ER-positive Advanced Breast Cancer Research Articles

Abstract OT2-6-01: Phase 2 study of palbociclib (CDK 4/6 inhibitor) for ER positive, HER2- negative post-menopausal advanced breast cancer patients recurring after hormonal therapy (to reverse endocrine resistance - TREnd trial)

Abstract Background: Palbociclib (PD-0332991) is an orally active, potent and highly selective inhibitor of CDK4/6 that prohibits progression of the cell cycle from G1 into S phase and has shown activity in ER positive breast cancer in vivo and in vitro. Recently, in phase 2 settings, palbocilcib extended PFS in combination with letrozole as first-line hormonal treatment for advanced breast cancer (ABC) (Finn R.S. et al. Cancer Res., Dec 2012; 72: S1-6) and showed single agent activity in patients with ER positive ABC relapsed to several lines of therapy (DeMichele A. et al., ASCO 2013). Given pre-clinical evidence on the relevance of Cyclin D-CDK4/6-E2F signalling in the development of acquired resistance to hormonal therapy, CDK4-6 inhibition might be a strategy to overcome resistance in tumors who have progressed after hormonal therapy for metastatic disease. Study design: This is an investigator initiated, open-label, multicenter, randomized, Phase 2 trial for patients with ER+ HER2 negative ABC who have experienced progression on first or second line hormonal therapy. Other eligibility criteria include: ≤1 previous line of chemotherapy for ABC; measurable disease; and available archival tumor tissue for translational studies. Consenting patients are randomized (1:1) to receive, until progression of disease, unacceptable toxicity or consent withdrawal, either ARM A) palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment or ARM B) palbociclib in combination with the hormonal therapy to which the patient has experienced progression in the previous line of treatment (anastrozole 1 mg/d, letrozole 2.5 mg/d, exemestane 25 mg/d, fulvestrant 500mg/4 weeks). Patients are stratified according to: number or prior lines of hormonal therapy (1 vs. 2); disease site (visceral vs. non visceral); duration of prior line of hormonal therapy (>6 vs. ≤6 months); treating center. The primary endpoint is clinical benefit (CB) (i.e. complete response, partial response, stable disease≥ 24 weeks), based on local assessment of response using RECIST 1.1 criteria. Key secondary endpoints are: objective response rate, duration of response, time to progression, progression-free survival, overall survival and assessment of exploratory tissue markers of response. Statistical methods: A two-stage optimal phase 2 design is used to assess the activity of each of the two treatment regimens. Assuming P0≤20% (inactivity), P1≥ 40% (activity) and α = 10%, a sample size of 50 evaluable patients per treatment arm is required for a statistical power equal to 90%. In case of inactivity, enrolment could be stopped in each arm after 25 evaluable patients. This study does not provide adequate power for a two arm comparison. Target accrual: the study is actively recruiting in 3 Italian centers and is expected to involve additional 7 centers in Italy by the end of 2013. The first patient was enrolled in October 2012 and, as per June 2013, a total of 9 patients have been enrolled, 8 remain on treatment. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-01.

Abstract 943: RRM2: a key contributor in tamoxifen resistance in breast cancer.

Abstract Tamoxifen is primarily used for early and advanced ER positive breast cancer patients. Unfortunately about 58% of the patients fail to respond to tamoxifen and eventually relapse with more aggressive tumors. Therefore, understanding the molecular mechanism of resistance is necessary to design new therapeutic strategies to overcome resistance. In this study, we show that Ribonucleotide Reductase M2 subunit is highly expressed in Akt over-expressing breast cancer cell lines and these breast cancer cell lines are highly resistant to tamoxifen treatment In-vitro. In these breast cancer cell lines, RNA interference mediated by small interfering RNA against RRM2 sensitizes these cells to tamoxifen-induced toxicity and reversed the tamoxifen resistance. Also, Using Oncomine database, we demonstrate that RRM2 is overexpressed in breast cancer. This is the first demonstration that investigate role of RRM2 in tamoxifen resistance and could serve as a potential target to restore tamoxifen sensititivity in breast cancer cells. Citation Format: Khyati Niral Shah, David Peterson, Marie Evangelista, Jesika Faridi. RRM2: a key contributor in tamoxifen resistance in breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 943. doi:10.1158/1538-7445.AM2013-943

Emerging data on the efficacy and safety of fulvestrant, a unique antiestrogen therapy for advanced breast cancer

Introduction: Fulvestrant is an antiestrogen therapy with a unique mechanism of action. Unlike the selective estrogen receptor modulator tamoxifen, fulvestrant has no known estrogen agonist activity and is considered a pure antiestrogen. Its primary mechanism of action is thought to result from downregulation of the estrogen receptor (ER). Considerable data have demonstrated the efficacy of fulvestrant in postmenopausal women with ER-positive advanced breast cancer, both in the first-line setting and following disease progression on tamoxifen or aromatase inhibitors. Recent studies report improved benefit with alternative dosing strategies. At all administration schedules, fulvestrant has an excellent safety profile with no significant adverse effects.Areas covered: This article provides a review of the mechanism of action of fulvestrant and the preclinical and clinical data evaluating its use as a form of endocrine therapy. The reader will gain insight into the pharmacologic properties of the drug and its role in the treatment of advanced hormone receptor-positive breast cancer in postmenopausal women.Expert opinion: Based on data demonstrating the efficacy of fulvestrant, including prolonged clinical benefit in many patients, this well-tolerated antiestrogen is an important therapy for breast cancer. The optimal position of fulvestrant in the sequence of endocrine therapies for postmenopausal women and its role in combination regimens are not yet resolved.

Letrozole plus GnRH analogue as preoperative and adjuvant therapy in premenopausal women with ER positive locally advanced breast cancer

Patients with large ER positive tumors candidate to preoperative chemotherapy may also benefit from a concurrent endocrine intervention, but this issue has been scarcely investigated due to concerns arising from unfavorable results emerged from an adjuvant trial of concurrent tamoxifen and chemotherapy. We retrospectively investigated the activity of letrozole plus GnRH analogue (GnRH-a) administered concurrently with preoperative chemotherapy and as adjuvant treatment in premenopausal women with locally advanced ER positive breast cancer consecutively admitted at the European Institute of Oncology. Results were compared with those of a non-randomized unmatched control group of premenopausal women with locally advanced ER positive breast cancer receiving preoperative chemotherapy, followed by tamoxifen and GnRH-a after surgery. Primary endpoints were pathological complete response (pCR) rate, decrease of Ki67 and disease free survival (DFS). One-hundred and nineteen women constituted the study group, while 95 patients served as controls. The pCR rate was 5.0 vs 1.1% in the study and control group, respectively. A statistically significant greater suppression of Ki67 was observed in patients receiving chemoendocrine therapy as compared with controls (P = 0.003). At a median follow up of 59 months, 26 events occurred in the chemoendocrine group and 48 in the control group. Five-year DFS was 78 vs 41% in the study and in the control group, respectively [adjusted HR 0.46, 95% CI 0.27-0.79, P = 0.0047]. The concurrent administration of letrozole and GnRH-a with preoperative chemotherapy was highly effective in premenopausal women with large ER positive breast cancer in terms of decreased proliferation and of improved DFS. Randomized studies are warranted to establish the role of the addition of endocrine therapy to chemotherapy as standard preoperative approach for ER positive locally advanced breast cancer as well as of letrozole in combination with GnRH-a for the treatment of premenopauasal women with early breast cancer.

Three dose regimens of fulvestrant in postmenopausal Japanese women with advanced breast cancer: results from a double-blind, phase II comparative study (FINDER1)

BackgroundFINDER1 compared efficacy, tolerability and pharmacokinetics (PK) of three fulvestrant dose regimens in postmenopausal Japanese women with estrogen receptor (ER)-positive locally advanced/metastatic breast cancer recurring or progressing after prior endocrine therapy. Patients and methodsThe primary end point of this randomised, multicentre, phase II study was objective response rate (ORR) and the secondary end points included time to progression (TTP), clinical benefit rate (CBR), PK profiles and tolerability. Postmenopausal women with ER-positive advanced breast cancer were randomised to 28-day cycles of fulvestrant approved dose (AD), loading dose (LD) or high dose (HD) until disease progression. ResultsHundred and forty-three patients (median age 61 years) received fulvestrant AD (n = 45), LD (n = 51) or HD (n = 47). ORR was similar across dose regimens: 11.1%, 17.6% and 10.6% for AD, LD and HD, respectively, with overlapping confidence intervals. TTP and CBR were also similar between groups (median TTP: 6.0, 7.5 and 6.0 months, respectively; CBR: 42.2%, 54.9% and 46.8% for AD, LD and HD, respectively). Cmax and area under the plasma concentration-time curve were dose proportional and PK steady state was reached earlier with LD and HD than with AD. All three doses were well tolerated, with a similar adverse-event profile and no emerging safety concerns. ConclusionsFulvestrant AD, LD and HD had similar efficacy and tolerability profiles in postmenopausal Japanese women with ER-positive advanced breast cancer.

Fulvestrant 250 mg versus anastrozole for Chinese patients with advanced breast cancer: results of a multicentre, double-blind, randomised phase III trial

Fulvestrant, an oestrogen receptor (ER) antagonist with no known agonist effects, has shown activity in postmenopausal patients with ER-positive advanced breast cancer recurring or progressing following prior endocrine therapy. This double-blind, double-dummy, randomised phase III study (NCT00327769) was designed to compare the efficacy and safety of fulvestrant versus anastrozole in advanced breast cancer of Chinese postmenopausal women whose disease has progressed following prior endocrine treatment. A total of 234 patients were randomised to fulvestrant 250 mg/month (n = 121) or 1 mg/day anastrozole (n = 113), together with matching placebo. The primary endpoint was time to progression (TTP). Secondary endpoints included objective response rate (ORR), duration of response (DoR), clinical benefit rate (CBR) and time to treatment failure (TTF). Baseline characteristics were similar, with the possible exception that a higher number of fulvestrant patients had received two prior chemotherapy regimens. Median TTP was 110 days in the fulvestrant group versus 159 days in the anastrozole group (hazard ratio [HR], 1.314; 95% confidence intervals [CI], 0.948, 1.822; P = 0.101). ORR was 10% in the fulvestrant group and 14% in the anastrozole group. Median DoR from randomisation to progression was 436 days versus 432 days for the fulvestrant and anastrozole groups, respectively. CBR for fulvestrant (36.1%) versus anastrozole (48.2%) was not statistically different between the groups. TTF (110 days versus 147 days for the fulvestrant and anastrozole groups, respectively) was not statistically different between the treatments (HR, 1.307; 95% CI, 0.961, 1.778; P = 0.088). Both treatments were well tolerated, with only two patients treated with fulvestrant and four patients treated with anastrozole withdrawn from study treatment due to adverse events. These data demonstrate that fulvestrant 250 mg and anastrozole were similarly effective and well tolerated in the treatment of postmenopausal Chinese women with advanced breast cancer whose disease had progressed or recurred on prior endocrine treatment.

A 2009 Update on the Treatment of Patients with Hormone Receptor—Positive Breast Cancer

In up to 75% of breast cancers, estrogen receptor (ER) signaling is a key promoter of tumor proliferation, and inhibition of this pathway has clear therapeutic efficacy. The principal clinical means of inhibiting ER signaling comprise selective ER modulators, such as tamoxifen, that act as partial receptor agonists; measures to reduce the circulating level of estrogen, including ovarian ablation, gonadotropin-releasing hormone analogues, and aromatase inhibition; and antagonism and downregulation of ER by the antiestrogen fulvestrant. Each of these therapies is effective in a proportion of ER-positive breast cancers, but de novo and acquired resistance remain significant problems. Emerging knowledge of the biology of ER signaling will provide insights into the mechanisms of resistance and help guide development of therapeutic strategies to maximize response. This review summarizes the contemporary treatment of early-stage and advanced ER-positive breast cancer in premenopausal and postmenopausal women, with an emphasis on recently published or presented data. Mechanisms of resistance to endocrine interventions and trials exploring strategies to overcome them will also be discussed.

Correlations of estrogen receptor (ER) related genomic transcription and ER gene expression with increasing AJCC stage of ER-positive breast cancer

1044 Background: Advanced stages of ER-positive breast cancer may have decreased tumor dependence on estrogen, possibly due to biological selection and/or progression. The sensitivity to endocrine therapy (SET) index measures transcriptional activity of the ER genomic pathway (165 ER-related genes). We investigated whether expression of genes for receptors ER (ESR1), progesterone receptor (PGR), or HER-2 (ERBB2), the SET index, or a housekeeper gene (GAPDH) vary by stage of ER-positive breast cancer. Methods: We evaluated gene expression profiles (Affymetrix U133 microarrays, Affymetrix, Santa Clara, CA) from 956 patients’ clinical samples of ER-positive breast cancer, including 290 new samples profiled at MDACC and 666 samples from published datasets. Microarray data were uniformly normalized, log-transformed, and expression levels for single genes and the SET index were compared to pathologic AJCC stage (315 patients were stage I, 362 stage IIA, 151 stage IIB, 29 stage III, 27 stage IV at initial presentation, and 72 stage IV previously treated and/or at relapse) using a median ordered regression analysis (p < 0.05 was significant). Results: SET index significantly decreased with advancing pathologic stage (p < 0.001), and PGR expression levels showed a similar, but lesser, effect (p = 0.014). However, expression levels of ESR1 and ERBB2 did not vary by stage. Overall, GAPDH gene expression increased with stage (p < 0.001), but that effect was only observed in stages III and IV. Expression of these genes was not significantly different between stage IV disease at initial presentation or at relapse. Conclusions: Expression levels of ESR1 and ERBB2 receptor genes did not vary, but ER-related genomic transcription (SET index and, to a lesser extent, PGR) declined significantly with increasing pathologic stage. This suggests that ER-positive breast cancer tends to have less transcriptional dependence on estrogen with increasing pathologic stage. The observed increase in expression of GAPDH in stages III and IV might reflect higher metabolic activity in advanced ER-positive breast cancer and deserves further study. [Table: see text]

Economic evaluation of fulvestrant as an extra step in the treatment sequence for ER-positive advanced breast cancer.

Drug therapies for advanced breast cancer in hormone-receptor-positive disease include both hormonal and chemotherapies. Current UK practice is to minimise toxicity by using sequential hormonal agents for as long as clinically appropriate. A Markov model was developed to investigate the cost effectiveness of different sequences of therapies, particularly exploring the effects of adding an additional hormonal agent, fulvestrant, to the treatment pathway. A systematic review was undertaken and a panel of seven UK oncologists validated assumptions used for treatment efficacy, treatment pathways and resources used. Fulvestrant was found to be a cost-effective treatment option when added to the treatment sequence as a second- or third-line hormonal therapy for advanced disease. For a cohort of 1000 patients, fulvestrant as a second-line hormone therapy provided an additional 47 life years and 41 quality-adjusted life years (QALYs), at an additional cost of £301 359. This equated to £6500 per life years gained and £7500 per QALY. When used as a third-line option, the fulvestrant arm was dominant providing an increase in health benefit of 27 QALYs for the whole cohort, at a mean overall cost reduction of £430 per patient. Sensitivity analyses showed these results to be robust, demonstrating that fulvestrant is an economically viable additional endocrine option in the United Kingdom for the treatment of hormone responsive advanced breast cancer.

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

Recent Advances in Breast Cancer (the Twenty-fourth San Antonio Breast Cancer Symposium, December, 2001)

SummaryThis paper reviews the Twenty-fourth Annual San Antonio Breast Cancer Symposium. The preliminary results of the ATAC study have shown that Arimidex is superior to tamoxifen in postmenopausal women with ER-positive early breast cancer in terms of DFS, adverse effects and prevention of contralateral breast cancer. However, longer follow up is required to assess the drug safety regarding bone mineral density and cognitive function. Letrozole seems to be superior to tamoxifen as a first-line therapy in ER-positive advanced breast cancer in postmenopausal women. Although the incidence of acute myeloid leukaemia is significantly increased (cumulative incidence at 5 years = 1.1%) in breast cancer patients receiving cyclophosphamide and anthracyclines, the risk of this complication is easily outweighed by the benefits of chemotherapy. Adjuvant clodronate was found to be associated with a significant reduction in the incidence of bone metastases during the treatment period. A randomised trial comparing axillary dissection and axillary radiotherapy (RT) for early breast cancer reported no significant difference in survival at 15 years. However, axillary recurrence was significantly increased in the RT group. hTERT protein expression by IHC was found to correlate significantly with breast cancer-specific survival. There is no evidence to support the use of IHC of the sentinel node in routine clinical practice. LCIS is currently considered as a non-obligate precursor to breast cancer rather than just a risk factor.