First-line Therapy For Postmenopausal Women Research Articles

The 5-Year Disease-Free Survival of Third Generation Aromatase Inhibitor for Postmenopausal Women with HR-Positive HER2-Negative Non-Metastatic Breast Cancer.

Background: Several studies showed the superiority of aromatase inhibitor (AI) as first-line therapy for patients with hormone-receptor (HR)-positive breast cancer (BC). For the clinician, studies in the real world are warranted to determine treatment based on the efficacy of each drug. We compared a 5-y disease-free survival (DFS) of each AI in terms of survival benefit. Materials and Methods: We evaluated 450 medical records of postmenopausal women who were diagnosed with HR-positive HER2-negative BC (stage I - III) at Dr. Sardjito General Hospital from January to December 2019. All patients had undergone surgery and chemotherapy or radiation therapy. Moreover, study participants received anastrozole, letrozole, or exemestane for at least one year. Kaplan Meier estimation survival curve was used to analyze the survival rate. Result: Of 79 patients meeting inclusion criteria, there were 21.52% distant metastases documented. Time to disease progression of anastrozole, letrozole, and exemestane was 49 months, 58 months, and 53 months, respectively. Letrozole was found better than anastrozole (hazard ratio (HR)=4.342, 95% CI 0.95-19.95; p=0.038). Letrozole versus exemestane (HR=2.757, 95% CI 0.53-14.33; p=0,206) and anastrozole versus exemestane (HR=1.652, 95% CI 0.56-4.84; p=0.351) were found not significantly different. 5-y DFS rate of letrozole was better found (87.5%) than exemestane (73.7%) and anastrozole (61.4%). Conclusion: 5-year letrozole administration could be proposed as first-line therapy for postmenopausal women with HR-positive HER2-negative BC. A considerable subject and long-term follow-up are needed for validation.

LBA19 GEICAM/2014-12 (FLIPPER) study: First analysis from a randomized phase II trial of fulvestrant (F)/palbociclib (P) versus (vs) F/placebo (PL) as first-line therapy in postmenopausal women with HR (hormone receptor)+/HER2– endocrine sensitive advanced breast cancer (ABC)

LBA19 GEICAM/2014-12 (FLIPPER) study: First analysis from a randomized phase II trial of fulvestrant (F)/palbociclib (P) versus (vs) F/placebo (PL) as first-line therapy in postmenopausal women with HR (hormone receptor)+/HER2– endocrine sensitive advanced breast cancer (ABC)

Abstract 3830: Novel bromodomains and extra-terminal motif (BET) inhibitors developed against estrogen receptor positive, fulvestrant- and CDK4/6-resistant breast cancer models

Abstract Approximately 70% of breast cancer patients have estrogen receptor positive (ER+) tumors. Fulvestrant (FUL), a selective estrogen receptor degrader (SERD) able to ablate ER, was first introduced to clinical practice in 2002 as the second and third line treatment for ER+ metastatic breast cancer. In August 2017, FUL was added to first-line therapy in postmenopausal women by demonstrating superiority compared to first-line AI therapy, anastrozole, with improved progression-free-survival (PFS) and a 20% reduction in the risk of disease progression or death. However, acquisition of FUL-resistance in both first-line setting or as combination therapy with CDK4/6 inhibitor has been observed clinically, leaving patients and oncologists with chemotherapy as the only backup therapy. Little is known about resistance mechanisms to FUL alone or in combination with CDK4/6 inhibitors. Here, we showed that targeting epigenetic vulnerabilities in breast cancer using novel bromodomain and extra-terminal (BET) inhibitors can effectively inhibit growth of tamoxifen-, FUL- and CDK4/6- resistant breast cancer cells. We designed and developed a novel series of pyridinone-based BET inhibitors, optimized by growth inhibition in tamoxifen- and FUL- resistant breast cancer cell lines (MCF7:CFR) in both 2D and 3D cultures. Optimized compounds showed superior in vitro activity to BET inhibitors in clinical trials. Selected compounds were further evaluated for pharmacokinetics and shown efficacy in endocrine-resistant xenograft models. Citation Format: Rui Xiong, Yangfeng Li, Jiong Zhao, Debra Tonetti, Gregory Thatcher. Novel bromodomains and extra-terminal motif (BET) inhibitors developed against estrogen receptor positive, fulvestrant- and CDK4/6-resistant breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3830.

The Role of CDK4/6 Inhibitors in Breast Cancer.

Oral inhibitors of CDK4/6 have been shown to increase response rates and prolong disease control when combined with endocrine therapy in hormone-responsive (HR+) HER2-negative advanced breast cancer. Palbociclib, ribociclib and abemaciclib are all approved in combination with non-steroidal aromatase inhibitors in first-line therapy for post-menopausal women, with a 40-45% improvement in progression-free survival seen with the addition of any of these CDK4/6 inhibitors. Additional approved indications, including first- and second-line combination therapy for pre-menopausal women, combination with fulvestrant and use as monotherapy, vary with each agent and are reviewed fully in the subsequent texts. These agents also differ in their toxicity profiles and monitoring requirements, and prescribers should be aware of the individual requirements for each agent. Current clinical trials are investigating the expanded use of these agents in other breast cancer subtypes, such as HER2-positive and triple-negative breast cancer, as well as in the adjuvant and neoadjuvant treatments of early breast cancer. Resistance to CDK4/6 inhibition can occur through multiple mechanisms. Rational combinations with other therapies, such as PI3K inhibitors, HER2-directed therapies and immunotherapy, are being explored.

Abstract OT3-02-01: RIBANNA — Real-world evidence of ribociclib plus aromatase inhibitor, or endocrine monotherapy, or chemotherapy as first-line therapy for postmenopausal women with HR+, HER2– advanced breast cancer (aBC)

Abstract Background: In the pivotal phase 3 MONALEESA-2 trial, ribociclib, a highly selective oral CDK4/6 inhibitor in combination with letrozole significantly prolonged progression-free survival (PFS) compared to letrozole alone. In the year 2017, based on the results of MONALEESA-2, ribociclib in combination with an aromatase inhibitor (AI) was approved for the treatment of HR+, HER2– aBC in postmenopausal women with no prior therapy for their advanced disease (first-line treatment). Beyond phase 3 trials, further data for ribociclib are now becoming available from the phase 3b trials, RIBECCA and COMPLEEMENT-1, involving approximately 500 and 3000 patients with aBC, respectively. However, real-world evidence for the effectiveness, safety, and tolerability of ribociclib + AI in the routine clinical practice is needed to further support the use of this combination in the first-line therapy. Methods: RIBANNA is a non-interventional study, which started in October 2017 and plans to enroll 3020 patients across ˜400 sites in Germany. Postmenopausal women diagnosed with aBC will be enrolled into 3 cohorts (cohort 1: ribociclib + AI; cohort 2: endocrine monotherapy; and cohort 3: chemotherapy). Across all cohorts, patients will be treated in accordance with the respective German-prescribing guidelines. Data related to efficacy (with PFS as the primary efficacy criterion), safety, tolerability, duration of therapy, and impact on quality of life (QoL) will be collected. QoL will be assessed using the validated patient questionnaires. This study was especially designed to analyze the patient data from sequential lines of therapy in all three cohorts over a period of up to 7 years. For this purpose, RIBANNA will collect the data on each line of treatment and the reason for changing treatment in all 3 cohorts. The same accounts for QoL, which will also be assessed periodically, regardless of disease progression and initiation of subsequent therapies. RIBANNA is the first study to provide the real-world evidence regarding treatment of HR+, HER2− aBC with the CDK4/6 inhibitor, ribociclib. This study includes 3 treatment cohorts (ribociclib + AI, endocrine monotherapy, and chemotherapy) with subsequent treatment algorithms and assessment of QoL over the entire study period. Citation Format: Wöckel A, Fasching PA, Guderian G, Heim J, Jackisch C, Lück H-J, Lüftner D, Marmé F, Reimer T, Decker T. RIBANNA — Real-world evidence of ribociclib plus aromatase inhibitor, or endocrine monotherapy, or chemotherapy as first-line therapy for postmenopausal women with HR+, HER2– advanced breast cancer (aBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-02-01.

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 >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.

Efficacies of aromatase inhibitors in the treatment of hormone dependent metastatic breast cancer in postmenopausal women: a report of 148 cases

To evaluate the clinical efficacies of aromatase inhibitors in the treatment of postmenopausal metastatic breast cancer. A total of 148 postmenopausal women (including bilateral ovariectomy) with hormone dependent metastatic breast cancer receiving aromatase inhibitors (letrozole, anastrozole or exemestane) were analyzed retrospectively. Their clinical efficacies were evaluated. The median progression-free survival (PFS) was 6.5 months and the clinical benefit rate 63.5%. And the rates of PFS of patients on first-line and second-line or above treatments were 9.0 (95% CI: 6.95-11.05) and 3.0 months (95% CI: 1.8-10.1) respectively. The clinical benefit rates of two groups were 74.2% and 26.3% respectively. Aromatase inhibitors are both efficacious and well-tolerated for patients of postmenopausal metastatic breast cancer. It may be recommended as a first-line therapy for postmenopausal women with hormone dependent metastatic breast cancer.

Low-Dose Intravaginal Estriol and Pelvic Floor Rehabilitation in Post-Menopausal Stress Urinary Incontinence

Introduction: Pelvic floor muscle training (PFMT) and electrical stimulation (ES) are conservative models of therapy for treating female stress urinary incontinence (SUI). The presence of estradiol receptors in the lower urinary tract advances the case for estradiol therapy in SUI. The aim of our study was to investigate the effects of the combination of pelvic floor rehabilitation and intravaginal estriol (IE) on SUI treatment in postmenopausal women. Material and Methods: Sixty-two women with SUI were randomized to PFMT, ES and biofeedback (Group 1) or the same treatment plus 1 mg IE (Group 2) for 6 months. Patients were evaluated with medical history, pelvic examination, urodynamics, 24-hour pad test. Urinary incontinence was evaluated using the International Consultation on Incontinence questionnaire on urinary incontinence short form and quality of life using the Incontinence Impact Questionnaire-Short Form. Results: Two patients were lost at follow-up and one discontinued the study. Mean urine leakage at the 24-hour pad test dropped from 42.3 ± 20.2 g/die to 31.5 ± 14.2 g/die in Group 1 and from 48.3 ± 19.8 g/die to 22.3 ± 10.1 g/die in Group 2. Symptoms scores and incontinence status were statistically significant better in Group 2 when compared to Group 1. Conclusion: IE added to PFMT, ES and BF is a safe and efficacious first-line therapy in postmenopausal women with SUI.

Abstract P2-14-07: Evaluation of Aromatase Inhibitor failure and total healthcare expenditures among post-menopausal women with metastatic ER+/HER2− breast cancer in the US

Abstract Aromatase Inhibitors (AIs) have replaced tamoxifen as first-line therapy for post-menopausal women with metastatic, ER+ breast cancer (BC). However, little information is available on the real-world use of AIs. This retrospective administrative claims study compared healthcare expenditures of post-menopausal women with metastatic ER+/HER2− BC treated with AIs and experiencing 0 or ≥ 1 AI failures (AIF). Women ≥ 55 years of age newly diagnosed with stage IV BC (index) were identified in the 2006–2010 Thomson Reuters MarketScan databases and followed until the earliest of chemotherapy, combination therapy, end of enrollment, or end of study (03/31/2011). ER+/HER2− disease was defined as any endocrine therapy (ET: tamoxifen, fulvestrant) or AI (anastrozole, letrozole, or exemestane) use and no trastuzumab, lapatinib or toremifene use anytime in the 6-month pre-or variable length post-index periods. Those with post-index AI use except where use followed chemotherapy or combination therapy were retained for analysis. AIF post-index was defined as a switch to an alternative AI, ET, chemotherapy, or combination therapy. All-cause healthcare expenditures, defined as total provider payments (insurer + patient + COB) were examined by type of service and in total, and expressed as per patient per month (PPPM). A series of log-gamma regressions were used to examine the relationship between AIF and PPPM expenditures as a form of cost ratios (CRs), adjusting for potential confounding factors such as patient demographic and clinical characteristics. Among 4,249 eligible patients, 36% had ≥1 AIF. At index, AIF patients were more likely to have liver (8% vs. 5%), lung (11% vs. 8%), and bone metastases (60% vs. 49%), all p < 0.01; as likely to have brain metastases (6.5% vs. 6.6%, p = 0.880); and less likely to have metastases to other sites (39% vs. 48%, p < 0.001). Median days of follow-up were 395 for AIF and 466 for no AIF patients. Post-index, patients with AIF had significantly higher total unadjusted PPPM healthcare expenditures ($6507 vs. $3974), and across all service types including inpatient stays ($2529 vs. $1369), radiation treatments ($465 vs. $238), diagnostic radiology ($889 vs. $599), laboratory tests ($333 vs. $196), and other non-office visit outpatient services ($1546 vs. $932), all p < 0.001. Regression analysis showed that metastases to the lung (CR 1.32 CI: 1.17–1.50), brain (CR 1.76, CI: 1.54–2.01), liver (CR 1.96 CI: 1.67–2.30), bone (CR 1.53 CI: 1.40–1.68), and other sites (CR 1.41 CI: 1.29–1.55) at diagnosis significantly increased PPPM expenditures compared to having metastases at another site while controlling for AIF status and other confounders, while AIF also significantly increased costs (CR 1.50 CI: 1.39–1.61). Using the bootstrap approach, incremental adjusted PPPM costs in women with AIF relative to those with no AIF was estimated at $2051 (CI: $1666-$2426, p < 0.001). In real world practice, almost 40% of women with ER+/HER2− metastatic BC treated with AIs failed at least 1. AIF was associated with expenditures 50% higher than patients with no AIF. Furthermore, substantial costs were associated with metastases regardless of the site. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-14-07.

Real-world aromatase inhibitor use and failure in women with metastatic ER+/HER2- breast cancer.

593 Background: Aromatase Inhibitors (AIs) have replaced tamoxifen as first-line therapy for postmenopausal women with metastatic, ER+ breast cancer (BC). However, little information is available on the real-world use of AIs. The objectives of this retrospective claims study were to compare demographic, clinical and treatment characteristics of postmenopausal women with metastatic ER+/HER2- BC treated with AIs and experiencing 0, 1, 2 or ≥ 3 AI failures (AIF). Methods: Women ≥ 55 years old, newly diagnosed with metastatic BC (index) were identified in the 2006-2010 Thomson Reuters MarketScan databases and followed until chemotherapy or 03/31/2011. ER+/HER2- disease was defined as any endocrine therapy (ET: tamoxifen, fulvestrant) or AI (anastrozole, letrozole, or exemestane) use and no trastuzumab or lapatinib use in the 6-month pre-or variable post-index periods. Those with any post-index AI use were retained for study. AIF post-index was defined as a switch to an alternative AI, ET or chemotherapy, or AI discontinuation with no further BC treatment. Patients were stratified by number of post-index AIF: 0, 1, 2 or ≥ 3. Results: Among 4,274 patients identified, 61% had ≥ 1 AIF (1: 80%, 2: 15%, ≥3: 5%). There was no difference in pre-index AI use across AIF cohorts: 0, 1, 2, and ≥3 (54%, 52%, 48%, 56%; p=0.073). AIFs increased with Medicare-eligibility (51%, 56%, 60%, 61%) and bone metastases at index (48%, 53%, 62%, 63%). Among those with ≥1 AIF, median follow-up (FU) increased with each failure but there was no notable pattern to reason for FU end. Median FU of the 0 AIF cohort (408 days) fell between those of the 1 and 2 AIF cohorts, 335 and 517 days. Anastrozole was the most common first line treatment for all cohorts except ≥ 3 AIFs where letrozole was most common. Pre-index and first line fulvestrant use both increased with the number of post-index AIFs: 0.3%, 1.9%, 2.0%, 5.0% and 0.7%, 2.5%, 4.0%, 14.9% respectively. There was no association between number of AIFs and chemotherapy use (36%, 29%, 38%). Conclusions: Over 60% of women with ER+/HER2- metastatic BC treated with AIs failed at least 1 and 20% of those failed ≥ 2. Surprisingly, increased rates of prior fulvestrant treatment appear associated with increasing numbers of AIF.

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.

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.

Abstract 712: Characterization of exemestane metabolic pathways

Abstract The current standard of care for early-stage ER+ breast cancer in post-menopausal women includes endocrine therapy with aromatase inhibitors (AIs) alone or sequentially following treatment with tamoxifen (TAM). Clinical trials indicate that AIs, including exemestane (EXE), are superior to TAM as first-line therapy for postmenopausal women with metastatic breast cancer and that AIs are associated with longer disease-free survival than therapy with TAM alone in adjuvant therapy. Previous studies demonstrated that UGT2B17 was the major enzyme involved in the glucuronidation of the major EXE metabolite, 17-dihydroexemestane (17-DHE), and that human liver specimens from subjects homozygous for the UGT2B17 deletion exhibited a ∼20-fold decrease in 17-DHE-glucuronide formation. The purpose of this study was to fully characterize the pathways involved in EXE metabolism. In assays that included a NADPH-regenerating system, the cytosolic and microsomal fractions of normal human liver were screened using ultra performance liquid chromatography-mass spectrometry (UPLC-MS/MS). In human liver cytosols (HLC), 17-DHE was the predominant metabolite. Using purified cytosolic enzyme, AKR1C3 was shown to exhibit significant 17-DHE formation activity. In human liver microsomes (HLM), in addition to the major metabolite 17-DHE, at least 4 other EXE metabolites (EMs) were observed: 6α/β,17β-dihydroxy-6α/β-hydroxymethylandrosta-1,4-diene-3-one (EMI), 6α/β-hydroxy-6α/β-hydroxymethyl-androsta-1,4-diene-3,17-dione (EMII), 17β-hydroxy-6-hydroxymtheylandrosta-1,4,6-triene-3-one (EMIII) and 6-hydroxymethyl-androsta-1,4,6-triene-3-17-dione (EMIV). The relative content of each metabolite varied significantly between HLM from different individuals. Among the 4 metabolites, EMIV was the major primary metabolite formed directly from EXE while EMIII was a primary metabolite of 17-DHE. Using EMIII and EMIV as substrates, EMI and EMII were shown to be secondary metabolites formed from EMIII and EMIV, respectively. When UDPGA was added to EXE or 17-DHE metabolism assays, 17-DHE-glucuronide was the only glucuronide formed from HLM; as expected, no glucuronides were observed when HLC were examined. Using microsomes from CYP450-over-expressing human lymphoblast cells, CYPs 1A1, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4 and 3A5 all exhibited activity against EXE to form EMIV and 17-DHE, and exhibited activity against 17-DHE to form EMIII. In addition to the above enzymes, CYP4A11 also exhibited metabolizing activity to form 17-DHE from EXE and EMIII from 17-DHE. CYPs 1A2 and 2A6 were found to metabolize EMIV to EMII, whereas CYP1A1 and 2C19 were found to metabolize EMIII to EMI. These data suggest that several enzymes contribute to EXE metabolism. Kinetic analysis will help better assess the importance of each to EXE metabolism and their potential role in EXE pharmacogenetics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 712. doi:10.1158/1538-7445.AM2011-712

Exemestane as First-Line Therapy in Postmenopausal Women With Recurrent or Metastatic Breast Cancer

Antiestrogen therapies generally offer significant disease control to hormone receptor-positive recurrent or metastatic breast cancer patients and are substantially better tolerated than standard chemotherapy regimens, thus representing an attractive first treatment option. The steroidal aromatase inhibitor (AI) exemestane exhibits antitumor effects by lowering full-body estrogen production in postmenopausal women and is an established treatment option for metastatic breast cancer. We review data from 2 recent phase III clinical trials that have confirmed exemestane activity in the first-line metastatic breast cancer setting, with moderate improvements in median progression-free survival (10-12 months) and objective response rates (37%-46%) compared with tamoxifen. The activity of first-line exemestane is comparable with other antiestrogen therapies, including fulvestrant and the nonsteroidal AIs letrozole and anastrozole. Additional findings demonstrating the clinical benefits of exemestane in women who previously progressed on nonsteroidal AIs highlight a partial lack of cross-resistance between these therapies and reinforce the opportunity to use multiple antiestrogen treatments sequentially. Future therapeutic developments in hormone receptor-positive metastatic breast cancer could include combinations with other targeted compounds plus AIs or other antiestrogen-based combinations and the identification of new strategies to evaluate differences among antiestrogen therapies to help optimize the treatment sequence and potential combinations.

Letrozole

Letrozole (Femara), an aromatase inhibitor that blocks estrogen synthesis by inhibiting the final step of the estrogen biosynthetic pathway, is approved for use in a wide range of breast cancer settings. Randomised clinical trials in postmenopausal women with hormone-responsive early-stage breast cancer have demonstrated that, as adjuvant therapy, letrozole has greater efficacy than tamoxifen. It is also more effective than placebo as extended adjuvant therapy after completion of tamoxifen therapy in these patients. In women with hormone-responsive advanced breast cancer, letrozole is superior to tamoxifen in prolonging the time to disease progression and time to treatment failure in a first-line setting, and is at least as effective as anastrozole and more effective than megestrol for some endpoints (in one of two trials) in a second-line setting. Letrozole is generally well tolerated, and in a health-related quality-of-life analysis from a large clinical trial, patient well-being with letrozole as extended adjuvant therapy did not differ from that with placebo. Modelled analyses from the UK and the US suggest that, in postmenopausal women with hormone-receptor-positive early-stage breast cancer, letrozole is likely to be a cost-effective alternative to tamoxifen as adjuvant therapy; moreover, using letrozole as extended adjuvant therapy after tamoxifen, rather than no further treatment, is also a cost-effective treatment strategy. Sensitivity analyses have shown these results to be robust. In terms of direct healthcare costs, pharmacoeconomic models suggest that letrozole is a cost-effective alternative to tamoxifen as first-line therapy in postmenopausal women with hormone-responsive advanced breast cancer from the perspectives of the UK NHS, the Canadian and Italian public healthcare systems and the Japanese national health insurance system. Incremental costs per QALY or progression-free year gained over tamoxifen were well within the recommended limits for acceptability of new agents that are more effective and more expensive than existing therapies in the UK, Japan and Canada. Modelled analyses from the UK and Canada have also suggested that letrozole is cost effective as second-line therapy for advanced breast cancer in postmenopausal women who have disease progression following anti-estrogen therapy. In conclusion, letrozole is an effective and well tolerated treatment for postmenopausal women with early-stage or advanced hormone-responsive breast cancer. Pharmacoeconomic analyses from UK and North American perspectives support the use of letrozole in hormone-responsive early-stage breast cancer in both the adjuvant and extended adjuvant settings. In addition, other modelled analyses conducted in a variety of healthcare systems across different countries consistently suggest that letrozole is cost effective in advanced treatment settings.

Goserelin plus anastrozole as first-line endocrine therapy for premenopausal women with oestrogen receptor (ER) positive advanced breast cancer (ABC)

731 Background We have previously reported the use of goserelin plus anastrozole as second-line endocrine therapy for premenopausal women with ER-positive ABC. With randomised data showing superiority of third-generation aromatase inhibitors over tamoxifen as first-line therapy for postmenopausal women with ER-positive ABC, we now report our clinical experience of using anastrozole alongside ovarian suppression (with goserelin) in the same setting in premenopausal women. Methods Twenty premenopausal patients (mean age = 42 (30 - 57) years) (advanced primary = 3, soft tissue = 2, bone = 8, pleura/lung = 3, stomach = 1, liver = 2, bone + liver = 1) with ER-positive ABC seen over a 3-year period were treated with goserelin 3.6 mg 4-weekly plus anastrozole 1 mg daily as first-line therapy. Endocrine therapy was considered therapy of choice except in two patients with liver metastases who did not have chemotherapy due to pulmonary embolism or patient choice. All have disease assessable by UICC criteria and have received the therapy for at least 6 months (except for those who progressed prior). Results Twelve patients (60%) derived clinical benefit (CB) (objective response or durable stable disease for at least 6 months) while eight progressed before 6 months. For the 12 patients who have derived CB, the median duration of response is 20+ months (range: 6 - 36 months). At the time of analysis, therapy is continuing in nine patients. When the two patients with liver metastases for whom chemotherapy was therapy of choice were excluded, the CB rate rose to 66%. Therapy has been well tolerated and no patients came off it because of side effects. Conclusion A combined use of goserelin and anastrozole produces CB with long duration in significant proportion of premenopausal women with ER-positive ABC when used as first-line therapy. Further studies with more patients and longer follow-up are warranted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca

Phase III Study of Letrozole Versus Tamoxifen As First-Line Therapy of Advanced Breast Cancer in Postmenopausal Women: Analysis of Survival and Update of Efficacy From the International Letrozole Breast Cancer Group

Purpose: To analyze overall survival (OS) and update efficacy data for letrozole versus tamoxifen as first-line therapy in postmenopausal women with locally advanced or metastatic breast cancer. Patients and Methods: This multicenter phase III trial randomly assigned 916 patients with hormone receptor–positive or unknown tumors letrozole 2.5 mg (n = 458) or tamoxifen 20 mg (n = 458) daily until disease progression. Optional cross-over was permitted at the treating physician’s discretion. This report updates efficacy at a median follow-up of 32 months. Results: The superiority of letrozole to tamoxifen was confirmed for time to progression (median, 9.4 v 6.0 months, respectively; P < .0001), time to treatment failure (median, 9 v 5.7 months, respectively; P < .0001), overall objective response rate (32% v 21%, respectively; P = .0002), and overall clinical benefit. Median OS was slightly prolonged for the randomized letrozole arm (34 v 30 months, respectively). Although this difference in OS is not signifi...

Cost-effectiveness of anastrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer

Background: In a recent trial of first-line therapy in 353 postmenopausal women with predominantly hormone receptor-positive advanced breast cancer (the North American trial), anastrozole 1 mg QD produced a significantly longer time to disease progression (TTP) than tamoxifen 20 mg QD (11.1 months vs 5.6 months; P = 0.005). Both treatments were well tolerated, but there were fewer thromboembolic events and a reduced incidence of vaginal bleeding with anastrozole. Objective: The aim of this study was to conduct an economic analysis of anastrozole versus tamoxifen based on data from the North American trial. Methods: Quality-adjusted TTP (QATTP) was determined by combining TTP values with uniform or graded weights for adverse events using the Quality-adjusted Time Without Symptoms and Toxicity method. Direct health care costs before and after disease progression were determined from the perspective of 4 types of health care insurers in the United States: health maintenance organizations (HMOs), indemnity plans, preferred provider organizations (PPOs), and point-of-service (POS) plans. Results: Median QATTP with graded weights was 9.7 months for anastrozole, compared with 4.6 months for tamoxifen ( P = 0.003). A resultant reduction in health care resource utilization was observed, particularly the requirements for hospitalization, outpatient visits, and chemotherapy, but the statistical significance of this observation was not assessed. Incremental cost savings per patient before and after disease progression were observed with anastrozole compared with tamoxifen ($9064 for HMO, $9678 for indemnity plan, $14,273 for PPO, and $12,715 for POS; all P < 0.01). Conclusions: In the US managed care setting, anastrozole produced a higher QATTP and incurred lower treatment costs than tamoxifen in a population of postmenopausal women with predominantly hormone receptor-positive advanced breast cancer. Therefore, anastrozole was more cost-effective than tamoxifen as first-line endocrine therapy in the population studied.

Endocrine therapy in the treatment of metastatic breast cancer

The goals of treating patients with metastatic breast cancer are to prolong survival, slow or halt disease progression, and enhance the patient's quality of life. In patients with estrogen receptor (ER)-positive cancers that are not progressing rapidly, endocrine therapy is generally the first treatment option. If a patient initially responds to an endocrine agent and then progresses, another endocrine agent may still provide benefit. Tamoxifen has been used as first-line therapy for metastatic breast cancer for many years. Until recently, no other endocrine agent has shown superiority to tamoxifen in this setting. The nonsteroidal aromatase inhibitors, anastrozole and letrozole, have been widely accepted as second-line therapy after failure of tamoxifen; they have replaced megestrol acetate in this setting. Recently, anastrozole was shown to have at least equivalent efficacy and a superior side effect profile compared with tamoxifen for treating postmenopausal women in the first-line setting. Thus, this aromatase inhibitor has become a viable option for first-line therapy in postmenopausal women. Trials of letrozole in this setting are nearing completion. Exemestane has been shown to be an effective second-line agent and to have at least some efficacy as a third-line agent even after failure of a nonsteroidal aromatase inhibitor. Results are anxiously awaited from trials of new endocrine agents including the first member of a new class of endocrine agent, the estrogen-receptor downregulator class.

A stochastic economic evaluation of Letrozole versus Tamoxifen as a first-line therapy for postmenopausal women with advanced breast cancer

A stochastic economic evaluation of Letrozole versus Tamoxifen as a first-line therapy for postmenopausal women with advanced breast cancer