.73–1.08). The AUC of Predict-1B at 10 years was 0.59 (95% PI: 0.52–0.66); calibration was slightly lower. Decision curve analysis for preventive contralateral mastectomy showed potential clinical utility of PredictCBC-1A between thresholds of 4–10% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers.ConclusionsWe developed a reasonably calibrated model to predict the risk of CBC in women of European-descent; however, prediction accuracy was moderate. Our model shows potential for improved risk counseling, but decision-making regarding contralateral preventive mastectomy, especially in the general breast cancer population where limited information of the mutation status in BRCA1/2 is available, remains challenging.

Risk of Contralateral Breast Cancer in Women with Ductal Carcinoma In Situ Associated with Synchronous Ipsilateral Lobular Carcinoma In Situ.

Lobular carcinoma in situ (LCIS) is a risk factor for breast cancer, but the effect of LCIS found in association with ductal carcinoma in situ (DCIS) is unknown. In this study, we compared contralateral breast cancer (CBC) and ipsilateral breast tumor recurrence (IBTR) rates among women with DCIS with or without synchronous ipsilateral LCIS treated with breast-conserving surgery (BCS). DCIS patients undergoing BCS from 2000 to 2011 with a contralateral breast at risk were stratified by the presence or absence of synchronous ipsilateral LCIS with the index DCIS (DCIS + LCIS vs. DCIS). Those with contralateral, bilateral, or prior ipsilateral LCIS were excluded. Associations of patient, tumor, and treatment factors with CBC and IBTR were evaluated. Of 1888 patients identified, 1475 (78%) had DCIS and 413 (22%) had DCIS + LCIS. At median follow-up of 7.2 (range 0-17) years, 307 patients had a subsequent first breast event; 207 IBTR and 100 CBC. The 10-year cumulative incidence of IBTR was similar in both groups: 15.0% vs. 14.2% (log-rank, p = 0.8) for DCIS + LCIS vs. DCIS, respectively. The 10-year cumulative incidence of CBC was greater in the DCIS + LCIS group: 10.9% vs. 6.1% for DCIS (log-rank, p < 0.001). After adjustment for other factors, CBC risk remained higher in DCIS + LCIS compared with DCIS (hazard ratio 2.06, 95% confidence interval 1.36-3.11, p = 0.001); there was no significant difference in IBTR risk. Compared with DCIS alone, DCIS + LCIS is associated with similar IBTR risk but double the risk of CBC. This finding should inform treatment decisions, in particular regarding endocrine therapy for risk reduction.

Association of Common Genetic Variants With Contralateral Breast Cancer Risk in the WECARE Study.

Women with unilateral breast cancer (UBC) are at risk of developing a subsequent contralateral breast cancer (CBC). Common variants are associated with breast cancer risk. Whether these influence CBC risk is unknown. Participants were breast cancer cases from the population-based Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study. Sixty-seven established breast cancer risk loci were genotyped directly or by imputation in 1459 case subjects with CBC and 2126 UBC control subjects. An unweighted polygenic risk score (PRS) was created by summing the number of risk alleles for each directly genotyped single nucleotide polymorphism (SNP), or for imputed loci, the imputed dosage. A weighted PRS was calculated similarly, but where each SNP's contribution was weighted by the published per-allele log odds ratio. Unweighted and weighted polygenic risk scores and CBC risk were modeled using conditional logistic regression. Cumulative CBC risk was estimated and benchmarked using Surveillance, Epidemiology, and End Results population incidence rates. Both unweighted and weighted PRS were statistically significantly associated with CBC risk. The adjusted risk ratio of CBC in women in the upper quartile of unweighted PRS compared with the lowest quartile was 1.63 (95% confidence interval [CI] = 1.33 to 2.00). The estimated 10-year cumulative risk for women in the upper quartile of the unweighted PRS was 7.4% (95% CI = 6.0% to 9.1%). For women in the upper quartile of the weighted PRS, the risk ratio for CBC was 1.75 (95% CI = 1.41 to 2.18) compared with women in the lowest quartile. There was no statistically significant heterogeneity by age, treatment (radiation therapy dose, tamoxifen, chemotherapy), estrogen receptor status of the first primary, histology of the first primary, length of at-risk period for CBC, or breast cancer family history. Common genomic variants associated with the development of first primary breast cancer are also associated with the development of CBC; the risk is strongest among those who carry more risk alleles.

Abstract P3-02-02: Predictive value of breast MRI in detecting mammographically occult contralateral breast cancer: Can we target women more likely to have contralateral breast cancer based on primary tumor clinicopathologic factors?

Abstract Background: Use of preoperative magnetic resonance imaging (MRI) staging in newly diagnosed breast cancer increases detection of synchronous contralateral breast cancer (CBC) over other screening modalities; however, it is associated with a high false positive rate, additional biopsies, extensive surgical procedures, and possibly increased psychological morbidity. Specific Aims: To determine predictors of synchronous, mammographically-occult but MRI-detected CBC in women newly diagnosed with breast cancer. Methods: We performed a retrospective review of patients at Allina Health, Abbott Northwestern Hospital who had preoperative breast MRI prior to surgical resection of their breast cancer from 2010–2014. We collected patient demographic and clinicopathologic data. To determine the association between MRI-detected CBC versus benign findings based on clinicopathologic data, we performed univariate analysis (p&amp;lt;0.05). Multivariate Logistic Regression was used to adjust for covariates and factors predictive of CBC. Area under the Receiver Operating Characteristic Curve provided a measure of model accuracy. Findings: 1894 patients had pre-operative MRI during the study period. Of those, 201 had suspicious findings on contralateral breast MRI requiring biopsy (table 1). Overall 3% (60/1894) had synchronous CBC (invasive carcinoma or DCIS) detected on MRI. The majority of CBCs (n=60) were stage 0 or IA (85%), ER/PgR+ (98%), HER2- (89%), and low/intermediate grade (80%). Women more likely to have mammographically-occult CBC were older (p&amp;lt;0.001), had lobular versus ductal index cancer (p=0.03), and had ER positive (p=0.027) or PgR positive (p=0.002) tumors. On multivariate logistic regression analysis (ROC area=0.75), PgR positive status (p=0.022), and older age (p=0.004) were predictive of CBC. With each year of additional age, odds of CBC increased by 5%. No CBC was identified in women &amp;lt; age 45 with high risk index cancers (ER- or HER2 +). CBC was 11 times more likely when PgR status was positive versus negative. CBCs were diagnosed significantly more frequently in patients with index cancers that were hormone receptor positive and HER2 negative compared to HER2 positive or triple negative invasive index cancers (Fisher's exact test; p=0.041). Risk of CBC by Index Cancer TypeIndex CancerCBC n (%)DCIS (n=51)15 (29)Invasive carcinoma (n=150)45 (30)ER+/HER2- (n=121)41 (34)HER2 positive (n=18)3 (17)Triple Negative (n=11)1 (9)Total (n=201)60 (30) Conclusions: Preoperative MRI is effective in detecting mammographically-occult early stage, hormone receptor positive CBC in older women. MRI-detected CBC is more common in patients originally presenting with hormone receptor positive and HER2 negative index cancers. Our results suggest that it may be possible to determine a subset of patients who are less likely to benefit from a preoperative breast MRI, an important implication in an era of increasing healthcare cost utilization awareness. Citation Format: Susnik B, Lillemoe TJ, Swenson KK, Tsai ML, Finkelstein MJ, Schneider L, Braatz CM, Krueger JL, Rueth N. Predictive value of breast MRI in detecting mammographically occult contralateral breast cancer: Can we target women more likely to have contralateral breast cancer based on primary tumor clinicopathologic factors? [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-02-02.

Aromatase inhibitors and the risk of contralateral breast cancer in BRCA mutation carriers.

3 Background: Contralateral breast cancer (CBC) risk in BRCA1 &amp; 2 mutations is up to 64%. Patients (pts) with estrogen receptor positive (ER+) breast cancer (BC) are offered tamoxifen (TAM) or Aromase inhibitors (AI) adjuvantly. Reports suggest that TAM may reduce the risk of CBC in BRCA mutation; however there is no such data on the effect of AIs. Here, we evaluate the effect of TAM and AI as potential CBC risk reducers in a cohort of women with known BRCA status. Methods: 1043 BC pts receiving genetic counseling and BRCA testing were included. 13 had metastasis, 168 had a variant BRCA, and 50 had synchronous BC, and were excluded. Of the 812 remaining pts, 153 had a deleterious BRCA 1 or 2 mutations. Pts were followed from the diagnosis of BC until CBC, death, or last follow-up. The study had IRB approval. Univariate analyses were performed to test the significance of each variable in relation to BRCA status using chi-square tests for categorical variables and t tests for continuous variables. Results: The median age at diagnosis of BC was 42.3 years (range: 21-84). Median follow up was 8.6 years. 86% (700) had ER+ tumors, 80% were diagnosed with T1-2, and 81% had N0-N1. 76% (622) received TAM, and 37% (304) received AI. A total of 68 (8.7%) CBCs occurred of which 14% (21/153) occurred in BRCA carriers vs 7% (47/659) in BRCA non-carriers. Multivariate analyses indicated that BRCA status and AI use were significantly associated with CBC. Specifically, compared with BRCA negative, pts with BRCA1+ or BRCA2+ had larger hazard of developing CBC, Hazard Ratio (HR) (95% confidence interval (CI)) = 2.49 (1.21, 5.10), p = 0.013 for BRCA1+ vs Negative. HR (95%CI) = 1.97 (1.05, 3.73), p = 0.036 for BRCA2+ vs Negative. Compared to pts who did not receive AI, those who received AI had smaller hazard of developing CBC, HR (95%CI) = 0.42 (0.22, 0.81), p = 0.01. The interaction between AI and BRCA status was not significant (p = 0.4), hence all pts benefited from AI use in terms of CBC risk reduction. TAM use did not show significant effect on the risk of CBC in univariate and multivariate analyses (p &gt; 0.13). Conclusions: This is the first report showing that AIs can reduce risk of CBC in women with BC who have a BRCA mutation. This finding should be validated in larger independent cohorts.

CHEK2 1100DELC germline mutation: a frequency study in hereditary breast and colon cancer Brazilian families

CHEK2 encodes a cell cycle checkpoint kinase that plays an important role in the DNA damage repair pathway, activated mainly by ATM (Ataxia Telangiectasia Mutated) in response to double-stranded DNA breaks. A germline mutation in CHEK2, 1100delC, has been described as a low penetrance allele in a significant number of families with breast and colorectal cancer in certain countries and is also associated with increased risk of contralateral breast cancer in women previously affected by the disease. About 5%-10% of all breast and colorectal cancers are associated with hereditary predisposition and its recognition is of great importance for genetic counseling and cancer risk management. Here, we have assessed the frequency of the CHEK2 1100delC mutation in the germline of 59 unrelated Brazilian individuals with clinical criteria for the hereditary breast and colorectal cancer syndrome. A long-range PCR strategy followed by gene sequencing was used. The 1100delC mutation was encountered in the germline of one (1.7%) individual in this high risk cohort. This indicates that the CHEK2 1100delC is not commonly encountered in Brazilian families with multiple diagnoses of breast and colorectal cancer. These results should be confirmed in a larger series of families and further testing should be undertaken to investigate the molecular mechanisms underlying the hereditary breast and colorectal cancer phenotype.

Risk-reducing Surgery in Women at Risk for Familial Breast or Ovarian Cancer.

An estimated 5 % of breast cancers and 10 % of ovarian cancers may be due to inherited autosomal dominant breast and ovarian cancer alleles BRCA1 und BRCA2. According to population-based studies 1 or 2 women per 1000 carry such a risk allele. The cumulative cancer risk for healthy women with a BRCA-mutation is between 60 and 85 % for breast cancer and between 20 and 60 % for ovarian cancer. Recent studies have reported an increased risk for contralateral breast cancer in women after unilateral breast cancer. Since 1997 the German Cancer Aid has supported an interdisciplinary approach for high-risk women consisting of genetic testing, counselling and prevention in 12 specialised centres. Since 2005 this concept has received additional support from health insurance companies, and results have been assessed with regard to outcomes (e.g. reduced mortality due to more intensive early diagnosis). The number of centres has increased to 15 at various university hospitals. These interdisciplinary centres offer women the opportunity to participate in a structured screening programme for the early diagnosis of breast cancer and provide non-directive counselling on the options for risk-reducing surgery, e.g., prophylactic bilateral salpingo-oophorectomy, prophylactic bilateral mastectomy or contralateral prophylactic mastectomy after unilateral breast cancer. Such surgical interventions can significantly reduce the risk of disease, the respective disease-specific mortality and - particularly prophylactic bilateral salpingo-oophorectomy - total mortality in BRCA-mutation carriers.

Bisphosphonates: Beyond Prevention of Bone Metastases

Bisphosphonates have traditionally been indicated for treatment and control of osteoporosis because they inhibit osteoclastmediated bone resorption and reduce the release of calcium into the blood stream (1). They are currently being used by millions of people (mostly women) worldwide (2). Accumulating evidence over the past 10 years has demonstrated that the use of third-generation nitrogen-containing bisphosphonates can effectively treat bone metastases in women with breast cancer (3). It has been hypothesized that bisphosphonates can also prevent bone metastases altogether and could therefore be implemented in an adjuvant setup in women with breast cancer (4,5). A recent randomized controlled study failed to demonstrate such an effect using third-generation bisphosphonate (6). If bisphosphonate use is associated with a generalized reduced risk of malignancy, one would expect to see reduced risk of developing breast cancer or other cancers in regular users of secondgeneration bisphosphonates, such as osteoporotic women. One would also expect to see reduced risks of developing contralateral breast cancer in women with breast cancer who were further treated with bisphosphonates. Three descriptive studies have thus far shown a strong and similar negative association between the use of common second-generation oral bisphosphonates and the risk of breast cancer (7–9). These findings raised the possibility of con founding by indication. Bisphosphonates are used by osteoporotic women, and osteoporosis is the result of reduced circulating estrogen levels. Estrogen is strongly associated with risk of breast cancer, and women with low estrogen levels are expected to have lower breast cancer rates. Thus, the negative association with bisphosphonate use could actually reflect a negative association with low estrogen levels in the body. However, evidence that the degree of breast cancer risk reduction among bisphosphonate users was not correlated with the degree of bone density loss (7), that risk reduction was seen only after a year of treatment (8), and that postmenopausal bisphosphonates users also demonstrated a reduced risk of colorectal cancer (10,11), all suggest that the association between bisphosphonate use and reduced risk of cancer is real. Mechanistically, nitrogen-containing bisphosphonates inhibit protein prenylation by blocking the mevalonate pathway. Selective inhibition of farensyl pyrophosphate synthase by bisphosphonates can lead to diminished posttranslational prenylation of small GTPase proteins (including signaling molecules such as proteins of the Ras and Rho families) that promote tumorigenesis and metastases (12). In a mouse model, use of bisphosphonates was associated with the suppression of Rho and Ras pathways (13). Further support for a possible role of bisphosphonates in primary prevention of cancer comes from numerous previous reports on the negative association between the use of statins and the risk of cancer in various organs [eg, (14–20)]. Statins, which use the same mevalonate pathway as do bisphosphonates (acting upstream of the farensylation–geranylation step), have been shown to be associated with cancer risk reduction and with possibly improved survival of patients with cancers in multiple sites (21).

Surveillance mammography for detecting ipsilateral breast tumour recurrence and metachronous contralateral breast cancer: a systematic review

ObjectivesTo determine the diagnostic accuracy of surveillance mammography for detecting ipsilateral breast tumour recurrence and metachronous contralateral breast cancer in women previously treated for primary breast cancer.MethodsA systematic review of surveillance mammography compared with ultrasound, magnetic resonance imaging (MRI), specialist-led clinical examination or unstructured primary care follow-up, using histopathological assessment for test positives and follow-up for test negatives as the reference standard.ResultsNine studies met our inclusion criteria. Variations in study comparisons precluded meta-analysis. For routine ipsilateral breast tumour detection, surveillance mammography sensitivity ranged from 64–67% and specificity ranged from 85–97%. For MRI, sensitivity ranged from 86–100% and specificity was 93%. For non-routine ipsilateral breast tumour detection, sensitivity and specificity for surveillance mammography ranged from 50–83% and 57–75% and for MRI 93–100% and 88–96%. For routine metachronous contralateral breast cancer detection, one study reported sensitivity of 67% and specificity of 50% for both surveillance mammography and MRI.ConclusionAlthough mammography is associated with high sensitivity and specificity, MRI is the most accurate test for detecting ipsilateral breast tumour recurrence and metachronous contralateral breast cancer in women previously treated for primary breast cancer. Results should be interpreted with caution because of the limited evidence base. Key Points • Surveillance mammography is associated with high sensitivity and specificity • Findings suggest that MRI is the most accurate test for detecting further breast cancer • Robust conclusions cannot be made due to the limited evidence base • Further research comparing surveillance mammography and other diagnostic tests is required

Metachronous contralateral breast cancer: An analysis of risk factors and prognosis in 42,670 women in Sweden.

1568 Background: The number of breast cancer survivors is rising and therefore the number of women at risk of developing contralateral breast cancer (CBC). We analysed the risk of and prognosis after CBC in relation to tumour characteristics. Methods: In a cohort of 42,670 women diagnosed with primary breast cancer in Uppsala/Örebro and Stockholm regions in Sweden between 01/01/1992 and 12/31/2008, factors associated with the risk of developing metachronous CBC were assessed using Cox proportional hazard modelling. We also evaluated breast cancer-specific survival for women with CBC in comparison to women with unilateral breast cancer (UBC), where characteristics of the contralateral tumour were entered as time-dependent covariates. Results: Women aged < 50 at the initial cancer diagnosis had the highest incidence of CBC. We observed an increased risk of CBC in women with increasing tumour size (p-trend < 0.05) and with ≥10 affected lymph nodes compared to node-negative cancer (adjusted HR 1.8, 95% CI 1.2-2.7). Lobular histology of the initial cancer also increased the risk of CBC (adjusted HR 1.3, 95% CI 1.1-1.6). Women with CBC had a worse prognosis than women with UBC, especially women with a short interval between the two cancers (adjusted HR 2.8, 95% CI 2.3-3.5 for CBC ≤5 years and HR 2.1, 95% CI 1.5-2.9 for CBC >5 years, compared to UBC). Increasing size of the contralateral tumour further increased the risk of dying from breast cancer (p-trend < 0.0001), as did affected lymph nodes (HR 4.6, 95% CI 3.4-6.2 vs. HR 2.1, 95% CI 1.6-2.6), high grade (p-trend < 0.001), lobular histology (HR 3.8, 95% CI 2.6-5.6 vs. HR 2.3, 95% CI 1.8-2.9 for ductal) and hormone receptor negativity (ER: HR 4.9, 95% CI 3.6-6.5 vs. HR 1.7, 95% CI 1.3-2.2; PR: HR 3.5, 95% CI 2.7-4.6 vs. HR 1.6, 95% CI 1.2-2.2). Conclusions: The influence of advanced stage of breast cancer on the risk of CBC together with a substantially poor prognosis for women in whom CBC occurred shortly after the initial cancer may imply that for some women CBC is a manifestation of active disease rather than a new primary. These findings indicate that surveillance and treatment plans may have to be adapted accordingly for women with a short interval between the initial and CBC.

Successful Use of Multi-Detector Row Computed Tomography for Detecting Contralateral Breast Cancer

We retrospectively evaluated whether multi-detector row computed tomography (MDCT) could contribute to the early detection of contralateral breast cancer in women with a diagnosis of breast cancer and no suspicious lesions on a mammogram or an ultrasonogram of the contralateral breast. A total of 518 women with newly diagnosed unilateral breast cancer underwent MDCT. Multi-detector row CT was performed using a 16-detector row CT scanner set for 2-mm collimation, 120 kilovolt (peak), and 180 mA. Axial images of the contralateral breast were evaluated. Four hundred fifty-nine women were eligible for this study. There were suspicious malignant lesions only on MDCT in 21. Multi-detector row CT contributed to the diagnosis of contralateral occult breast cancer in 12 women (2.6%), including 1 in whom breast cancer was later diagnosed at another institution. Multi-detector row CT has a potential role in detecting contralateral breast cancer in women who are at high risk.

Clinical Benefits of Multidetector-Row Computed Tomography for Detecting Contralateral Breast Cancer.

Abstract Background: It is not uncommon that the use of multidetector-row computed tomography (MDCT) for assessing the intraductal spread of breast cancer results in the detection of enhancing lesion of the contralateral breast. We retrospectively evaluated whether MDCT could contribute to the early detection of contralateral breast cancer in women with a diagnosis of breast cancer and no suspicious lesions on mammogram or ultrasonogram of the contralateral breast.Methods: MDCT has been routinely used since 2004 to assess the intraductal spread of breast cancer in women who are scheduled for breast conserving surgery at our institution. A total of 518 women with newly diagnosed unilateral breast cancer who had no allergy to contrast material and were candidates for breast conserving surgery underwent MDCT at our institution between January 2004 and April 2009. MDCT was performed using a 16-detector row MDCT scanner set for 2mm collimation, 120 kVp and 180mA. Axial images of the contralateral breast were obtained for evaluation.Results: Of the 518 women with breast cancer, previous contralateral mastectomy in 13 cases, post primary chemotherapy in 43 cases, and ipsilateral breast recurrence in 2 cases, plus one case of male breast cancer were subsequently determined to be ineligible. Thus 459 women were eligible for participation in this study. The mean age was 56.9 years.Clinical stage 0 to II of index breast cancer accounted for 95.9% of patients.There were 168 premenopausal patients and 291 postmenopausal patients. Of 459 lesions, the histological diagnosis of index cancer was ductal carcinoma in situ in 56, invasive ductal carcinoma in 363, invasive lobular carcinoma in 14, and other in 26. Among 36 women with enhancing breast lesions, there were malignant suspected lesions on mammogram and ultrasonogram in 15, and suspicious lesions on only MDCT images in 21. Targeted ultrasonography was performed in suspicious lesions identified by MDCT for cytological or pathological biopsy, and all lesions were detected by targeted ultrasonography.The maximum diameter of suspicious lesions detected only with MDCT was under 5.0 mm in 10 lesions, 5.1-10.0 mm in 9 lesions, 10.1-15.0mm in one lesion, and over 15.1 mm in one lesion. Ultrasound-guided fine needle aspiration was performed in 11 women, and a histological diagnosis was made in 17 women. We performed ultrasound-guided vacuum-assisted biopsy and incisional biopsy in 14 and 3 women, respectively. There were 6 benign and 11 malignant tumors. MDCT contributed to the diagnosis of contralateral occult breast cancer in 12 women (2.6%), including one with a suspicious lesion by fine needle aspiration and in whom breast cancer was later diagnosed at another institution.Conclusions: In this study, MDCT contributed to the diagnosis of contralateral occult breast cancer.Women with breast cancer have an increased risk of developing a second breast cancer. MDCT has a potential role in detecting contralateral breast cancer in women who are at high risk for such cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5022.