Abstract Background: Anastrozole (A) blocks estrogen production by inhibiting the activity of CYP19 aromatase. Fulvestrant (F) blocks estrogen receptor (ER) signaling by competitive binding, leading to ER degradation by ubiquitination. SWOG S0226 ("Phase III Randomized Trial of Anastrozole versus Anastrozole and Fulvestrant (250mg LD) as First Line Therapy for Post Menopausal Women with Metastatic Breast Cancer," ClinicalTrials.gov Identifier:NCT00075764) demonstrated that combination of A+F is superior to A alone as first-line therapy for patients with ER positive metastatic breast cancer (Mehta et al, NEJM, 2012). Our functional preclinical studies have shown that single nucleotide polymorphisms (SNPs) in SULT1A1 and UGT1A4, drug conjugation enzymes that inactivate A and F, result in decreased enzyme activity toward these drugs (Edavana et al, DMD, 2013; Edavana et al Pharmgenomics Pers Med 2013). We therefore hypothesized that these SNPs will be associated with disease outcomes in S0226 patients due to altered drug levels. Methods: Germline DNA was available for 295 (43.5%) patients enrolled in S0226 overall (157 on A and 138 on A+F). SNPs in SULT1A1 and UGT1A4 were determined either by direct sequencing or allele-specific PCR (TaqMan) assays. Results: There was no difference in progression-free survival (PFS) or overall survival (OS) comparing patients with or without available germline DNA (p = 0.86 and 0.36, respectively). The SULT1A1 G902A allele (rs6839), which confers decreased mRNA and enzymatic activity, was associated with improved PFS (GG/GA vs. AA; HR 0.74, 95% CI 0.56-0.98, p=0.033) and OS (HR 0.70, 95% 0.50-0.98, p=0.039). In exploratory subset analyses of PFS, the SULT1A1 G902A association was similar across both treatment arms (A HR=0.75; 95% CI 0.51-1.10; A+F HR=0.73; 95% CI 0.48-1.11). For OS there was some evidence of a difference by treatment (A HR=0.60; 95% CI 0.38-0.96; A+F HR=0.82; 95% CI 0.50-1.32), though no significant interaction was evident (p=0.30). The UGT1A4 G-163A promoter variant, which leads to decreased protein expression, was not associated with PFS (AA/AG vs. GG HR 0.88, 95% CI 0.68-1.14, p=0.33); however, this variant was associated with OS (HR 0.71, 95% CI 0.52-0.96, p=0.027). In subset analyses with OS, the difference was marginally stronger in the A arm (HR 0.63, 95% CI 0.42-0.97, p=0.035) compared to the A+F arm (HR 0.77, 95% CI 0.49-1.21, p=0.25), though the interaction was not significant (p=0.40). Conclusion: SULT1A1 and UGT1A4 gene variants resulting in decreased enzyme activity were associated with better PFS, OS or both in patients enrolled in SWOG S0226. Planned validation studies correlating these SNPs with drug levels and disease outcomes in additional patient cohorts will establish their clinical utility in identifying patients who benefit from A and F alone or in combination. Funding: Supported by NIH/NCI CA118981; NIH/NCI/NCTN grants CA180888, CA180819, and CA180863; and in part by AstraZeneca. Citation Format: Kadlubar SA, Barlow WE, Mehta RS, Daniels JR, Albain KS, Vandengerg TA, Dakhil SR, Tirumali NR, Lew DL, Gralow JR, Livingston RB, Hortobagiyi GN, Hayes DF, Rae JM. Association between gene variants in SULT1A1 and UGT1A4 and disease outcomes in patients enrolled in SWOG S0226 and treated with anastrozole alone or in combination with fulvestrant for metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-64.
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.
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 >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.
Abstract BACKGROUND: The SWOG S0230/POEMS study demonstrated a 70% reduction in ovarian failure (OF) with goserelin coadministration during chemotherapy (CT) for ER-negative early breast cancer (BC; Moore H et al, NEJM 2015). Goserelin use was also associated with more pregnancies as well as favorable disease free survival (DFS) and overall survival (OS). Here we report the final analysis after 5 years of follow-up. METHODS: Premenopausal women age <50 with stage I-IIIA ER/PR-negative BC to be treated with cyclophosphamide-containing CT were randomized to receive standard CT with or without monthly goserelin 3.6 mg SQ starting at least 1 week prior to the first CT dose. The primary endpoint was OF at 2-years, defined as amenorrhea for the prior 6 months and post-menopausal FSH. Secondary endpoints included pregnancies, disease free survival (DFS) and overall survival (OS). An unplanned analysis of rate of menses recovery at 2 years (presence of menses within 6 months of the 2 year time-point or pregnancy within the first 2 years) was also conducted. OF and pregnancy endpoints were analyzed using multivariable logistic regression adjusting for stratification factors (age and CT regimen); DFS and OS were examined using multivariable Cox regression, adjusting for stratification factors and stage. Two-sided p-values are reported unless otherwise specified in accordance with protocol design. RESULTS: Among 257 randomized participants, 218 were eligible and evaluable. One hundred thirty-six eligible and evaluable patients had OF data and 186 had menstrual data. Median age was 37.7 years. Among the 136 patients with OF data, the odds ratio (OR) for OF at 2 years was 0.30 (95% CI 0.1-0.98; one-sided p=0.023) comparing CT with goserelin to standard CT alone. Among 186 patients with menstrual data, 80% recovered menses by 2 years in the goserelin arm compared with 70% in the standard arm (OR=1.74, 95% CI: 0.83-3.66, p=0.15). Pregnancies, DFS and OS are reported for all 218 eligible and evaluable patients. With a median follow-up of 5.1 years, 22% of patients in the goserelin group had at least one pregnancy compared with 12% in the standard group (OR 2.38, 95% CI 1.08-5.26, p=0.03). Cumulative incidence of pregnancy at 5 years is 23% in the goserelin arm compared with 12% in the standard group. Five-year Kaplan-Meier DFS estimates are 88% in the goserelin arm compared with 79% in the standard arm (HR=0.50, p=0.05). Five-year OS is 92% with goserelin versus 83% in the standard arm (HR=0.47, p=0.06). Including all 257 randomized patients, HR for DFS and OS are 0.67 and 0.48 (p=0.18 and p=0.05). CONCLUSION: Ovarian suppression with goserelin during chemotherapy for hormone receptor-negative breast cancer reduces OF risk and, after 5 years of follow-up, continues to be associated with more pregnancies and improved survival compared with chemotherapy without goserelin. SUPPORT: NIH/NCI grant awards CA189974, CA180888, CA180819, CA074362; AstraZeneca Citation Format: Moore HCF, Unger JM, Phillips K-A, Boyle F, Hitre E, Moseley A, Porter D, Francis PA, Goldstein LJ, Gomez HL, Vallejos CS, Partridge AH, Dakhil SR, Garcia AA, Gralow J, Lombard JM, Forbes JF, Martino S, Barlow WE, Fabian CJ, Minasian L, Meyskens FL, Gelber RD, Hortobagyi GN, Albain KS. Final analysis of SWOG S0230/Prevention of early menopause study (POEMS) [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 P1-15-01.
Abstract Abstract #2109 Background: Despite the impressive results of the recently released trastuzumab adjuvant therapy trials, 15% of patients with HER2 overexpressing or amplified breast cancer developed tumor relapse at 4 years. Lapatinib is a small molecule reversible TKI that inhibits both ErbB1 and ErbB2. The current study was developed to assess the cardiac safety and feasibility of adding lapatinib to paclitaxel and trastuzumab following as part of adjuvant therapy.
 Methods: A single-arm phase II study of doxorubicin (A, 60 mg/m2 day 1) and cyclophosphamide (C, 600 mg/m2 day 1) [q2w or q3w for 4 cycles]; followed by paclitaxel (P, 80 mg/m2 days 1, 8, 15), trastuzumab (T, 4 mg/kg loading dose then 2 mg/kg days 1, 8, 15), and lapatinib (L, 1000 mg days 1-21) [12 weeks]; followed by T (6 mg/kg day 1) and L (1000 mg days 1-21) [40 weeks] was conducted. The primary endpoint was the incidence of congestive heart failure. The current unplanned safety analysis was undertaken due to the observance of a high rate of G3/4 diarrhea.
 Results: From April 2007 to June 2008, 98 pts were enrolled and initiated study treatment. Median age was 51 (range 32-72). Among 83 pts with adverse event (AE) data available, 50 (60%) pts have experienced a G3/4 non-hematologic AE. During post-AC treatment, among 53 pts with AE data available, 31 (58.5%) patients have experienced a G3/4 non-hematologic AE with 24 (45%) patients reporting G3/4 diarrhea. Median cycle of onset of G3/4 diarrhea was cycle 5 (first cycle of PTL) with 16 (64%) cases first reported during cycle 5 and 5 (20%) cases first reported during cycle 6. Among 57, 46, 38, and 32 pts receiving treatment with PTL during cycles 5-8, 65%, 57%, 61%, and 72% of patients received the full L dose, respectively. 31 patients have ended active treatment with 10 due to patient refusal and 8 due to adverse events.
 Conclusions: Preliminary data suggest that L given concurrently with P and T at a dose of 1000 mg per day induces an unacceptable rate of moderate to severe diarrhea. Careful monitoring of diarrhea as well as L dose reduction and initiation of loperamide at first occurrence of diarrhea are recommended. The dose of L when given concurrently with P and T has been amended to 750 mg per day in the current study and safety data for the 1000 mg and 750 mg per day cohorts will be presented. Implications for the ongoing ALTTO study will also be presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2109.
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