Incidence Of Contralateral Breast Cancer Research Articles

Abstract P1-09-01: Long-term effect of tamoxifen use on the risk of contralateral breast cancer

Abstract Background: Tamoxifen has been used widely in the treatment of breast cancer due to its beneficial effects on recurrences and mortality. Both randomized trials and observational studies give evidence that tamoxifen also reduces the incidence of contralateral breast cancer. The effect of tamoxifen seems to be present not only during treatment but also after termination of treatment, but the question is how long this effect lasts. Few studies have presented long-term follow-up data on risk of contralateral breast cancer after tamoxifen treatment. Material and Methods: In the Danish Breast Cancer Cooperative Group (DBCG) Database, we identified 50,323 women who had undergone surgery for invasive breast cancer and who had received treatment according to DBCG guidelines during 1978–2007. Among these women, 16,319 were users of tamoxifen while 34,004 were non-users. Contralateral breast cancer cases were identified in the Danish Cancer Registry and in the DBCG Database through 2009. The incidence of contralateral breast cancer among users of tamoxifen was compared to that of non-users by estimating incidence rate ratios (IRRs) in Cox regression analyses with adjustment for age at first breast cancer diagnosis, calendar period at first breast cancer diagnosis, histology of first breast cancer, radiotherapy, chemotherapy and other endocrine treatments besides tamoxifen. Results: During follow-up, 295 cases of contralateral breast cancer were observed among users of tamoxifen while 1,485 cases were observed among non-users resulting in an IRR of 0.82 (95% CI = 0.71–0.94) after adjustments. Further analyses will include calculation of IRRs for contralateral breast cancer by time since breast cancer diagnosis, duration of tamoxifen and time since cessation of tamoxifen as well as calculation of IRRs after restriction to estrogen receptor positive breast cancer patients. Results of these analyses will be presented. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-09-01.

Incidence of contralateral breast cancer in Japanese patients with unilateral minimum-risk primary breast cancer, and the benefits of endocrine therapy and radiotherapy

Tamoxifen is recommended as adjuvant endocrine therapy for patients with minimum-risk breast cancer. It is primarily effective at prevention of contralateral and ipsilateral breast cancer recurrence after breast-conserving surgery. The incidence of contralateral breast cancer and the absolute benefit of endocrine therapy among patients with unilateral minimum-risk breast cancer in Japan, where the incidence of breast cancer is low, are unknown. We retrospectively studied the incidence of contralateral breast cancer, and the efficacy of endocrine therapy, in a cohort of 2074 Japanese women with unilateral breast cancer whose primary tumor was pTis (n=1905) or pT1mic (n=169) (unknown for endocrine therapy, n=4; unknown for radiotherapy, n=2). We also assessed the efficacy of endocrine therapy and radiotherapy for prevention of ipsilateral and contralateral breast cancer recurrence in 1205 patients who underwent breast-conserving surgery (unknown for endocrine therapy, n=2; unknown for radiotherapy, n=2). The incidence of contralateral breast cancer per 1000 person-years was 5.1 (95% confidence interval (CI), 3.7-7.1) among patients without endocrine therapy (n=1364) and 3.6 (95% CI 2.1-6.1) among those with endocrine therapy (n=706). The incidence of ipsilateral breast cancer recurrence after breast-conserving surgery per 1000 person-years was 9.2 (95% CI 6.5-13) among patients without endocrine therapy (n=753) and 4.2 (95% CI 2.2-8.1) among those with endocrine therapy (n=450). The incidence of ipsilateral breast cancer recurrence after breast-conserving surgery per 1000 person-years was 9.9 (95% CI 6.3-15.6) among patients without radiotherapy (n=380) and 5.9 (95% CI 3.9-9.0) among those with radiotherapy (n=823). The incidence of contralateral breast cancer among minimum-risk breast cancer patients in Japan, where the incidence of breast cancer is low, was similar to that in Western countries. Endocrine therapy is indicated for this population.

Tumor characteristics and the clinical outcome of invasive lobular carcinoma compared to infiltrating ductal carcinoma in a Chinese population

BackgroundWe sought to compare the baseline demographics, standard pathologic factors and long-term clinical outcomes between ILC and infiltrating ductal carcinoma (IDC) using a large database.MethodsClinicopathologic features, overall survival (OS), and recurrence/metastasis-free survival (RFS) were compared between 2,202 patients with IDC and 215 patients with ILC.ResultsILC was significantly more likely to be associated with a favorable phenotype, but the incidence of contralateral breast cancer was higher for ILC patients than for IDC patients (8.4% vs. 3.9%; P =0.001). The frequencies of recurrence/metastasis (P = 0.980) and death (P = 0.064) were similar among patients with IDC and patients with ILC after adjustment for tumor size and nodal status. The median follow-up was 42.8 months.ConclusionsChinese women with ILCs do not have better clinical outcomes than their counterparts with IDC. Management decisions should be based on individual patient and tumor biologic characteristics, and not on lobular histology.

Postmenopausal Women with DCIS Post-Mastectomy: A Potential Role for Aromatase Inhibitors

For postmenopausal women with ductal carcinoma in situ (DCIS) where optimal local control or patient preference results in mastectomy, despite substantial risk of contralateral invasive breast cancer, tamoxifen is uncommonly prescribed based on unfavorable risk-benefit consideration. In the National Cancer Institute of Canada Clinical Trial Group (NCIC CTG) MAP.3 primary prevention trial, in postmenopausal women exemestane reduced invasive breast cancer incidence by 65% without increasing life-threatening side effects. In adjuvant breast cancer trials, the aromatase inhibitor exemestane as well as anastrozole and letrozole have all reduced new contralateral breast cancer incidence. Thus, aromatase inhibitors, and perhaps particularly exemestane, provide an option to address the risk of contralateral breast cancer in postmenopausal women with DCIS managed with mastectomy.

The Appropriate Extent of Surgery for Early-Stage Breast Cancer

Attitudes regarding the appropriate extent of surgery for breast cancer and the effect of surgery on breast cancer-specific survival have varied over time. Failure to maintain local control is associated with decreased survival, but the extent of surgery necessary for local control has decreased as other treatment modalities, such as radiotherapy and systemic therapy, have become more widely used. Both endocrine therapy and chemotherapy considerably reduce rates of local recurrence in the breast, as well as the incidence of contralateral breast cancer, and as efficacy in reducing metastatic disease increases, so does the benefit in reducing local recurrence. The excellent rates of local control in the ACOSOG Z11 trial after elimination of axillary dissection in patients with positive sentinel nodes receiving whole-breast irradiation and systemic therapy are a model for reducing surgical morbidity in the era of multimodality therapy.

Changes in Breast Density and Circulating Estrogens in Postmenopausal Women Receiving Adjuvant Anastrozole

Factors associated with an increased risk of breast cancer include prior breast cancer, high circulating estrogens, and increased breast density. Adjuvant aromatase inhibitors are associated with a reduction in incidence of contralateral breast cancer. We conducted a prospective, single-arm, single-institution study to determine whether use of anastrozole is associated with changes in contralateral breast density and circulating estrogens. Eligible patients included postmenopausal women with hormone receptor-positive early-stage breast cancer who had completed local therapy, had an intact contralateral breast, and were recommended an aromatase inhibitor as their only systemic therapy. Participants received anastrozole 1 mg daily for 12 months on study. We assessed contralateral breast density and serum estrogens at baseline, 6, and 12 months. The primary endpoint was change in contralateral percent breast density from baseline to 12 months. Secondary endpoints included change in serum estrone sulfate from baseline to 12 months. Fifty-four patients were accrued. At 12 months, compared with baseline, there was a nonstatistically significant reduction in breast density (mean change: -16%, 95% CI: -30 to 2, P = 0.08) and a significant reduction in estrone sulfate (mean change: -93%, 95% CI: -94 to -91, P < 0.001). Eighteen women achieved 20% or greater relative reduction in contralateral percent density at 12 months compared with baseline; however, no measured patient or disease characteristics distinguished these women from the overall population. Large trials are required to provide additional data on the relationship between aromatase inhibitors and breast density and, more importantly, whether observed changes in breast density correlate with meaningful disease-specific outcomes.

Aromatase inhibitors in the treatment of breast cancer in post-menopausal female patients: an update

Estrogen and its metabolites play a significant role in the proliferation of hormone receptor-positive breast cancer. In postmenopausal women, aromatase inhibitors can significantly reduce estrogen levels by blocking enzyme-mediated estrogen synthesis within tissues. Third-generation aromatase inhibitors have now surpassed tamoxifen as first-line therapy for postmenopausal women with metastatic, hormone receptor-positive, breast cancer, showing improved response rates and time to progression. Aromatase inhibitors have shown incremental improvements in disease-free survival, lower local recurrence rates, lower metastatic recurrence rates, and a lower incidence of contralateral breast cancer over tamoxifen when used in the adjuvant setting. Aromatase inhibitors are recommended to be used as adjuvant therapy within the first 5 years of hormonal therapy and may be used either upfront for 5 years or sequenced with tamoxifen. No superiority of one aromatase inhibitor over another has yet been shown. The side effect profiles of aromatase inhibitors have some key differences compared with tamoxifen. These differences may influence treatment choices as well as impact compliance.

Prophylactic mastectomy of the contralateral breast

The use of contralateral prophylactic mastectomy (CPM) is increasing in the United States. Tuttle et al., using SEER data, reported that the percentage of patients with ductal carcinoma in situ (DCIS) undergoing CPM increased from 6% to 18% between 1998 and 2005. During the period from 1998 through 2003, rates of CPM among women with invasive cancer increased from 4% to 11%. The use of CPM was most frequent in Stage I breast cancer, increasing from 5% to 12% of cases, but rates were observed to increase in women with Stage II and III disease as well. The increase in the use of CPM is somewhat surprising since the incidence of contralateral breast cancer has declined with the widespread use of adjuvant systemic therapy and second primary breast cancer is now an infrequent event.

Contralateral breast cancer risk in patients with familial breast cancer who tested negative for BRCA1 and BRCA2.

1013 Background: A high incidence of contralateral breast cancer has been reported in patients with BRCA1or BRCA2 mutations while the risk in patients with familial non-BRCA-associated breast cancer remains unclear. This study was undertaken to estimate the risk for contralateral breast cancer in patients of BRCA1- and BRCA2-negative high risk families and to determine predictive risk factors. Methods: A retrospective, multicenter, cohort study was performed from 1996 until 2010 and comprised 3,580 women with unilateral breast cancer from 2,793 high-risk families who were tested negative for BRCA1 or BRCA2 mutations. Kaplan-Meier analysis was used to estimate age-dependent contralateral breast cancer risks. Cox regression analysis was applied to assess the impact of age at first breast cancer on contralateral breast cancer risk. Results: The cumulative risk for contralateral breast cancer 25 years after first breast cancer was 19% (95%CI 16% to 22%) for patients from families with non-BRCA-associated breast cancer. This rate is significantly lower compared to BRCA1 and BRCA2 mutation carriers (46% and 36%, respectively). Younger age at first breast cancer was associated with a significantly higher risk of contralateral breast cancer. After 25 years, 29% (95%CI 20% to 37%) of non-carriers who were younger than 40 years of age at first breast cancer developed contralateral breast cancer, compared with only 15% (95%CI 10% to 20%) of those who were older than 50 years. These incidences are similar to patients with sporadic breast cancer. Conclusions: Contralateral breast cancer risk in patients with familial non-BRCA-associated breast cancer is similar to the risk in patients with sporadic breast cancer and depends on age at first breast cancer. Therefore, risk-reducing contralateral mastectomy does not seem to be adequate for non-BRCA1/2 breast cancer patients.

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.

Declining Incidence of Contralateral Breast Cancer in the United States From 1975 to 2006

Contralateral breast cancer (CBC) is the most frequent new malignancy among women diagnosed with a first breast cancer. Although temporal trends for first breast cancers have been well studied, trends for CBC are not so well established. We examined temporal trends in CBC incidence using US Surveillance, Epidemiology, and End Results database (1975 to 2006). Data were stratified by estrogen receptor (ER) status of the first breast cancer for the available time period (1990+). We estimated the annual percent change (EAPC) in CBC rates using Poisson regression models adjusted for the age at and time since first breast cancer diagnosis. Before 1985, CBC incidence rates were stable (EAPC, 0.27% per year; 95% CI, -0.4 to 0.9), after which they declined with an EAPC of -3.07% per year (95% CI, -3.5 to -2.7). From 1990 forward, the declines were restricted to CBC after an ER-positive cancer (EAPC, -3.18%; 95% CI, -4.2 to -2.2) with no clear decreases after an ER-negative cancer. Estimated current age-specific CBC rates (per 100/year) after an ER-positive first cancer were: 0.45 for first cancers diagnosed before age 30 years and 0.25 to 0.37 for age 30 years or older. Rates after an ER-negative cancer were higher: 1.26 before age 30 years, 0.85 for age 30 to 35 years, and 0.45 to 0.65 for age 40 or older. Results show a favorable decrease of 3% per year for CBC incidence in the United States since 1985. This overall trend was driven by declining CBC rates after an ER-positive cancer, possibly because of the widespread usage of adjuvant hormone therapies, after the results of the Nolvadex Adjuvant Trial Organisation were published in 1983, and/or other adjuvant treatments.

Abstract S1-1: Final Analysis of NCIC CTG MA.27: A Randomized Phase III Trial of Exemestane Versus Anastrozole in Postmenopausal Women with Hormone Receptor Positive Primary Breast Cancer

Abstract Background: The non-steroidal reversible aromatase inhibitor (AI), anastrozole (A) is approved as adjuvant monotherapy in hormone receptor (HR) positive early breast cancer (EBC). The steroidal irreversible AI exemestane (E) is approved in sequence after an initial 2-3 years of tamoxifen. MA27 tested the hypothesis that exemestane would have greater efficacy and better end-organ safety than anastrozole for several reasons: E is an irreversible and more potent AI than A; unlike A, E does not induce intra-tumoral aromatase and; through its mild androgenic activity E may exert a second anti-tumor effect and a more favorable bone and lipid metabolism profile than A. Initially the study also tested the role of a cyclooxygenase-2 inhibitor, celecoxib, used in combination with an AI. However, celecoxib was discontinued early in MA27 following identification of cardiovascular toxicity with COX-2 inhibitors. Methods: Postmenopausal women with hormone receptor positive primary breast cancer were randomized after adequate local treatment to 5 years of adjuvant A (1mg/day) or E (25mg/day) with or without celecoxib/placebo (400mg/plac twice daily for 3 years). The primary objective is the comparison of event free survival (EFS) between women treated with A or E. Secondary objectives include overall survival (OS), distant recurrence (DDFS), incidence of contralateral breast cancer (CBC) and safety. Quality of Life in a subset of women has been evaluated, and a very extensive tissue bank created. Stratification included: prior chemotherapy; lymph node status, celecoxib (during use), aspirin use (during randomization to celecoxib), and trastuzumab use (since November 2005). The primary endpoint (EFS) will look for an improvement from 87.5% to 89.9%; HR 0.80, 2-sided 5% level and 80% power, with 644 events required. Results: 7576 women were randomized between June 2003 and July 2008. Celecoxib/placebo, was discontinued 2 years into the trial in December 2004 after 1635 patients had received celecoxib. The number of events required for final analysis was reached April 2010. Patient characteristics were balanced for age (median 64.1yrs); race; ECOG PS; mastectomy; TNM staging and; prior adjuvant chemotherapy. EFS, OS, DDFS, and CBC as well as clinical fractures, cardiovascular events and adverse events will be presented by arm in the final analysis. Conclusions: NCIC CTG MA.27 is the first definitive EBC trial comparing a non-steroidal and steroidal AI as initial adjuvant therapy. Exemestane is not currently approved as initial adjuvant treatment and superiority or equivalence will lead to its inclusion as a first-line option for EBC in postmenopausal HR positive breast cancer. Efficacy, clinical fractures, cardiovascular events and AI related symptoms will help to define the cost-benefit ratios of these two AIs. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S1-1.

Prophylactic mastectomy for the prevention of breast cancer

Recent progress in understanding the genetic basis of breast cancer has increased interest in prophylactic mastectomy (PM) as a method of preventing breast cancer. (i) To determine whether prophylactic mastectomy reduces death rates from any cause in women who have never had breast cancer and in women who have a history of breast cancer in one breast, and (ii) to examine the effect of prophylactic mastectomy on other endpoints, including breast cancer incidence, breast cancer mortality, disease-free survival, physical morbidity, and psychosocial outcomes. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, 2002), MEDLINE and Cancerlit (1966 to June 2006), EMBASE (1974 to June 2006), and the WHO International Clinical Trials Registry Platform (WHO ICTRP) search portal (until June 2006). Studies in English were included. Participants included women at risk for breast cancer in at least one breast. Interventions included all types of mastectomy performed for the purpose of preventing breast cancer. At least two authors independently abstracted data. Data were summarized descriptively; quantitative meta-analysis was not feasible due to heterogeneity of study designs and insufficient reporting. Data were analyzed separately for bilateral prophylactic mastectomy (BPM) and contralateral prophylactic mastectomy (CPM). All 39 included studies were observational studies with some methodological limitations; randomized trials were absent. The studies presented data on 7,384 women with a wide range of risk factors for breast cancer who underwent PM.BPM studies on the incidence of breast cancer and/or disease-specific mortality reported reductions after BPM particularly for those with BRCA1/2 mutations. For CPM, studies consistently reported reductions in incidence of contralateral breast cancer but were inconsistent about improvements in disease-specific survival. Only one study attempted to control for multiple differences between intervention groups and this study showed no overall survival advantage for CPM at 15 years. Another study showed significantly improved survival following CPM but after adjusting for bilateral prophylactic oophorectomy, the CPM effect on all-cause mortality was no longer significant.Sixteen studies assessed psychosocial measures; most reported high levels of satisfaction with the decision to have PM but more variable satisfaction with cosmetic results. Worry over breast cancer was significantly reduced after BPM when compared both to baseline worry levels and to the groups who opted for surveillance rather than BPM.Case series reporting on adverse events from PM with or without reconstruction reported rates of unanticipated re-operations from 4% in those without reconstruction to 49% in patients with reconstruction. Sixteen studies have been published since the last version of the review, without altering our conclusions. While published observational studies demonstrated that BPM was effective in reducing both the incidence of, and death from, breast cancer, more rigorous prospective studies (ideally randomized trials) are needed. BPM should be considered only among those at very high risk of disease. There is insufficient evidence that CPM improves survival and studies that control for multiple confounding variables are needed.

Increased risk of contralateral breast cancers among overweight and obese women: a time-dependent association

Breast cancer (BC) survivors are at increased risk of second cancers. Obesity is commonly recognized as a risk factor of BC in postmenopausal period and a prognosis factor in BC regardless of menopausal status. Our aim was to study whether overweight BC survivors were at increased risk of contralateral BC (CBC). Our population was a large cohort of women followed since a first BC without distant spread and/or synchronous CBC. Body mass index (BMI) was assessed at diagnosis time. Binary codings of BMI were used to oppose overweight and obese patients to the others. Survival analyses were used including Cox models. Assumed hypothesis of proportional hazards was explored using graphical methods, Schoenfeld residuals and time-dependant covariates. In case of non-proportional hazards, survival models were computed over time periods. Over 15,000 patients were included in our study. Incidence of CBC was 8.8 (8.3-9.3)/1000 person-years and increased during follow-up. A significant time-dependent association between overweight and CBC was observed. After 10years of follow-up, we found a significant increased hazard of CBC among patients with a BMI above 25kg/m(2): the adjusted hazard ratio was 1.50(1.21-1.86), P=0.001. After 10years of follow-up, our study found a poorer prognosis among overweight BC survivors regarding CBC events. While benefits from diet habits and weight control may be expected during the long-term follow-up, they have yet to be established using randomized clinical trials.

Contralateral risk-reducing mastectomy in young women

Contralateral risk-reducing mastectomy consists in the surgical removal of the contralateral breast to reduce the risk of breast cancer there [1]. Patients with unilateral primary breast cancer have an increased risk of developing a contralateral breast cancer [2]. In a large-scale study, Quan et al. [3] evaluated the incidence, stage and outcomes of women with contralateral synchronous (defined as tumors diagnosed within 12 months of the initial diagnosis) and metachronous (tumors diagnosed beyond 12 months after the initial diagnosis) breast cancer over a 9-year study period. In the 28,787 cases of breast cancer identified, the mean annual incidence of contralateral breast cancer was 0.1%, while the cumulative incidence of contralateral synchronous cancer was 2.1%, and the cumulative incidence of metachronous cancer was 1.2%. Using the Surveillance, Epidemiology and End Results database (SEER), Gao et al. [4] found that the 5-, 10-, 15-, and 20-year actuarial incidence of developing contralateral breast cancer was 3, 6, 9 and 12%, respectively. The average incidence of contralateral breast cancer per year of follow-up per patient was estimated at 0.6%. Based on these, and other retrospective studies, the incidence rate of contralateral breast cancer in breast cancer patients has been estimated to range from approximately 0.5 to 1.8% per year. Benefits of contralateral risk-reducing mastectomy

Testosterone and risk of breast cancer: appraisal of existing evidence.

The objective of this review was to examine data from preclinical, clinical and epidemiological studies to evaluate if testosterone (T) poses increased risk of breast cancer in women. Appraisal of the existing literature produced several lines of evidence arguing against increased breast cancer risk with T. These include: (i) Data from breast tumor cell lines treated with androgens did not corroborate the notion that T increases breast cancer risk. On the contrary, androgens appear to be protective, as they inhibit tumor cell growth. (ii) Many of the epidemiological studies claiming an association between T and breast cancer did not adjust for estrogen levels. Studies adjusted for estrogen levels reported no association between T and breast cancer. (iii) Data from clinical studies with exogenous androgen treatment of women with endocrine and sexual disorders did not show any increase in incidence of breast cancer. (iv) Women afflicted with polycystic ovary disease, who exhibit high levels of androgens do not show increased risk of breast cancer compared to the general population. (v) Female to male transsexuals, who receive supraphysiological doses of T for long time periods prior to surgical procedures, do not report increased risk of breast cancer. (vi) Finally, women with hormone responsive primary breast cancer are treated with aromatase inhibitors, which block conversion of androgens to estrogens, thus elevating androgen levels. These women do not experience increased incidence of contralateral breast cancer nor do they experience increased tumor growth. In conclusion, the evidence available strongly suggests that T does not increase breast cancer risk in women.

Adherence of Adjuvant Hormonal Therapies in Post-Menopausal Hormone Receptor Positive (HR+) Early Stage Breast Cancer: A Population Based Study from British Columbia.

Abstract Background: Adjuvant hormonal therapies for early-stage breast cancer significantly reduce the risk of recurrence, incidence of contralateral breast cancer and death from breast cancer. Optimal compliance to prescribed therapies is associated with improved patient outcomes. However, non-adherence to adjuvant tamoxifen and aromatase inhibitors (AIs) has been reported to range from 17-49% and 19-31% respectively.Objective: To evaluate medication adherence for a large population of post-menopausal women with HR+ early stage breast cancer that were prescribed initial adjuvant hormonal therapies in a publicly funded health care system, and to assess for predictive factors associated with higher rates of non-adherence.Methods: A retrospective cohort of post-menopausal patients diagnosed with HR+ stage I-III breast cancers referred to the BCCA between 2005-2008 whom were prescribed initial adjuvant hormonal therapies (either tamoxifen or an AI) were identified using the British Columbia (BC) Breast Cancer Outcomes Unit database. Cases were matched with the provincial BCCA pharmacy data repository to evaluate patterns of prescription filling. Factors including age, stage, tumor characteristics, use of chemotherapy, hormonal agent prescribed, and prescribing physician were pre-identified as potential factors predicting for non-adherence. Non-adherence was defined as less than 80% of days covered with a prescription.Results: A total of 4,592 patients were prescribed adjuvant hormonal therapies through the BCCA from 2005-2008. 2,414 patients were available for analysis after applying pre-defined inclusion criteria. Overall non-adherence rate was 40%, with non-adherence to tamoxifen and aromatase inhibitors at 42% and 37% respectively. The non-adherence cohort were older, had smaller tumor size, less nodal involvement, lower grade and lower rate of initial chemotherapy (all p&amp;lt;0.001). Non-adherence rates specific to individual physician prescribers ranged from 16% to 67% (p&amp;lt;0.001), and non-adherence rates between specialist provider groups were 34% among medical oncologists compared with 47% in radiation oncologists (p&amp;lt;0.001).Conclusion: Overall non-adherence to adjuvant tamoxifen and AIs in this large population of postmenopausal women with HR+ positive early stage breast cancer was 40%. This likely represents a true reflection of both non-adherence and multiple factors associated with non-adherence given the population size, public health care setting and follow-up strategies. The non-adherent cohort may be the group that is most likely to benefit from hormonal therapy (lower tumor grade) and require hormonal therapy (less adjuvant chemotherapy). Future directions should include interventions directed at physicians in addition to patients given the discrepancy in non-adherence rates among prescribers. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 36.

Breast-Conserving Surgery in BRCA1/2 Mutation Carriers: Are We Approaching an Answer?

Approximately 10% of patients with breast cancer who are treated with breast-conserving surgery (BCS) develop an ipsilateral-breast tumor recurrence (IBTR). The optimal local therapy for women with BRCA-associated breast carcinoma remains controversial. We report the outcome of BCS in BRCA mutation carriers followed at a single institution. A total of 54 women with BRCA1/2-associated breast cancer treated with BCS and whole breast radiotherapy were matched for age, tumor size, and time of surgery with 162 patients with sporadic breast cancer who had the same treatment between February 1994 and October 2007. Primary end points were cumulative incidence of IBTR and contralateral breast cancer (CBC). Median follow-up was 4 years for both groups. Median age was 36 and 37 years for mutation carriers and controls, respectively; mean tumor size was 1.8 cm in carriers and 1.9 cm in controls. Ten-year cumulative incidence of IBTR was 27% for mutation carriers and 4% for sporadic controls (hazard ratio 3.9; 95% confidence interval 1.1-13.8; P = 0.03). Ten-year cumulative incidence of CBC was 25% for mutation carriers and 1% for sporadic controls (P = 0.03). Our data suggest that IBTR risk after BCS in BRCA1/2 mutation carriers is increased compared with patients who have sporadic breast cancer. Likewise, the risk of CBC seems to be increased in this group. These risks and the likelihood of developing new primary tumors should be discussed with carriers interested in breast conservation as well as when choosing risk-reducing strategies.

Tamoxifen reduces the risk of contralateral breast cancer in premenopausal women: Results from a controlled randomised trial

Background Adjuvant treatment with tamoxifen reduces the risk of contralateral breast cancer in hormone-responsive postmenopausal patients, whereas the effect in premenopausal women has not been fully elucidated. We have therefore studied the effect of tamoxifen on contralateral breast cancer in premenopausal women in a controlled randomised trial. Patients and methods Premenopausal women (564) with stage II breast cancers were randomised to 2 years of tamoxifen versus control irrespective of oestrogen receptor (ER) and progesterone receptor (PgR) status. The median follow-up for patients not developing a contralateral cancer was 14 years. Results In the control group 35 women, and in the tamoxifen group 17 women, developed a contralateral breast cancer as a primary event. Tamoxifen significantly reduced the risk of contralateral breast cancer in all women regardless of age (hazard ratio (HR) 0.5, p = 0.02). In subgroup analysis the risk reduction was most pronounced in patients <40 years of age (HR 0.09, p = 0.02). A risk reduction was also seen in women 40–49 years of age or ⩾50 years of age, although in these subgroups this did not reach statistical significance. The reduced risk of contralateral breast cancer was persistent during the whole follow-up time. Conclusion In this randomised trial, adjuvant treatment using tamoxifen for 2 years reduced the incidence of contralateral breast cancer by 50% in all premenopausal women, and by 90% in women <40 years of age. The effect of tamoxifen was not significantly dependent on time.

Effect of simvastatin on the pharmacokinetics of anastrozole

1517 Background: When used in the adjuvant setting, aromatase inhibitors (AIs) reduce the incidence of contralateral breast cancer and are therefore under investigation for primary breast cancer prevention. Statins hold promise for chemoprevention based on preclinical and epidemiological data. Adding statin to AI has the potential to enhance breast cancer prevention and to protect women from AI-related side effects. Prior to initiating a chemoprevention trial of combination therapy, we evaluated the potential for pharmacokinetic drug-drug interaction between anastrozole and simvastatin in postmenopausal women taking adjuvant anastrozole to ensure that the combination will not influence anastrozole concentration or affect its ability to reduce estrogen. Methods: Postmenopausal women with hormone receptor-positive, stage 0-III breast cancer who had been on adjuvant anastrozole (1 mg/day) for at least 30 days were prescribed 14 days of simvastatin (40 mg/day). We collected serum at baseline (anastrozole alone) and after 14 days of simvastatin initiation (combination therapy). Anastrozole and hydroxyanastrozole, its hydroxylated metabolite, concentrations were determined using liquid chromatography-tandem mass spectrometry assay. Estrogen concentrations will be determined using radio-immunoassay. Significant change in anastrozole was predetermined to be greater than a 30% decrease in concentrations. Percent changes from baseline in anastrozole and hydroxyanastrozole were evaluated using Wilcoxon signed-rank tests. Results: From December 2006 to September 2008, 11 women (10 Caucasian, 1 Black, all reported non-Hispanic with a mean age of 60 yrs [range 51–69]) were enrolled in the study. Of these women, nine had evaluable anastrozole concentrations. After 14 days of simvastatin, there were nonsignificant changes in anastrozole (median percentage difference = 10.1% [-13.5%, 38.4%], p = 0.36) and hydroxyanastrozole (median percentage difference = -3.0% [-19.1%, 11.2%], p = 0.65). Estrogen data will be available for presentation. Conclusions: Simvastatin is unlikely to alter the pharmacokinetics of anastrozole in a clinically meaningful way. Combination studies to assess chemopreventive properties of the combination are planned. [Table: see text]