Estrogen Receptor-positive Advanced Breast Cancer Research Articles

Neoadjuvant endocrine therapy in breast cancer

SUMMARY Preoperative therapy in breast cancer was initially considered a therapeutic tool to downstage large tumors. In the last few years, neoadjuvant endocrine therapy has emerged as an active approach for the treatment of locally advanced estrogen receptor-positive breast cancer. Moreover, the parallel results obtained with neoadjuvant and adjuvant endocrine trials suggest that rationale for future adjuvant designs should be based on previously confirmed positive outcomes obtained in neoadjuvant studies. Ki-67, a proliferation-associated antigen determined by serial biopsies during therapy, has been validated as a biomarker and can provide useful information to define prognosis and establish therapeutic decisions. This review focuses on the classical indications of neoadjuvant endocrine therapy, the parallelism between adjuvant and neoadjuvant studies and the potential role of this approach to predict outcomes based on short-term molecular markers in estrogen receptor-positive breast cancer.

Abstract OT3-2-01: A phase 2 randomized, double-blind, placebo-controlled multicenter trial evaluating the efficacy and safety of enzalutamide in combination with exemestane in estrogen or progesterone receptor-positive and HER2 non-amplified advanced breast cancer

Abstract Background Androgen receptor (AR) is expressed in 75% of patients (pts) with ER/PgR+ breast cancer (BC). In some studies, AR expression has been associated with lack of response to endocrine therapies, and forced overexpression in ER+ cell lines can lead to hormone-resistance. Androgens can stimulate in vitro and in vivo growth of ER+/AR+ cells lines which can be blocked by enzalutamide (ENZA), a potent inhibitor of AR. Furthermore, ENZA can block in vitro and in vivo estradiol-mediated growth in MCF7 cells. Treatment with aromatase inhibitors (AIs) increases androgen levels, which in turn could stimulate growth of AR+ ER+ tumors. Trial design This phase 2 trial will evaluate ENZA 160mg/day vs placebo in 240 pts with advanced BC treated concurrently with exemestane (EXE). AR expression will be assessed centrally. Two cohorts will each enroll 120 patients (pts) who have received no (Cohort 1: C1) or one (Cohort 2: C2) prior hormone treatment for advanced BC. Randomization is stratified 1:1 by prior hormone (Y/N: C1 only), prior AI (Y/N), and hormone resistance (disease recurrence within 24 mo of initiating hormone treatment in the adjuvant setting [C1]; and, disease progression within 24 wks of initiating hormone treatment in the advanced setting [C2]). The primary endpoint is progression-free survival (PFS) in C1, C2 and the subgroups with AR+ disease. Upon disease progression, eligible pts may choose to receive open-label ENZA in addition to continuing EXE. This trial will be enrolling at time of presentation. Eligibility criteria Women with advanced ER+ or PgR+ and HER2-non-amplified (HER2-) BC; 0-1 prior chemotherapy regimens for advanced disease; ECOG performance status ≤1 with measurable or bone-only nonmeasurable disease. Advanced BC is defined as metastatic or locally advanced disease not amenable to curative surgery or radiotherapy. ER/PgR+ disease is defined as ≥1% tumor cell staining by IHC; HER2- disease is defined as 0 or 1+ IHC staining or FISH HER2 negative. Pts with current or previously treated brain metastases or history of seizure are excluded. Prior therapy (>28 days) with EXE for advanced disease is not permitted. Study endpoints The primary objective is PFS by cohort and in subgroups with AR+ disease. Secondary endpoints include clinical benefit rate (complete/partial response or stable disease at ≥24 weeks); best objective response per RECIST 1.1, duration and time to response, and safety and tolerability of ENZA. Statistical methods Efficacy analyses will be conducted on all randomized pts. Primary analyses for each cohort will be identical and performed separately depending on data maturity for PFS. Primary analysis will use a minimum of 90 PFS events per cohort. The 95% confidence interval (CI) of the PFS hazard ratio (HR) will be reported. For all secondary endpoints, unadjusted P-values will be used to make inferences as appropriate. For a target HR of PFS = 0.67 for each cohort, at least 55 PFS observed events in the AR+ subset (60% of study population) provides an 85% CI that the HR will exclude 1. Contact information amy.peterson@medivation.com. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-2-01.

The Kinase-Independent, Second Life of CDK6 in Transcription

CDK6 is an oncogenic kinase regulating the cell cycle. In this issue of Cancer Cell, Kollmann and colleagues demonstrate that CDK6 performs a kinase-independent transcriptional function in regulating expression of VEGF-A and p16INK4a. These observations link the cell cycle machinery and angiogenesis and reveal the presence of a fail-safe antiproliferative mechanism.

Safety of everolimus in estrogen receptor–positive advanced breast cancer.

103 Background: Despite advances in treatment of estrogen receptor–positive (ER+) breast cancer (BC), resistance to endocrine therapy remains a frequent cause of disease recurrence. The mTOR pathway has been identified as a point of deregulation in patients resistant to standard therapy. Everolimus (EVE), an oral mTOR inhibitor, was evaluated as a potential antitumor therapy. Treatment-emergent adverse events (AEs) and their management are presented. Methods: BOLERO-2 (NCT00863655), a phase III trial, evaluated EVE in postmenopausal women with ER+ advanced BC refractory to letrozole or anastrozole. Patients with documented recurrence or progression were randomized 2:1 to receive daily oral EVE (10 mg) or matching placebo, in addition to exemestane (EXE; 25 mg/d), stratified by sensitivity to prior hormonal therapy and the presence of visceral metastasis. Results: At 12.5 months’ follow-up, PFS was 7.4 months in the EVE + EXE arm (n = 485) vs 3.2 months in the EXE-only arm (n = 239) (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.36-0.53; p < 1 × 10-l6). Notable AEs (all grades) in the EVE + EXE vs EXE-only treated patients included stomatitis (59% vs 11%), rash (39% vs 6%), pneumonitis (15% vs 0), and hyperglycemia (14% vs 2%). Grade 3-4 AEs of interest in the EVE + EXE vs EXE-only treated patients were stomatitis (8% vs <1%), anemia (7% vs <1%), hyperglycemia (5% vs <1%), pneumonitis (3% vs 0), and rash (1% vs 0). EVE doses could be reduced or interrupted for the management of AEs. Exploratory analyses of antitumor effects of EVE in patients who received time-averaged EVE doses <7.5 mg/d compared with ≥7.5 mg/d were consistent (HR, 0.4 [95% CI, 0.31-0.52] vs HR, 0.45 [95% CI, 0.37-0.56], respectively). Stomatitis was managed with topical corticosteroids and/or mouthwashes containing nonsteroidal anti-inflammatories or anesthetics. Noninfectious pneumonitis was managed by a combination of radiographic imaging, oral corticosteroids, and temporary cessation of treatment. Conclusions: Addition of EVE to EXE significantly prolonged PFS and was generally well tolerated. AEs were manageable with appropriate care. Knowledge of AE management strategies is essential to optimize EVE tolerability and patient outcomes.

Oral Metronomic Cyclophosphamide and Methotrexate Plus Fulvestrant in Advanced Breast Cancer Patients: A Mono-Institutional Case-Cohort Report

Fulvestrant is effective in postmenopausal women with estrogen receptor-positive advanced breast cancer (ABC). So far, no published data exist on fulvestrant combined with chemotherapy. We retrospectively assessed the role of combining oral metronomic cyclophosphamide and methotrexate (CM) to fulvestrant in two cohorts (A and B) of heavily pre-treated estrogen receptor-positive advanced ABC patients. From October 2006 to September 2009, 33 postmenopausal patients received fulvestrant 250 mg via i.m. injection q28 days. In A, 20 patients added metronomic cyclophosphamide (50 mg p.o. daily) and methotrexate (2.5 mg p.o. twice daily on day 1 and day 4 weekly) after disease progression, continuing fulvestrant at the same dose. In B, 13 patients started fulvestrant plus metronomic CM upfront. Thirty-two patients were evaluable for response. Clinical benefit (partial response + stable disease >24 months) for A + B was 56% (95% CI 38-74%). The addition of metronomic CM did not determine relevant toxicities. Treatment with fulvestrant plus metronomic CM was effective in advanced ABC and was minimally toxic providing long-term disease control in a high proportion of patients. The prolonged clinical benefit, often desirable in such patients, supports this regimen as an additional and useful therapeutic tool.

Abstract 2670: Genetic variants in human epidermal growth factor receptor (HER) family gene predict tumor recurrence in breast cancer

Abstract Background: Epidermal growth factor receptor (EGFR or HER) family is composed of 4 members: HER1 (EGFR), HER2 (neu), HER3 and HER4. In breast cancer, besides HER2, other HER family members may also overexpressed and their dimerization may contribute to chemo-resistance. Single nucleotide polymorphisms (SNPs) in HER family genes have been associated with breast cancer risk and outcome. We tested 7 functional SNPs in HER family genes (HER1-4) (HER1 rs2227983, HER2 rs1136201, HER3 rs2271189 and HER4 rs4673628, rs839523, rs707284, rs6735267) in a cohort of Estrogen receptor (ER) positive breast cancer patients to determine their association with clinical outcome. Method: Tissue samples of 221 patients with ER positive primary invasive breast cancer (median age=56 years; range=28-90 years), who had undergone surgery at Charing Cross Hospital, London, UK between 1981 and 2003, were analyzed. The median follow-up was 6.5 years and 96 of 221 patients (43%) had tumor recurrence with a 5-year probability of recurrence of 40%. Genomic DNA was extracted from formalin fixed paraffin embedded (FFPE) tissue samples and SNPs were analyzed using direct DNA-sequencing or PCR-RFLP. Results: In univariable analysis, EGFR R497K (rs2227983), and HER2 I655V (rs1136201) were associated with time to tumor recurrence (TTR)(log-rank P=0.007 and 0.041, respectively). In multivariable analysis, EGFR R(G)497K(A) remained significantly associated with TTR. Patients with EGFR 497 AA genotype (n=15) had a shorter median TTR 4.8 years (95%C.I 0.9-6.3 years) compared to those harboring AG or GG genotype (n=201), had median TTR=6.9 years (95%C.I 5.3-8.4 years). (Wald test p value = 0.041 in the Cox model adjusting for lymph node status, tumor size and HER2 staining). Conclusion: Genetic variants in the HER family gene may be potential molecular markers to predict tumor recurrence in advanced ER positive breast cancer. Further large, prospective trials are needed to confirm our preliminary findings. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2670. doi:1538-7445.AM2012-2670

Optimizing Endocrine Therapy for Metastatic Breast Cancer

New therapies and advances in molecular biology provide opportunities for progress in the management of patients with advanced estrogen receptor-positive breast cancer. The near universal exposure of patients with early stage disease to endocrine therapy poses challenges of resistance when disease recurs. Analysis of tumor tissue at the time of recurrence, and after subsequent endocrine therapy where possible, is critical to understanding the most productive strategies for development and ultimately for individual patients.

BOLERO-2: Everolimus in combination with exemestane in the treatment of postmenopausal women with estrogen receptor-positive ADVANCED breast cancer refractory to letrozole or anastrozole

s / The Breast 20 (2011) S12–S55 S30 which benefit could be brought by the succession of CT lines in patients treated for MBC and to identify women who benefit from these treatments. Methods: This retrospective analysis included 980 women treated with CT for MBC at our Institution over a 7-year period (May 1999-July 2006). With overall survival (OS) data updated at December 1, 2008, themedian followup was 125 months (range 48-192), OS and time to treatment failure (TTF) were calculated according to the Kaplan-Meyer method for each CT line. Cox proportional hazards model was used to identify factors that could influence TTF and OS. Results: Median OS evaluated from day 1 of each CT line decreased with the line number from 34.8 months (980 patients, 1st line, range 4-208) to 22.6 months (838 patients, 2nd line), 14.6 months (684 patients, 3rd line), 12.4 months (302 patients, 4th line), 9.4 months (88 patients, 5th line), 8.2 months (45 patients, seven or more lines). Median TTF ranged from 9.2 months to 7.8 and 6.4 months for the first, second and third line, respectively, with no significant decrease observed beyond the 3rd line (median 5.2 months, range 4.8-6.2). In univariate analysis factors positively linked to a longer duration of TTF for each CT line were positive hormonal receptor status, absence of liver metastasis, adjuvant CT exposure, response to CT for the metastatic disease; in the multivariate analysis the duration of TTF for each CT line was the only one factor with significant impact on survival benefit for subsequent treatments (p<0.001). Conclusions: CT beyond the 2nd line may be beneficial in a significant subset of women treated for MBC, with improved TTF and OS. These findings could help physician in planning an appropriate strategy of subsequent schedules for women with symptomatic MBC who responded to their 1st line CT, while non responder patients should be considered for clinical trials.

Results of the CONFIRM Phase III Trial Comparing Fulvestrant 250 mg With Fulvestrant 500 mg in Postmenopausal Women With Estrogen Receptor–Positive Advanced Breast Cancer

We compared fulvestrant 500 mg regimen with the approved dose of fulvestrant 250 mg per month for treatment of postmenopausal women with estrogen receptor-positive advanced breast cancer who experienced progression after prior endocrine therapy. Comparison of Faslodex in Recurrent or Metastatic Breast Cancer (CONFIRM) is a double-blind, parallel-group, multicenter, phase III study. Patients were randomly assigned to fulvestrant 500 mg (500 mg intramuscularly [IM] on day 0, then 500 mg IM on days 14 and 28 and every 28 days thereafter) or 250 mg every 28 days. Primary end point was progression-free survival (PFS). Secondary end points included objective response rate, clinical benefit rate (CBR), duration of clinical benefit (DoCB), overall survival (OS), and quality of life (QOL). PFS was significantly longer for fulvestrant 500 mg (n = 362) than 250 mg (n = 374) (hazard ratio [HR] = 0.80; 95% CI, 0.68 to 0.94; P = .006), corresponding to a 20% reduction in risk of progression. Objective response rate was similar for fulvestrant 500 mg and 250 mg (9.1% v 10.2%, respectively). CBR was 45.6% for fulvestrant 500 mg and 39.6% for fulvestrant 250 mg. DoCB and OS were 16.6 and 25.1 months, respectively, for the 500-mg group, whereas DoCB and OS were 13.9 and 22.8 months, respectively, in the 250-mg group. Fulvestrant 500 mg was well tolerated with no dose-dependent adverse events. QOL was similar for both arms. Fulvestrant 500 mg was associated with a statistically significant increase in PFS and not associated with increased toxicity, corresponding to a clinically meaningful improvement in benefit versus risk compared with fulvestrant 250 mg.

Results of a phase II study comparing three dosing regimens of fulvestrant in postmenopausal women with advanced breast cancer (FINDER2)

The Faslodex Investigation of Dose evaluation in Estrogen Receptor-positive advanced breast cancer (FINDER)2 study evaluated the efficacy, safety, and pharmacokinetics (PK) of three fulvestrant dosing regimens. FINDER2 enrolled Western postmenopausal women recurring or progressing after prior endocrine therapy. Primary endpoint: objective response rate (ORR); secondary endpoints: time to progression (TTP), clinical benefit rate (CBR), tolerability, and PK parameters. Patients were randomized to receive fulvestrant: 250 mg/month (approved dose [AD]); 250 mg plus loading dose (loading dose [LD]; 500 mg on day 0, 250 mg on days 14, 28, and monthly thereafter); or 500 mg (high dose [HD]; 500 mg/month plus 500 mg on day 14 of Month 1). Treatment continued until disease progression or discontinuation. 144 patients were randomized: fulvestrant AD (n = 47); LD (n = 51); HD (n = 46). ORRs were: 8.5% (95% confidence interval [CI]: 2.4, 20.4%), 5.9% (1.2, 16.2%), and 15.2% (6.3, 28.9%) in the AD, LD, and HD arms, respectively. CBRs were: 31.9% (95% CI: 19.1, 47.1%), 47.1% (32.9, 61.5%), and 47.8% (32.9, 63.1%) for the AD, LD, and HD arms, respectively. Median TTP (months) was numerically longer for HD (6.0) and LD (6.1) versus AD (3.1). Tolerability was similar across dosing regimens. Steady-state plasma fulvestrant concentrations were predictable and achieved earlier with LD and HD. While there appeared to be a trend toward improved efficacy with HD and LD versus AD, no significant differences could be shown. A parallel study (FINDER1) has reported similar findings in Japanese patients.

A Phase II Study (FINDER 2) Comparing Three Dosing Regimens of Fulvestrant in Postmenopausal Women with Estrogen Receptor-Positive Advanced Breast Cancer.

Abstract Background: The Faslodex Investigation of Dose evaluation in Estrogen Receptor-positive (ER+) advanced breast cancer (FINDER) 2 study investigated the efficacy, safety, and pharmacokinetic (PK) profile of 3 fulvestrant dosing regimens in postmenopausal women with ER+ advanced breast cancer, recurring/progressing after prior endocrine therapy.Objectives: Primary: to evaluate the objective response rate (ORR). Secondary included assessment of: time to progression (TTP), clinical benefit rate (CBR), duration of response (DOR), tolerability, and PK parameters.Methods: This randomized, double-blind, parallel-group, multicenter, Phase II study, evaluated patients (pts) randomized 1:1:1 to different doses of fulvestrant: 250 mg (approved dose [AD]; given on Days 0, 28 and every 28 days thereafter), 250 mg plus loading dose (LD; 500 mg on Day 0, then 250 mg on Days 14, 28 and every 28 days thereafter), and 500 mg (high dose [HD]; Days 0, 14 and 28 and every 28 days thereafter). Treatment continued until disease progression, or until any other criterion for discontinuation was met.Results: In total, 144 pts were randomized from 34 centers in 8 countries and 143 received treatment: fulvestrant AD (n=47); LD (n=50); HD (n=46). ORRs were: 8.5% (95% confidence interval [CI] 2.4-20.4%), 5.9% (1.2-16.2%), and 15.2% (6.3-28.9%) in the AD, LD, and HD arms, respectively. CBRs were: 31.9% (95% CI 19.1-47.1%), 47.1% (32.9-61.5%), and 47.8% (32.9-63.1%) for the AD, LD, and HD arms, respectively. Median TTP was numerically longer for the HD (6.0 months) and LD (6.1 months) arms vs the AD arm (3.1 months). The low number of responders in all treatment arms prevented DOR assessment. The incidence of adverse events (AEs) was similar in all groups (76.6% AD, 72.0% LD, 69.6% HD); few pts experienced serious AEs (4 pts AD, 9 LD, 4 HD) with no clustering of event type. AEs with an incidence of ≥10% (in any arm) were back pain, arthralgia, fatigue, injection-site pain, nausea, dyspnea, cough, and hot flash. Concentrations in the AD arm approached steady state in the 3rd month of dosing and within the 1st month for LD and HD. Exposure (AUC, Cmin and Cmax) appeared to be linear across the dose range studied and, for the 250mg arms, similar to that previously reported in Western populations (Studies 9238IL/0020 &amp; 0021).Conclusion: No statistically significant differences in efficacy could be proven between AD, LD and HD given the widely overlapping CIs for median TTP. The tolerability profile was similar across the three dosing regimens. Steady-state concentrations were achieved earlier with LD and HD. A parallel study in Japanese pts will be used for comparisons of fulvestrant efficacy and tolerability in Japanese and non-Japanese pts. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4095.

CONFIRM: A Phase III, Randomized, Parallel-Group Trial Comparing Fulvestrant 250 mg vs Fulvestrant 500 mg in Postmenopausal Women with Estrogen Receptor-Positive Advanced Breast Cancer.

Abstract Background: Fulvestrant (Faslodex®) is an estrogen-receptor (ER) antagonist licensed for the treatment of postmenopausal women with advanced breast cancer who have progressed or recurred following prior endocrine therapy. The efficacy of fulvestrant at the approved dose (250 mg/month; F250) is well established; however, increasing the dose to 500 mg (500 mg i.m. on Day 0, then 500 mg i.m. on Days 14 and 28 and every 28 days thereafter; F500) may further improve clinical outcome. Data from the NEWEST and FIRST studies have suggested improved biological and clinical activity for F500 in the neoadjuvant and 1st-line advanced disease settings respectively. Further data are required to clarify the clinical role of F500 in ER+ advanced breast cancer.Methods: CONFIRM (COmparisoN of Faslodex In Recurrent or Metastatic breast cancer) is a randomized, double-blind, parallel-group, multicenter, Phase III study (9238IL/0064; NCT00099437) comparing F250 with F500 in postmenopausal women with ER+ advanced disease recurring or progressing after prior endocrine therapy (anti-estrogen or aromatase inhibitor). Eligible patients (pts) were randomized 1:1 to F250 or F500, and assessed for tumor progression every 12 weeks. The primary objective was to compare the efficacy of F250 and F500 in terms of time to progression (TTP). Secondary objectives included: objective response rate (ORR), clinical benefit rate (CBR; complete or partial response or stable disease lasting ≥24 weeks), duration of clinical benefit (DoCB)(all by modified RECIST criteria), overall survival and quality of life (QoL). Safety and tolerability were also assessed. Treatment with fulvestrant continued until disease progression, or discontinuation for any other reason. All patients were followed up for disease progression and survival, regardless of treatment discontinuation, unless consent was withdrawn.Results: In total, 736 women (median age 61.0yrs) were recruited between Feb '05 and Aug '07 from 128 centers in 17 countries (F500: n=362; F250: n=374). TTP was significantly longer for F500 vs F250 (HR 0.80 [95% CI: 0.68, 0.94]; p=0.006), corresponding to a 20% reduction in risk of progression. The treatment effect was consistent for all predefined subgroups analysed. ORR was similar for F500 and F250 (13.8% vs 14.6%; odds ratio 0.94 [95% CI 0.57, 1.55]; p=0.795). There was a numerical advantage in CBR for pts receiving F500 vs F250 (45.6% vs 39.6%; odds ratio 1.28 [95% CI 0.95, 1.71]; p=0.1) and in DoCB (16.6 vs 13.9 months for F500 [n=165] and F250 [n=148] respectively). There was a trend for improved overall survival for pts treated with F500 compared with F250 (HR 0.84 [95% CI: 0.69, 1.03] p=0.091). QoL (n=145) was similar for both arms. F500 was well tolerated, with a safety profile consistent with that of F250 and no evidence of dose-dependence for any AE.Discussion: The CONFIRM trial has shown a statistically significant increase in TTP for F500 compared with F250, without increase in toxicity. This translates into a clinically meaningful advantage for F500 over F250. We anticipate that the 500mg regimen will become the established dose for fulvestrant. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 25.

Progesterone receptor levels are associated with time to aromatase inhibitor treatment failure in estrogen receptor-positive advanced breast cancer.

Abstract Abstract #6051 Background: Aromatase inhibitors (AIs) play a key role in the endocrine treatment of hormone receptor-positive breast cancer, yet surprisingly little information is available on the effectiveness of AIs in advanced breast cancer according to quantitative levels of ER and PgR or HER-2 status. In this work, we assess expression of these three biomarkers in primary breast tumours of women who subsequently received an AI for advanced disease. This extends an earlier study [1], improving the statistical power and excluding patients who received neo-adjuvant therapy.&amp;#x2028; Methods: Tissue microarrays were constructed from 177 archival FFPE primary or locally recurrent breast tumours from women, diagnosed between 1963 and 2003, who received no neo-adjuvant therapy prior to surgery and were treated with 3rd generation AI treatment for advanced disease (anastrozole n = 92; letrozole n = 82; exemestane n = 3). ER, PgR and HER-2 protein levels were assessed by IHC with FISH performed if HER-2 staining was equivocal. The study endpoint of time to AI treatment failure (TTF) was defined as time from commencement of AI treatment to progression of disease or cessation of treatment due to toxicity or death. Disease-free interval (DFI) was defined as time from date of diagnosis to date of first relapse.&amp;#x2028; Results: 146/177 patients were assessed as ER+ by IHC. When both ER+ and ER- patients were considered, higher ER and PgR levels were associated with increased TTF (HR: 0.90; 95% CI: 0.83-0.98; p = 0.011 and HR: 0.86; 95% CI: 0.80-0.93; p &amp;lt; 0.001 respectively) whereas HER-2 positivity was associated with decreased TTF (HR: 1.61; 95% CI: 1.01-2.59; p = 0.048). Longer DFI was also associated with increased TTF (HR: 0.79; 95% CI: 0.65-0.97; p = 0.022) with both PgR level and DFI remaining significant in multivariate analysis. When ER+ patients only were considered, higher PgR levels maintained an association with increased TTF (HR: 0.88; 95% CI: 0.81-0.97; p = 0.007) with this relationship appearing to be even stronger amongst the population considered PgR+ (HR: 0.73; 95% CI: 0.54-0.98; p = 0.037). No significant relationship was observed between ER levels and TTF in the ER+ subgroup. ER+HER-2+ patients (n = 13) showed a trend for decreased TTF compared to ER+HER-2- patients (n = 131), but this was not significant in this small subset of patients (HR: 1.34; 95% CI: 0.75-2.38; p = 0.32).&amp;#x2028; Conclusions: Higher PgR level is significantly associated with increased TTF in ER+ patients receiving AI treatment for advanced disease, especially within the ER+PgR+ subgroup. ER+HER-2+ patients may show decreased TTF on AI treatment compared to ER+HER-2- patients. Larger prospective studies are required to confirm these data. These observations highlight the importance of PgR as a predictor of TTF even in advanced breast cancer patients.&amp;#x2028; Supported by the Mary-Jean Mitchell Green Foundation.&amp;#x2028; [1] Anderson H. et al., J Steroid Biochem Mol Biol 106 (2007) 49-54. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6051.

PET-based estradiol challenge as a predictive biomarker of response to endocrine therapy in women with estrogen-receptor-positive breast cancer

To determine if response to endocrine therapy of breast cancer can be predicted by either a metabolic "flare reaction" detected by positron emission tomography (PET) with 2-[(18)F]-fluoro-2-deoxyglucose (FDG), induced by an estradiol challenge, or by estrogen-receptor (ER) status, determined by PET with the estrogen analog 16alpha-[(18)F]fluoroestradiol-17beta (FES). Fifty-one post-menopausal women with advanced estrogen-receptor positive breast cancer were studied. Patients underwent FES-PET and FDG-PET at baseline and repeat FDG-PET after 30 mg estradiol. Tracer uptakes was measured as the standardized uptake value (SUV). Patients were subsequently treated with either an aromatase inhibitor or fulvestrant. A prospectively defined cut-off SUV >or= 2 for FES was considered positive for ER expression. A cutoff of >or=12% increase in SUV for FDG, determined by ROC analysis, represented metabolic flare. PET results were correlated with responsiveness to endocrine therapy. Seventeen patients responded and 34 patients did not respond to endocrine therapy. Four responders and one non-responder had a clinical flare reaction, while only the responders demonstrated metabolic flare. After estradiol challenge, a significantly higher mean (+/-SD) percent change in SUV for FDG was noted in responders (20.9 +/- 24.2) compared with non-responders (-4.3 +/- 11.0, P < 0.0001). On FES-PET, a higher tumor SUV was noted in responders (3.5 +/- 2.5) compared with non-responders (2.1 +/- 1.8, P = 0.0049). There was significantly longer overall survival in patients with metabolic flare than in those without flare regardless of type of endocrine therapy (P = 0.0062). Baseline tumor FES uptake and metabolic flare after an estradiol challenge are both predictive of responsiveness to endocrine therapy in ER+ breast cancer.

Anastrozole

Recent trials have indicated that the aromatase inhibitors (anastrozole, letrozole, exemestane) are more effective than tamoxifen, the standard adjuvant treatment for estrogen receptor-positive breast cancer, both in adjuvant and first-line advanced settings. This paper reviews the mode of action and the main clinical trials done with anastrozole, the only aromatase inhibitor currently licensed for use in the adjuvant setting in estrogen receptor-positive tumors. Results from studies using anastrozole as a first-line treatment in advanced disease strongly suggest that this drug should now be considered as an alternative first-line therapy to tamoxifen in postmenopausal women with estrogen receptor-positive advanced breast cancer. As a second-line treatment in tamoxifen failures, anastrozole has shown a better survival rate and a better side-effect profile than megestrol acetate. Similarly, the use of anastrozole in the adjuvant setting has shown a significantly prolonged disease-free survival time and improved tolerability compared to tamoxifen in postmenopausal breast cancer survivors.

Cost utility and budget impact of third-generation aromatase inhibitors for advanced breast cancer: a literature-based model analysis of costs in the Italian national health service

Background: Third-generation aromatase inhibitors are effective alternatives to tamoxifen in patients with advanced breast cancer. However, their acquisition costs might burden fixed-budget health care systems. Objective: This study is a decision analysis of the clinical and economic consequences of alternative first-line hormone therapies for postmenopausal women with estrogen receptor-positive metastatic breast cancer in a real-life Italian health care setting. Methods: A Markov model was developed to describe disease evolution according to data from previously published, randomized clinical trials. The costs incurred by a local community hospital in the Italian National Health Service were considered (year-2003 values). Clinical data were taken from previously published trials. A 3% discount rate was applied to both resources and life-years gained. Results: Based on model estimates, mean survival times with the third-generation aromatase inhibitors anastrozole and letrozole were 30.72 and 30.64 months, respectively, as opposed to 27.28 months with tamoxifen. Mean survival times after adjustment for quality of life were 18.84 and 18.78 months with anastrozole and letrozole, respectively, and 16.14 months with tamoxifen. Baseline analysis produced incremental cost-effectiveness ratios per quality-adjusted life-year gained of Conclusions: In this cost-effectiveness analysis using previously published clinical data and year-2003 cost data from a community hospital in the Italian National Health Service, anastrozole and letrozole were both cost-effective alternatives to tamoxifen for first-line therapy of postmenopausal women with advanced estrogen receptor-positive breast cancer.

Treatment of advanced breast cancer with 20 mg toremifene, a phase II study. Preliminary communication

Fourteen postmenopausal women with estrogen-receptor positive advanced breast cancer and no prior cytostatic treatment received 20 mg toremifene daily as a single dose after a loading dose (120→60→60 mg) for the first 3 days. All were evaluable and had undergone at least 6 weeks' treatment. Results were: no complete remissions (CR), 3 partial remissions (PR), 8 no change (NC) and 3 cases of progressive disease (PD). Three patients had mild side effects: nausea, insomnia, sweating and arm pain.

The importance of local synthesis of estrogen within the breast

Tumor aromatase has been correlated with clinical response to treatment with aminoglutethimide in patients with estrogen receptor-positive advanced breast cancer. There was a significant positive relationship between aromatase status and likelihood of response to therapy, none of five patients with aromatase-negative tumors responding compared with 11 of 18 having aromatase-positive cancers. Measurement of in vitro aromatase in sequential biopsies of large primary tumors before and during treatment with aminoglutethimide-hydrocortisone showed a marked but paradoxical rise in activity following therapy. Assays of aromatase in adipose tissue from the different quadrants of mastectomy specimens from patients with breast cancer indicate that activity was always higher in quadrants associated with tumor as compared with non-involved quadrants. These results emphasize the importance of local estrogen synthesis within the breast in terms of both the natural history and behavior of breast cancers.