Use Of Adjuvant Tamoxifen Research Articles

Characterization of patients with recurrent breast cancer submitted to neoadjuvant therapy in a Brazilian cancer center.

e13013 Background: Breast cancer patients submitted to neoadjuvant therapy have clinical-pathological factors that can correlate with favorable outcomes, such as pathologic complete response (pCR). However, patients who achieve pCR may develop recurrence due to other identifiable risk factors, and some molecular subtypes lack a prognostic marker such as pCR, depending on other factors to determine the risk of recurrence. Objective: Analyse clinical-pathological data from patients with recurrent breast cancer who received neoadjuvant therapy, and identify possible risk factors in this population. Methods: This is an observational, descriptive, retrospective study of patients with recurrent breast cancer, submitted to neoadjuvant therapy between January 2007 and December 2018, at the AC Camargo Cancer Center; São Paulo, Brazil. Of the 1145 patients treated with neoadjuvant therapy, we evaluated 304 who recurred, and crossed data with 841 patients that didn't present recurrence. Results: We analysed 304 patients (26.6%), 60.1% pre-menopause, 6.5% with BRCA1/2 gene mutation, 85.9% had invasive ductal carcinoma (IDC), 53.8% were histologic grade (HG) III, and 84.2% had KI67 >20%. Clinical stage was 44.7% cT4, 28.3% cT3, 25.7% cT2 and 1.3% cT1, while 13.3% were cN3, 21.1% cN2, 43.8% cN1 and 21.7% cN0. Grouped clinical stage was 74.4% III, 25% II and 0.7% I. Molecular subtypes were 52.4% hormone receptor positive/HER2 negative (HR+/HER2-), 12.2% HR+/HER2+, 6.9% HR-/HER2+ and 28.6% HR-/HER2-. Regarding neoadjuvant chemotherapy, 92% received anthracycline and taxane, 23% dose-dense, 17.4% received trastuzumab with or without pertuzumab, and 20% of ER-/HER2- received carboplatin. Chemotherapy interruption occurred in 13.2% of patients, and 31.1% interrupted anti-HER2 therapy. Surgery was 82.9% mastectomy, 77% axillary dissection and 16.4% breast-conserving surgery. Residual Cancer Burden (RCB) score was 13.1% RCB 0, 5.8% RCB I, 35.3% RCBII and 45.8% RCB III. Ninety percent received adjuvant radiotherapy, 9.2% adjuvant capecitabine and 45% of HR+ adjuvant tamoxifen. We observed recurrence association with HG III ( p = 0,001), Ki67 >20% ( p = 0,001), clinical stage III ( p < 0,001), cT4 and cN2/3 ( p < 0,001), RBC > II/III ( p = 0,001), molecular subtypes HR+/HER2- and HR-/HER2- ( p = 0,042), interruption of neoadjuvant therapy ( p = 0,002) and anti-HER2 therapy ( p = 0,012), and use of adjuvant tamoxifen ( p < 0,001). Adjuvant capecitabin and radiotherapy had no correlation with the outcome. Conclusions: Recurrence was associated with intrinsic factors, such as HG III, Ki67>20%, cT4, cN3/4 and molecular subtype, as well as RCB > II/III, treatment interruption and choice of adjuvant hormonal therapy, pointing out possible risk factors in our population.

Comparing the prognostic and predictive utility of serum thymidine kinase 1 and CA 15-3 in patients with hormone receptor positive metastatic breast cancer starting first-line endocrine therapy in SWOG S0226.

1076 Background: Serum levels of thymidine kinase 1 activity (TKa), a fundamental enzyme in DNA synthesis and cellular proliferation, are prognostic of benefit from endocrine therapy (ET) in patients (pts) with hormone receptor positive (HR+) metastatic breast cancer (MBC) who participated in SWOG S0226, a prospective randomized trial comparing anastrozole vs. anastrozole and fulvestrant given in 4 week cycles. The assay for TKa (DiviTum TKa) was FDA approved in July 2022 for monitoring of postmenopausal HR+ MBC pts. The assay for circulating MUC1, CA 15-3, is routinely utilized in monitoring of pts with MBC. We compared the prognostic and predictive utilities of CA 15-3 and TKa in pts from S0226. Methods: TKa was measured in 1725 sera from 432 pts while CA 15-3 was measured in 1298 sera from 326 pts at baseline (BL), cycles 2, 3, 4 and 7. Prespecified cutoff levels of ≥ 250 DuA and ≥ 30 U/mL were considered high for TKa and CA 15-3 respectively. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier and Cox regression stratified by prior adjuvant tamoxifen use. To examine markers over time, a landmarked Cox regression analysis was done starting at initiation of Cycle 4. BL and recent (Cycle 3 if available, otherwise Cycle 2) markers were assessed for simultaneous prediction of subsequent PFS and OS. Results: BL TKa was elevated in 190/432 (44%) and CA 15-3 was elevated in 254/326 (78%). Agreement between assays was 53%. Pts with high versus low BL TKa had significantly worse PFS (median 11.6 vs. 17.2 months, HR = 1.68, 95% confidence interval (CI) 1.37-2.06) and OS (median 34 vs. 58 months, HR = 2.16, 95% CI 1.73-2.70) whereas pts with high versus normal BL CA 15-3 had no significant difference in PFS (median 13.6 vs. 16.1 months, HR = 1.23, 95% CI 0.93-1.62) but worse OS (median 45 vs. 66 months, HR = 1.82, 95% CI 1.30-2.53). A multivariable Cox model with both markers shows only TKa as being prognostic for PFS (TKa HR = 1.61, 95% CI 1.28-2.03; CA 15-3 HR = 1.21, 95% CI 0.91-1.59), but both prognostic for OS (TKa HR = 2.09, 95% CI 1.61-2.71; CA 15-3 HR = 1.70, 95% CI 1.22-2.38). In the landmarked multivariable analysis, positive TKa at BL was a strong predictor of PFS (HR = 1.65, 95% CI 1.28-2.14), but recent TKa was not (HR = 1.25, 95% CI 0.93-1.68). In contrast, positive CA15-3 at BL was not a predictor of PFS (HR = 0.73, 95% CI 0.46-1.17), but recent CA15-3 was (HR = 1.97, 95% CI 1.26-3.06). Conclusions: BL TKa is highly prognostic in pts with HR+ MBC initiating first-line systemic ET, with low BL TKa conferring superior prognosis. In contrast, CA 15-3 is only modestly prognostic at BL, but is prognostic after 3 cycles of treatment. These hypothesis-generating data suggest further study is needed to determine how these biomarkers should be employed in a complementary manner to monitor response to systemic therapy in HR+ MBC. Clinical trial information: NCT00075764 .

Relationship between tamoxifen and cataracts: a nationwide cohort study of women in South Korea

Although prospective randomized clinical trials have reported that the use of prophylactic tamoxifen in patients at a high risk of breast cancer is associated with an increased risk of cataracts development, such findings are inconsistent. This study aimed to clarify the relationship between adjuvant tamoxifen use and cataracts risk using a nationwide longitudinal population-based registry. This retrospective cohort study was conducted using the Korean National Health Insurance claims database over a 15-year period (January 2007-December 2021). Data from all female patients diagnosed with ductal carcinoma in situ (DCIS) between 2009 and 2015 were extracted. We evaluated the incidence of cataracts diagnosis and surgery after adjuvant tamoxifen administration in patients with DCIS. A total of 43,434 patients who met the inclusion criteria were diagnosed with DCIS between 2009 and 2015. Data from 2849 patients receiving tamoxifen and 1615 patients not receiving tamoxifen were analyzed before matching. After matching for comorbidities, type of breast surgery, and age, both groups consisted of 1597 patients. Both before and after matching, adjuvant tamoxifen was not a significant factor for an increased risk of cataracts diagnosis alone or with surgery. Our study showed that adjuvant tamoxifen was not a risk factor for increased cataracts diagnosis and surgery in patients with DCIS. This finding provides a basis for physicians to reduce their ocular toxicity concerns regarding the risk of patients developing cataracts by tamoxifen treatment.

Cholesterol Depletion Modulates Drug Resistance Pathways to Sensitize Resistant Breast Cancer Cells to Tamoxifen

Cancer drug resistance poses a significant risk of relapse and mortality. Adjuvant tamoxifen use has significantly reduced breast cancer mortality; however, many patients relapse due to acquired resistance. We aim to assess the potential of a cholesterol depletor (acetyl plumbagin) combined with tamoxifen to reduce cholesterol accumulation and cancer drug resistance. Cell viability, apoptosis and cholesterol staining was assessed following combination treatment. Gene and protein expression in cancer drug resistance and lipoprotein signalling pathways were assessed using RT2 Profiler™ PCR arrays and STRING networks. Combined treatment led to an increase in apoptosis and reduced intracellular cholesterol in MCF-7 and long-term estrogen deprived (LTED) cells compared to single compound treatments. Furthermore, the combination treatment perturbed several cholesterol-related and cancer-drug resistance pathways. The present study demonstrates the efficacy of tamoxifen combined with acetyl plumbagin in potentially disrupting the PI3K/Akt/PKB and Akt/mTORC1 signalling pathways in MCF-7 cells, reducing breast cancer cell proliferation and resistance.

Impact of adjuvant chemotherapy or tamoxifen-alone on the ovarian reserve of young women with breast cancer.

To determine the longitudinal impact of adjuvant chemotherapy and tamoxifen-only treatments on the reproductive potential of women with breast cancer by using a sensitive ovarian reserve marker anti-Mullerian hormone (AMH) as a surrogate. One-hundred-and-forty-two women with a primary diagnosis of breast cancer were prospectively followed with serum AMH assessments before the initiation, and 12, 18 and 24months after the completion of adjuvant chemotherapy or the start of tamoxifen-only treatment. The chemotherapy regimens were classified into Anthracycline-Cyclophosphamide-based (AC-based) and Cyclophosphamide-Methotrexate + 5-Fluorouracil (CMF). Longitudinal data were analyzed by mixed effects model for treatment effects over time, adjusting for baseline age and BMI. Both chemotherapy regimens resulted in significant decline in ovarian reserve compared to the tamoxifen-only treatment (p < 0.0001 either regimen vs. tamoxifen for overall trend). AMH levels sharply declined at 12months but did not show a significant recovery from 12 to 18 and 18 to 24months after the completion of AC-based or CMF regimens. The degree of decline did not differ between the two chemotherapy groups (p = 0.53). In contrast, tamoxifen-only treatment did not significantly alter the age-adjusted serum AMH levels over the 24-month follow up. Likewise, the use of adjuvant tamoxifen following AC-based regimens did not affect AMH recovery. Both AC-based regimens and CMF significantly compromise ovarian reserve, without a recovery beyond 12months post-chemotherapy. In contrast, tamoxifen-only treatment does not seem to alter ovarian reserve. These data indicate that the commonly used chemotherapy regimens but not the hormonal therapy compromise future reproductive potential.

Biomarkers of neoadjuvant/adjuvant endocrine therapy for ER-positive/HER2-negative breast cancer.

Endocrine therapy is one of the key therapeutic components for patients with hormone receptor-positive early stage breast cancer. A lot of efforts have been made in order to explore biomarkers to select optimal endocrine treatment and optimal duration of the treatment. Estrogen receptor (ER) is the most intensively-studied and well-established biomarker for selection of endocrine treatment. Currently, a number of other markers including conventional immunohistochemical markers and molecular markers such as genetic markers and multigene assays have been investigated. Although the clinical utility of PgR expression has been tested in a number of clinical trials of neoadjuvant/adjuvant endocrine therapy, no validated results have been obtained. Oncotype DX Recurrence Score has been reported to be associated with benefit of adjuvant tamoxifen use and the clinical response to neoadjuvant endocrine therapy but more powerful tool is desired for clinical use to optimize endocrine therapy. Neoadjuvant endocrine therapy is considered as a promising strategy to explore biomarkers for endocrine responsiveness as well as to develop a new treatment option in combination with molecular target agents and to study mechanisms underlying endocrine response and resistance. In this manuscript, current understanding on biomarkers of neoadjuvant/adjuvant endocrine therapy for both predictive and prognostic utilities is discussed.

Accelerated Onset of Liver Failure after Prolonged Adjuvant Tamoxifen Use in Breast Cancer Patients

Use of adjuvant endocrine therapy for women with hormone-receptor (HR)-positive breast cancer has become the standard of care. Tamoxifen, an orally available selective estrogen receptor modulator (SERM), is a commonly used endocrine therapy agent currently recommended for use in pre- or post-menopausal women with HR-positive breast cancer. Current evidence suggests that prolonged tamoxifen use may be implicated in causing hepatotoxicity which may manifest as non-alcoholic steatohepatitis (NASH), cholestasis, cirrhosis, or hepatic necrosis. We herein present two cases of suspected tamoxifen-induced NASH resulting in fulminant liver failure. We also discuss literature surrounding tamoxifen-related hepatoxicity and implications in clinical practice.

The Effects of Adjuvant Tamoxifen Use on Macula Pigment Epithelium Optical Density, Visual Acuity and Retinal Thickness in Patients with Breast Cancer

ABSTRACTPurpose: We aimed to compare best corrected visual acuity, macular pigment optical density and macular thickness in patients with breast cancer, who received oral adjuvant hormone therapy.Materials and Methods: We enrolled consecutive eligible patients with breast cancer who were receiving regular medical tamoxifen treatment. The participants were divided into two groups as cases and controls. Best-corrected visual acuity and retinal thickness were examined. Macular pigment optical density was measured by fundus reflectometry using the one-wavelength reflection method. The output parameters included max optical density, mean optical density, volume and area of the right eye.Results: A total of 104 eyes, cases (n: 50) and controls (n: 54) were included in the study. Mean age in cases was 49.95 ± 9.2 years and 50.21 ± 9.3 years in controls (p = .151). The mean foveal optical density and the maximum optical density differed between cases (0.13 ± 0.03 density units (DU)/0.35 ± 0.07 DU) and controls (0.18 ± 0.04 DU/0.41 ± 0.06 DU) (p = .002/p = .009). Macular pigment optical density volume was 8102.84 ± 2412.67 in cases versus 8280.18 ± 2904.56 in controls (p = .034), and mean MPOD area was 59567.79 ± 11538.06 in cases versus 61748.14 ± 10591.19 in controls (p = .023). The best corrected visual acuity and retinal thickness were similar in both groups (p > .05).Conclusions: Patients in care of oral tamoxifen therapy were found to have significantly reduced macular pigment optical density. In addition, higher drug use duration correlated significantly with reduced macular pigment optical density, suggesting that the poor long-term effects may play a role in macular pigment absorption and incorporation in the retinal tissue.

Adjuvant endocrine therapy for premenopausal women: risk stratification, type and duration

Updated results from the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT) have helped to identify differential value of various adjuvant endocrine therapy strategies in high-risk and low-risk premenopausal early breast cancer. With a median follow-up of 8 years in SOFT, there is now a significant improvement in disease-free survival (DFS) for those assigned to receive 5 years of tamoxifen plus ovarian function suppression (T + OFS) as compared with tamoxifen (T). Further improvement in DFS was observed for those assigned exemestane plus OFS (E + OFS). While the relative treatment effect from the addition of OFS to tamoxifen in the no chemotherapy and prior chemotherapy cohorts in SOFT was similar, larger absolute improvement in DFS was observed with endocrine therapy escalation in the premenopausal cohort who had received chemotherapy. Despite some improvement in DFS in the lower risk no-chemotherapy cohort, the 8-year results for that cohort continue to show a low risk of distant metastases with the use of adjuvant tamoxifen as sole systemic therapy. A small overall survival advantage from the addition of OFS to tamoxifen has now emerged in SOFT, which appears more clinically meaningful in the prior chemotherapy cohort.In the joint analysis of SOFT and TEXT, there is currently no overall survival improvement at 8 years for those assigned E + OFS versus T + OFS, despite a significant reduction in distance recurrences with E + OFS. Assessing absolute improvements in freedom from distant recurrence observed with the different endocrine strategies across the risk spectrum of patients with HER2-negative tumours in SOFT and TEXT, may assist decision-making for premenopausal patients.

Efficacy of extended aromatase inhibitors for hormone-receptor–positive breast cancer: A literature-based meta-analysis of randomized trials

BackgroundEndocrine treatment with Tamoxifen and aromatase inhibitors (AIs) is a staple in the management of hormone receptor positive breast cancer (HR + BC). It has become clear that HR + BC carries a consistent risk of relapse up to 15 years post-diagnosis. While increasing evidence supports the use of extended adjuvant Tamoxifen over 5 years, controversial data are available on the optimal duration of extended AIs adjuvant treatment.We performed a meta-analysis to assess the real impact of extended adjuvant therapy with AIs on disease-free survival (DFS). MethodsA literature-based meta-analysis of randomized controlled trials (RCTs) was undertaken. Relevant publications from PubMed, the Cochrane Library, and abstracts from American Society of Clinical Oncology (ASCO) and San Antonio Breast Cancer (SABCS) symposia were searched. Primary and secondary endpoints were Disease Free Survival (DFS) and overall survival (OS) respectively. A subgroup analysis was also performed to elucidate the impact of nodal involvement. ResultsThe pooled analysis revealed a significant increase in DFS in the extended AIs group (hazard ratio (HR): 0.78, 95% CI: 0.68–0.90; P = 0.0006). The subgroup analysis according to nodal status showed a greater DFS benefit with extended AIs in patients with positive nodes (HR = 0.67 versus 0.80). Our analysis also demonstrated no improvement in OS with extended AIs (HR = 0.99, 95%CI: 0.87–1.12; P = 0.84). ConclusionThis work confirmed the efficacy of extended adjuvant treatment with AIs for HR + early breast cancer, with a 22% increase in DFS, but no impact on OS. Greater efficacy was observed in women with positive nodal status.

Overall Survival with Fulvestrant plus Anastrozole in Metastatic Breast Cancer

BackgroundWe previously reported prolonged progression-free survival and marginally prolonged overall survival among postmenopausal patients with hormone receptor–positive metastatic breast cancer who had been randomly assigned to receive the aromatase inhibitor anastrozole plus the selective estrogen-receptor down-regulator fulvestrant, as compared with anastrozole alone, as first-line therapy. We now report final survival outcomes.MethodsWe randomly assigned patients to receive either anastrozole or fulvestrant plus anastrozole. Randomization was stratified according to adjuvant tamoxifen use. Analysis of survival was performed by means of two-sided stratified log-rank tests and Cox regression. Efficacy and safety were compared between the two groups, both overall and in subgroups.ResultsOf 707 patients who had undergone randomization, 694 had data available for analysis. The combination-therapy group had 247 deaths among 349 women (71%) and a median overall survival of 49.8 months, as compared with 261 deaths among 345 women (76%) and a median overall survival of 42.0 months in the anastrozole-alone group, a significant difference (hazard ratio for death, 0.82; 95% confidence interval [CI], 0.69 to 0.98; P=0.03 by the log-rank test). In a subgroup analysis of the two strata, overall survival among women who had not received tamoxifen previously was longer with the combination therapy than with anastrozole alone (median, 52.2 months and 40.3 months, respectively; hazard ratio, 0.73; 95% CI, 0.58 to 0.92); among women who had received tamoxifen previously, overall survival was similar in the two groups (median, 48.2 months and 43.5 months, respectively; hazard ratio, 0.97; 95% CI, 0.74 to 1.27) (P=0.09 for interaction). The incidence of long-term toxic effects of grade 3 to 5 was similar in the two groups. Approximately 45% of the patients in the anastrozole-alone group crossed over to receive fulvestrant.ConclusionsThe addition of fulvestrant to anastrozole was associated with increased long-term survival as compared with anastrozole alone, despite substantial crossover to fulvestrant after progression during therapy with anastrozole alone. The results suggest that the benefit was particularly notable in patients without previous exposure to adjuvant endocrine therapy. (Funded by the National Cancer Institute and AstraZeneca; ClinicalTrials.gov number, NCT00075764.)

Abstract PD5-07: A phase III randomized trial of anastrozole and fulvestrant versus anastrozole or sequential anastrozole and fulvestrant as first-line therapy for postmenopausal women with metastatic breast cancer: Final survival outcomes of SWOG S0226

Abstract Background: Anastrozole depletes estrogen via aromatase inhibition and fulvestrant binds and degrades estrogen receptor. In a Phase III trial we compared the concurrent use of these agents to anastrozole alone or sequential anastrozole and fulvestrant in first-line therapy of hormone receptor-positive metastatic breast cancer in postmenopausal women, and demonstrated improved progression-free (PFS) and overall survival (OS)-NEJM 2012. Now we report PFS and OS five years after the initial positive findings. Methods: A total of 707 patients were randomized to either 1 mg anastrozole P.O. daily (Arm 1) or to the combination of anastrozole and fulvestrant (Arm 2). Fulvestrant was administered as a loading dose of 500 mg on day 1, 250 mg on days 14, 28 and monthly thereafter. Randomization was stratified by adjuvant tamoxifen use. The primary endpoint was PFS with OS a secondary outcome. 40% patients not in visceral crisis crossed over to fulvestrant after progression on arm 1. Analysis of survival was by 2-sided stratified log-rank tests and Cox regression using intent-to-treat. Subset analyses include treatment effect by adjuvant tamoxifen exposure, initial sites of metastases and time from diagnosis. Results: There were 646 PFS events (328 and 318 for arms 1 and 2, respectively) among 694 eligible patients (345 and 349, respectively). Overall, median PFS was 13.5 months for arm 1 and 15.0 months for the arm 2 (log-rank p=0.007; HR=0.81 (95% CI 0.69-0.94)). This benefit extended similarly in visceral and non-visceral subgroups. In subset analysis for Arms 1 and 2, respectively, in tamoxifen-naive women (60%, n=414), median PFS was 12.7 vs. 16.7 months (log-rank p=0.002; HR=0.73 (95% CI 0.60-0.89) while in women exposed to tamoxifen, median PFS was 13.9 vs. 13.6 months (log-rank p=0.57; HR=0.93 (95% CI 0.73-1.19)). An improved OS in the combination arm was seen, median OS 42 and 50 months in arms 1 and 2, based on 261 and 247 deaths, respectively (log-rank p=0.028; HR=0.82 (95% CI 0.69-0.98)). In subset analysis in tamoxifen-naive women, median OS was 40.3 vs. 52.2 months for Arms 1 and 2, respectively (log-rank p=0.007; HR=0.73 (95% CI 0.58-0.92)) while in women exposed to tamoxifen, median OS was 43.5 vs. 48.2 months (log-rank p=0.85; HR=0.97 (95% CI 0.74-1.27). Patients with initial diagnosis &amp;gt;10 years benefitted most from the combination (HR=0.66 (95% CI 0.49-0.89)) regardless of tamoxifen exposure. Patients in Arm 1 who crossed over had post-progression survival similar to post-progression survival of Arm 2 patients. Conclusion: The addition of fulvestrant to anastrozole was associated with improved long-term PFS and OS compared to anastrozole alone, despite the use of fulvestrant at a dose lower than the approved, and despite the substantial cross over to fulvestrant after progression on anastrozole alone. The benefit was especially notable in those without recent exposure to adjuvant endocrine therapy. Ongoing translational medicine studies will further refine the need for up front fulvestrant. ClinicalTrials.gov:NCT00075764. Funding: NIH/NCI U10CA180888, U10CA180819 and AstraZeneca. Citation Format: Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NL, Lew DL, Hayes DF, Gralow JR, Linden HM, Livingston RB, Hortobagyi GN. A phase III randomized trial of anastrozole and fulvestrant versus anastrozole or sequential anastrozole and fulvestrant as first-line therapy for postmenopausal women with metastatic breast cancer: Final survival outcomes of SWOG S0226 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD5-07.

Association of Adjuvant Tamoxifen and Aromatase Inhibitor Therapy With Contralateral Breast Cancer Risk Among US Women With Breast Cancer in a General Community Setting

Within 10 years after breast cancer diagnosis, roughly 5% of patients develop contralateral breast cancer (CBC). Randomized trials have found that therapy including tamoxifen citrate and aromatase inhibitors (AIs) reduces CBC risk. But little is known about the magnitude and duration of protective associations within the context of real-world clinical management settings, where varying durations of and gaps in treatment are common. To determine the association between adjuvant tamoxifen and AI therapy and CBC risk within a general community setting. A retrospective cohort study of CBC risk among 7541 patients diagnosed with a first primary unilateral invasive breast cancer at Kaiser Permanente Institute for Health Research (Colorado) or Kaiser Permanente Northwest Center for Health Research (Oregon) between January 1, 1990, and December 31, 2008. Data were analyzed from 1 year after diagnosis of the first breast cancer through the earliest of the following events: CBC diagnosis, other second cancer diagnosis, death, last tumor registry follow-up, exit from the Kaiser Permanente health care plan, or end of study follow-up (December 31, 2010, for Oregon and December 31, 2011, for Colorado). Adjuvant tamoxifen use and AI therapy were treated as time-dependent exposures, assessed using electronic prescription records. Incident CBC based on long-term systematic follow-up. Among 7541 women with invasive breast cancer, median age at initial breast cancer diagnosis was 60.6 years (age range, 24.9-84.9 years). Women were predominantly (92.9% [7009 of 7541]) of white race. During a median of 6.3 years (range, 1-20.9 years) of follow-up, 248 women developed CBC (45 in situ and 203 invasive). Contralateral breast cancer risk decreased significantly with increasing tamoxifen therapy duration. In current users, the relative risk (RR) per year of tamoxifen use was 0.76 (95% CI, 0.64-0.89), with an estimated 66% (RR, 0.34; 95% CI, 0.29-0.40) RR reduction for 4 years of use compared with nonusers. Risk reductions were slightly smaller for past users but were still significant at least 5 years after stopping tamoxifen therapy (RR per year of use, 0.85; 95% CI, 0.71-0.995). In addition, AI use without tamoxifen therapy was associated with reduced CBC risk (RR for AI users compared with nonusers, 0.48; 95% CI, 0.22-0.97). Risk reductions were most apparent among women whose primary and CBCs were estrogen receptor positive. Tamoxifen therapy was associated with reduced CBC risk during treatment and after its cessation, with risk progressively decreasing as tamoxifen therapy duration increased. Among those surviving at least 5 years, tamoxifen use for at least 4 years was estimated to prevent 3 CBCs per 100 women by 10 years after an estrogen receptor-positive first breast cancer, an absolute risk reduction that is consistent with findings from clinical trials. If adjuvant endocrine therapy is indicated for breast cancer treatment, these findings in concert with trial data suggest that women should be encouraged to complete the full course.

Evaluation of Metachronous Breast and Endometrial Cancers: Preroutine and Postroutine Adjuvant Tamoxifen Use.

The time interval between diagnoses of breast cancer (BC) and endometrial cancer (EC) is not well established in women with metachronous primary tumors. We sought to examine this interval and identify associations with treatment-related and clinicopathologic factors. We identified 141 patients who developed both cancers during 1966 to 2013. Patients were divided into 2 groups: group 1, BC first, and group 2, EC first. Subanalysis performed of group 1 (59 patients) stratified around adjuvant tamoxifen use: pre-1990 BC diagnosis and post. Fifty-nine and 82 patients were in groups 1 and 2, respectively. The mean time interval was comparable (76 vs 74 months, P = 0.861). Subanalysis divided group 1 into pre- (n = 27) and post- (n = 32) 1990 and resulted in different mean time intervals between diagnosis of metachronous cancers (106 vs 50 months, respectively [P = 0.042]). Median progression-free survival (PFS) and overall survival (OS) for EC were longer in the pre group (PFS, 51 vs 26 months [P = 0.169]; OS, 59 vs 27 months [P = 0.190]). Median PFS and OS for BC were also longer in this group (PFS, 147 vs 109 months [P = 0.005]; OS, 166 vs 114 months [P < 0.001]). Our data indicate the mean time interval between the diagnosis of EC and BC was approximately 6 years. Disease-specific EC survival was worse for patients with a previous diagnosis of BC. Stratification around implementation of tamoxifen use shows comparable grade and stage but different time interval and survival, suggesting resulting effects from adjuvant therapy for BC. These results are useful in counseling women at risk.

Abstract P1-13-02: Benefit/risk of invasive breast cancer adjuvant tamoxifen or aromatase inhibitor use by age, race/ethnicity, and co-morbidity

Abstract Background: Older age, minority race/ethnicity, and co-morbidities adversely influence early stage IBC outcome. Further, as AI compared to tamoxifen use has different effects on IBC recurrence and other health outcomes including hip fracture, endometrial cancer, stroke, pulmonary embolism and, perhaps especially, coronary heart disease (CHD), an approach to summarize relative benefit/risk of these agents is needed. Methods: Incidence rates for health outcomes by age and race/ethnicity, absent AI or tamoxifen use, were obtained from the placebo arms of the three primary Women's Health Initiative clinical prevention trials (n = 33,072). AI and tamoxifen effects on IBC distant recurrence (relative risk [PR] 0.82) were estimated from a meta-analysis of the ATAC and Big-1-98 trial results (n = 14,149) and on other health outcomes from published meta-analysis of side effects in seven AI vs tamoxifen trials (n = 30,023); RR of 1.47 for hip fracture, 0.34 for endometrial cancer, 0.84 for stroke, 0.55 for pulmonary embolism, 1.26 for CHD (Amir et al JNCI 2011;103:1299). Following the methodology of Freedman et al (JCO 2011;29:2327), mortality weights were assigned health outcomes (5 year mortality risk of 0.2 for MI, 0.8 for IBC distant recurrence, etc) to assess net all cause mortality benefit/risk for AI compared to tamoxifen by recurrence risk, age (decade), race/ethnicity, hysterectomy (yes/no) and, in separate analyses, in women with diabetes and in women with cardiovascular disease [CVD] history. Results: In these analyses, clinical outcome of women with early stage IBC was unfavorable (more deaths per 1000 women/years) with tamoxifen compared to AI adjuvant use regardless of age, race/ethnicity, diabetes or CVD history even with 10-year distant recurrence risk of only 10%. AI superiority was substantially greater in women with a uterus and, in exploratory analyses, when assuming a CVD relative risk for AI use of 1.0, rather than a CHD relative risk of 1.26 used in all other analyses, as the AI CHDrisk elevation is controversial. The net benefit of AI compared to tamoxifen influence on clinical outcomes are described in a series of tables to be presented which quantify benefit/risk in particular women groups. The example below illustrates the excess number of deaths/1000 woman years for tamoxifen vs. AI by recurrence risk, age, and hysterectomy status. Excess Number of Deaths per 1000 women/year for Tamoxifen Compared to AI Tamoxifen vs. AI (with uterus)Tamoxifen vs. AI (without uterus)10-year Distant Recurrence (%)Age GroupAge Group 50-59y60-69y70-79y50-59y60-69y70-79y1015120620010211111030326382375278287286 For a 60-69 year old woman with a uterus at 30% 10 year recurrence risk, there would be 382 more deaths per 1000 women/yr for tamoxifen vs. AI use. With prior hysterectomy, there would still be 287 more deaths for tamoxifen use. Conclusion: We developed an index to quantify the benefit risk for adjuvant AI vs. tamoxifen use. Even assessing a RR of 1.26 for CHD for AI use, tamoxifen compared to AI use had unfavorable outcome in all examined groups. This index can complement clinical evaluation in comparing use of these two adjuvant therapy approaches in women of different ages and racial/ethnic groups. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-13-02.

Highlights from the San Antonio Breast Cancer Symposium 2012

At the San Antonio Breast Cancer Symposium 2012, long-term follow-up data from large clinical trials support a change in practice for the use of sentinel node mapping after neoadjuvant therapy and the safety and efficacy of hypofractionated radiation therapy. The duration of adjuvant therapy was further defined, with advantages reported with the extended use of adjuvant tamoxifen for 10 years and for 12 months of adjuvant trastuzumab.

Adjuvant Tamoxifen Reduces Subsequent Breast Cancer in Women With Estrogen Receptor–Positive Ductal Carcinoma in Situ: A Study Based on NSABP Protocol B-24

The NSABP (National Surgical Adjuvant Breast and Bowel Project) B-24 study demonstrated significant benefit with adjuvant tamoxifen in patients with ductal carcinoma in situ (DCIS) after lumpectomy and radiation. Patients were enrolled without knowledge of hormone receptor status. The current study retrospectively evaluated the relationship between receptors and response to tamoxifen. Estrogen (ER) and progesterone receptors (PgR) were evaluated in 732 patients with DCIS (41% of original study population). An experienced central laboratory determined receptor status in all patient cases with available paraffin blocks (n = 449) by immunohistochemistry (IHC) using comprehensively validated assays. Results for additional patients (n = 283) determined by various methods (primarily IHC) were available from enrolling institutions. Combined results were evaluated for benefit of tamoxifen by receptor status at 10 years and overall follow-up (median, 14.5 years). ER was positive in 76% of patients. Patients with ER-positive DCIS treated with tamoxifen (v placebo) showed significant decreases in subsequent breast cancer at 10 years (hazard ratio [HR], 0.49; P < .001) and overall follow-up (HR, 0.60; P = .003), which remained significant in multivariable analysis (overall HR, 0.64; P = .003). Results were similar, but less significant, when subsequent ipsilateral and contralateral, invasive and noninvasive, breast cancers were considered separately. No significant benefit was observed in ER-negative DCIS. PgR and either receptor were positive in 66% and 79% of patients, respectively, and in general, neither was more predictive than ER alone. Patients in NSABP B-24 with ER-positive DCIS receiving adjuvant tamoxifen after standard therapy showed significant reductions in subsequent breast cancer. The use of adjuvant tamoxifen should be considered for patients with DCIS.

S1-1: A Phase III Randomized Trial of Anastrozole Versus Anastrozole and Fulvestrant as First-Line Therapy for Postmenopausal Women with Metastatic Breast Cancer: SWOG S0226.

Abstract Background: Anastrozole inhibits the aromatase enzyme-induced estrogen synthesis, and fulvestrant down-regulates estrogen receptors in hormone receptor-positive breast cancer. We hypothesized that the simultaneous disruption of the ligand-receptor axis with concurrent use of these agents may be potentially additive or synergistic in first-line therapy of hormone receptor-positive metastatic breast cancer in postmenopausal women. Materials and Methods: A total of 707 patients were randomized to either 1 mg anastrozole P.O. daily (Arm 1) or to the combination of anastrozole and fulvestrant (Arm 2). Fulvestrant was given as an intramuscular injection as follows: loading dose of 500 mg on day 0, followed by 250 mg on days 14, 28 and 250 mg maintenance monthly thereafter. The primary endpoint was progression-free survival (PFS), with a power of 90% and one-sided alpha of 0.025 to detect an expected median PFS of 10 months in Arm 1 versus 13 months in Arm 2. Randomization was stratified by adjuvant tamoxifen use with the possibility of differential benefit of fulvestrant in the two strata. Patients were encouraged to crossover to fulvestrant after progression on the anastrozole alone arm (40% did), if they were not candidates for immediate chemotherapy. Analysis of survival was by 2-sided stratified log-rank tests and Cox regression using intent-to-treat. Two interim analyses were performed with the final analysis using a 2-sided p-value of 0.04. Results: There were 548 events (287 and 261 by arms, respectively) among 694 eligible patients (345 and 349, respectively). Overall, median PFS was 13.5 months for anastrozole and 15.0 months for the combination of fulvestrant and anastrozole (log-rank p=0.0145; HR=0.81 (95% CI 0.68−0.96). In a subset analysis of tamoxifen-naive women (60%, n=414), median PFS was 12.6 months and 17.0 months for Arms 1 and 2, respectively (log-rank p=0.0069; HR=0.74 (95% CI 0.60−0.92)), and 14.1 months and 13.5 months for Arms 1 and 2, respectively, in the 40% of tamoxifen-pretreated women (log-rank p = 0.56; HR=0.93 (95% CI 0.71−1.20)). A trend for improved overall survival (OS) in the combination arm was seen (median OS was 42 and 48.6 months based on 152 and 137 deaths respectively, log-rank p = 0.094; HR=0.82 (95% CI 0.65−1.03)). On the combination arm, three treatment-related deaths occurred: due to pulmonary embolism (2) or cerebrovascular ischemia (1); one Grade 4 thrombosis/embolism and one Grade 4 neutropenia and lymphopenia were reported. On the anastrozole arm, four patients experienced Grade 4 toxicities: thrombosis/embolism, arthralgia, thrombocytopenia, and dyspnea. In general, Grade 3 or higher toxicity was rare (12.7% vs. 14.5% for Arms 1 and 2, respectively) and did not differ significantly. Discussion: The combination of anastrozole and fulvestrant was associated with improved PFS compared to anastrozole alone as well as a trend in OS despite substantial crossover, thus offering a new standard in the first-line treatment of hormone receptor-positive breast cancer in postmenopausal women, specifically in tamoxifen-naive patients. ClinicalTrials.gov:NCT00075764. Funding: NIH/NCI CA32102, CA38926 and AstraZeneca. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S1-1.

P1-06-02: Correlation between Gene Variants in CYP19 (Aromatase) and TCL1A with Disease and Tolerability Endpoints in the ATAC Trial.

Abstract Aim: To assess whether candidate polymorphisms in CYP19 (aromatase) and TCL1A were associated with recurrence, musculoskeletal symptoms (MSKs) or hot-flushes in primary estrogen receptor-positive breast cancer in postmenopausal women treated with tamoxifen or anastrozole. Background. Recently, variants rs10459592 and rs4775936 in CYP19 (aromatase) have been reported to be associated with aromatase inhibitor (AI) response in patients with metastatic breast cancer (Park, et al, CCP, 2011) and variants in CYP19 and at the 3’ end of TCL1A (rs11849538) with AI-induced arthralgia (Ingle, et al, JCO, 2010). These findings require validation before clinical application. The ATAC trial was a prospective randomized double-blind placebo-controlled trial that compared the adjuvant use of anastrozole versus tamoxifen for 5 years. The trial's detailed efficacy and safety data, long term (10-year) follow-up and high event rate make it an ideal setting for pharmacogenetic single nucleotide polymorphism (SNP) validation studies. Here we report our findings testing for correlations with 3 SNPs in CYP19 and TCL1A with clinical outcomes including any disease recurrence, distant recurrence, MSKs, and hot-flushes. Methods: Genotypes were determined using ABI Taqman assays without knowledge of the patient's treatment assignment or outcomes. Hazard ratios (HR) and corresponding 95% confidence intervals (CI) were estimated by the proportional hazards regression model and were adjusted for: age, tumor size, grade, and nodal status (for survival analyses) and age, hormone replacement therapy, body mass index, and smoking (for toxicity analyses). Results: 807 patients were genotyped for CYP19 SNPs rs10459592 and rs4775936 and 842 for TCL1A SNP rs11849538. The rs10459592 genotype frequencies were 16.6% Wt/Wt, 51.5% Wt/Vt, and 32% Vt/Vt. There was a trend towards decreased recurrence in Vt/Vt and Vt/Wt compared to Wt/Wt (HR=0.77 [0.50−1.22] and 0.68 [0.42−1.09], p[trend]=0.1), similar for both anastrozole- and tamoxifen-treated patients and also similar for distant recurrence. For the same SNP, there was a trend toward more MSKs in Vt/Vt and Vt/Wt compared to Wt/Wt (HR=1.22 [0.80−1.88] and 1.47 [0.94−2.30], p[trend]=0.08), primarily due to the effect in the tamoxifen cohort (HR=1.88 [0.89−3.99], p[trend]=0.1). The rs4775936 genotype frequencies were 26.0% Wt/Wt, 52.1% Wt/Vt and 21.9% Vt/Vt. Trends in the same direction as those for rs10459592 were found with rs4775936, albeit less significant. The TCL1A genotype frequencies were 77.5% Wt/Wt, 20% Wt/Vt and 2.5% Vt/Vt. No association was observed between TCL1A genotypes and recurrences or MSKs, however, the small number of Vt/Vt patients on tamoxifen had greater incidence of hot flushes (HR=1.99 [0.9−3.91], p=0.09). Conclusion: These data do not support an association between the TCL1A 3’ variant and AI-induced MSKs independent of severity. Our data do support the CYP19 SNP rs10459592 and the loosely linked rs4775936, which previously were associated with letrozole efficacy, as probably being associated with better disease outcome on anastrozole and tamoxifen and with worse drug side effects. The degree of association requires definition in further data sets. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-06-02.

P4-12-06: Risk Factors for Relative Weight Gain &amp;gt;10% in Breast Cancer Survivors: Findings from the SU.VI.MAX Cohort.

Abstract Purpose: Since extreme weight gain (EWG, defined as weight gain &amp;gt; 10% of baseline body weight) raises risk for recurrence among breast cancer survivors (Caan et al. AACR 2011) we undertook this study to identify risk factors for EWG after breast cancer. Methods: We screened the database of the SU.VI.MAX trial (13017 pts randomized between low-dose antioxidants and placebo, Arch Int Med 2004) to retrieve women with confirmed breast cancer occurring after inclusion, and post-cancer follow-up. The following data were collected at inclusion and during the study: anthropometric measurements, physical activity, tobacco and alcohol consumption, level of instruction and socio-economic status, current medications. Unlike other breast cancer survivor studies, data have been collected prospectively before breast cancer diagnosis. Data management and data analysis were performed using SAS software 9.1.3. We also screened questionnaires and medical reports to collect data that were not recorded in the study database: type of adjuvant therapy (chemo-and hormone therapy), use of vitamins and dietary supplements, concomitant medications (such as antidepressants, lipid lowering agents, thyroid hormones or anti-thyroid drugs), previous use of HRT, and whether patients were following a diet plan after breast cancer or no. Results: We identified 176 pts with breast cancer included since 1994 in the SU.VI.MAX 8-year Cohort Study. Among them, 25% (n=44) had weight gain &amp;gt;10% of baseline. The only variable significantly correlated with EWG was age at breast cancer diagnosis. Other differences, in particular level of physical activity or anthropometric measurements, did not reach statistical significance. No significant differences were seen between patients with EWG and others regarding the use of adjuvant chemotherapy (34 v 28%), aromatase inhibitors (18 v 22%), or tamoxifen (25 v 21%), previous HRT use (44 v 50%) or concomitant drugs including thyroid hormones (20 v 17%). A minority of patients was following a diet (16 v 17%) but consumption of vitamins or dietary supplements was slightly higher in patients without EWG (35 v 50%). Discussion: Weight gain after breast cancer is a well-known phenomenon affecting at various levels half of breast cancer survivors. Most recent studies suggest that patients with EWG could have an increased recurrence rate. Risk factors for weight gain are still matter of debate but the role of adjuvant chemotherapy is widely admitted. Our results however indicate that adjuvant therapy does not seem to be a major risk factor for EWG. Furthermore, lifestyle and diet do not seem to markedly affect the risk of EWG. The only significant difference observed in our study is age at diagnosis, suggesting that treatment-induced amenorrhea could play a role in some patients. Although identification of women at risk remains difficult, thus precluding a large proportion of this population from tertiary prevention, younger women seem to deserve particular attention. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-12-06.