Steroidal Aromatase Inhibitor Exemestane Research Articles

Abstract GS4-02: E2112: Randomized phase 3 trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer. A trial of the ECOG-ACRIN cancer research group

Abstract Background: Endocrine therapy resistance in advanced breast cancer remains a significant clinical problem that may be overcome with use of histone deacetylase (HDAC) inhibitors such as entinostat. The ENCORE 301 randomized phase II study reported an improvement in progression-free (PFS) and overall survival (OS) with the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in patients with advanced hormone receptor (HR)-positive, HER2-negative breast cancer. Protein lysine acetylation in peripheral blood mononuclear cells (PBMCs) was associated with prolonged PFS in the entinostat arm. Methods: E2112 is a multicenter randomized double-blind, placebo-controlled phase III study that enrolled men or women with advanced HR-positive, HER2-negative breast cancer whose disease had progressed on a non-steroidal AI in the adjuvant or metastatic setting (NCT02115282). Study participants were also required to have an ECOG performance status 0-1 with measurable or non-measurable (limited to 20% of the study population) disease. One prior chemotherapy for metastatic disease and prior treatment with fulvestrant and a CDK4/6 inhibitor was permitted but not required. Participants received exemestane 25mg po daily and entinostat (EE)/placebo (EP) 5mg po every week. Primary endpoints were PFS (central review) and OS. One-sided type 1 error 0.025 was split between two hypothesis tests: 0.001 for PFS test and 0.024 for OS. PFS tested in the first 360 pts, 88.5% power to detect 42% reduction in the hazard of PFS failure (median PFS, 4.1 to 7.1 months); OS tested in all 600 pts, 80% power to detect 25% reduction in the hazard of death (median OS, 22 to 29.3 months). Secondary endpoints included safety, objective response rate (ORR), and changes in protein lysine acetylation status in PBMCs (CD3+ T cells, CD14+ monocytes, CD19+ B cells, pan-leukocyte marker CD45+ cells, CD56+ NK cells) between C1D1 and C1D15 (integrated biomarker). Results: A total of 608 participants were randomized between March 2014 and October 2018 (305 EE, 303 EP), 98% enrolled in USA. Characteristics were well balanced between the arms. Median age was 63 years (range, 29-91), 99% female, 95% postmenopausal, 80% white and 15% black. A majority (84%) had disease resistant to AI in the metastatic setting at study entry, 78% had measurable disease and 60% visceral disease. Prior treatments included chemotherapy (60%), fulvestrant (30%), CDK4/6 inhibitor (35%), everolimus (3%). Median prior lines of chemotherapy was 1 (range, 0-4) and endocrine therapy was 2 (range, 1-7); in adjuvant/metastatic setting. Grade 3/4 adverse events in EE arm included neutrophil count decreased (20%), hypophosphatemia (14%), anemia (8%), white blood cell decreased (6%), fatigue (4%), diarrhea (4%), and platelet count decreased (3%). At final analysis, median PFS was 3.3 months (EE) versus 3.1 months (EP) (HR=0.87, 95% CI: 0.67, 1.13, p=0.30). Median OS was 23.4 months (EE) versus 21.7 months (EP) (HR=0.99, 95% CI: 0.82, 1.21, p=0.94). ORR was 4.6% (EE) and 4.3% (EP). The median fold change in lysine acetylation in PBMCs was approximately 1.5 in EE arm, and 1 in EP arm. Participants on EE had significantly higher increase in lysine acetylation by C1D15 than patients on EP (397 paired samples available for analysis, p<0.001 for all). Additional biomarker analyses will be presented at time of meeting. Conclusion: The combination of exemestane and entinostat did not improve survival in AI resistant advanced HR-positive, HER2-negative breast cancer. Pharmacodynamic analysis confirmed target inhibition in entinostat-treated patients. Citation Format: Roisin M Connolly, Fengmin Zhao, Kathy D Miller, Min-Jung Lee, Richard L Piekarz, Karen L Smith, Ursa Brown-Glaberman, Jennifer S Winn, Bryan A Faller, Adedayo A Onitilo, Mark E Burkard, George T Budd, Ellis G Levine, Melanie E Royce, Peter A Kaufman, Alexandra Thomas, Jane B Trepel, Antonio C Wolff, Joseph A Sparano. E2112: Randomized phase 3 trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer. A trial of the ECOG-ACRIN cancer research group [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS4-02.

Palbociclib and Exemestane are Active in Pretreated Low-Grade Serous Ovarian Cancer

We describe a case of a 55-year-old woman with a rare metastatic micropapillary low-grade serous ovarian cancer who had been heavily pretreated. A KRAS-mutation and c-MYC-amplification were detected, and we initiated a therapy with the CDK4/6- inhibitor Palbociclib in combination with the steroidal aromatase inhibitor exemestane. We postulated that the combination therapy leads to a blocking of the c-MYCamplification-activated cell cycle, proliferation, and inhibition of apoptosis, further enhanced by other oncogenes like mutated RAS. This therapy showed a good and lasting response representing a new opportunity for therapy in heavily pretreated metastatic micropapillary low-grade serous ovarian cancer.

Abstract ES8-1: Adjuvant endocrine therapy in 2020: It's complicated

Abstract Adjuvant endocrine therapy in 2020: It’s complicated Data regarding the use of adjuvant endocrine therapy in patients with hormone receptor-positive early breast cancer has grown over the past decades, and yet still uncertainty remains in management recommendations. In pre-menopausal women, treatment decisions are often driven by estimation of risk of recurrence, measured in terms of clinical and pathological parameters, algorithm-based prognostic modelling derived from breast cancer registries, molecular profiling and gene signature assays. Despite these significant advances, risk of distant disease recurrence is still over-estimated in a significant proportion of women. The addition of ovarian suppression to tamoxifen in pre-menopausal women has been shown to increase rates of both disease-free survival and overall survival than tamoxifen alone, with the use of the steroidal aromatase inhibitor exemestane producing further higher rates of freedom from recurrence. However, the addition of ovarian suppression in this generally low-risk population comes at the cost of increased adverse events and potential to interpose child-bearing years. Further to this, the SOFT/TEXT studies mandated five years of active treatment; little is known as to whether extended treatment beyond those five years would be comparatively equal, better or worse in terms of outcome endpoints. In the post-menopausal population, the updated ASCO Clinical Practice Guideline suggests that all women with node-positive disease should be offered extended therapy including an aromatase inhibitor for a total of ten years, as well as women with node-negative disease possessing high-risk prognostic factors. The question of how best to identify those women who may fare equally well with de-escalated, shorter therapy remains open. The issue of adverse events and drug-related side effects, particularly in the setting of extended therapy, is relevant and may impact negatively on overall treatment compliance and quality of life. As such, the choice of endocrine therapy remains an important consideration, as is evidence that intermittent administration of aromatase inhibitors may be feasible in selected patients. CDK4/6 inhibitors, administered in tandem with endocrine therapy, have radically changed the approach to managing metastatic endocrine receptor-positive disease. There is now much interest in moving these agents forward into the neoadjuvant and adjuvant setting, with a number of phase II and III trials ongoing. If positive data is consistently reported in adjuvant studies, this will undoubtedly create another layer of complexity to the clinical management of endocrine-sensitive disease. Citation Format: A McCartney, A Di Leo. Adjuvant endocrine therapy in 2020: It's complicated [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES8-1.

The potential clinical benefit of targeting androgen receptor (AR) in estrogen-receptor positive breast cancer cells treated with Exemestane

The development of acquired resistance to the aromatase inhibitors (AIs) used in clinic is being considered the major concern in estrogen-receptor positive (ER+) breast cancer therapy. Recently, androgen receptor (AR) has gained attention in the clinical setting, since it has been implicated in AIs-resistance, although, different roles for AR in cell fate have been described. In this work, our group elucidates, for the first time, the oncogenic role of AR in sensitive and resistant ER+ breast cancer cells treated with the potent third-generation steroidal AI Exemestane (Exe). We demonstrate that Exe promotes an overexpression/activation of AR, which has an oncogenic and pro-survival role in Exe-sensitive and Exe-resistant cells. Moreover, we also disclose that targeting AR with bicalutamide (CDX) in Exe-treated cells, enhances the efficacy of this AI in sensitive cells and re-sensitizes resistant cells to Exe treatment. Furthermore, by targeting AR in Exe-resistant cells, it is also possible to block the activation of the ERK1/2 and PI3K cell survival pathways, hamper ERα activation and increase ERβ expression. Thus, this study, highlights a new mechanism involved in Exe-acquired resistance, implicating AR as a key molecule in this setting and suggesting that Exe-resistant cells may have an AR-dependent but ER-independent mechanism. Hence we propose AR antagonism as a potential and attractive therapeutic strategy to overcome Exe-acquired resistance or to enhance the growth inhibitory properties of Exe on ER+ breast cancer cells, improving breast cancer treatment.

Abstract S1-02: PrECOG 0102: A randomized, double-blind, phase II trial of fulvestrant plus everolimus or placebo in post-menopausal women with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (MBC) resistant to aromatase inhibitor (AI) therapy

Abstract Background: Although AIs are an effective treatment for HR-positive MBC, whether used alone or in combination with CDK4/6 inhibitors, resistance to therapy and disease progression invariably develops. Therapeutic options for AI-resistant disease include the m-TOR inhibitor everolimus in combination with the steroidal AI exemestane, or the selective estrogen receptor downregulator (SERD) fulvestrant alone. We hypothesized that the combination of fulvestrant and everolimus would be more effective than fulvestrant alone in AI-resistant MBC. Methods: Major eligibility criteria included post-menopausal women with HR-positive, HER2-negative MBC, recurrence or progression while receiving prior non-steroidal or steroidal AI therapy, ECOG PS 0-1, and ≤1 prior chemotherapy regimen for metastases. All patients received fulvestrant (500mg IM q2 weeks for 3 doses, then q4 weeks) plus oral everolimus (10mg) or placebo (1:1 randomization). Prophylactic corticosteroid mouthwash was not used. Tumor assessment was performed at baseline and every 12 weeks. Treatment continued until progressive disease (PD) by RECIST 1.1 criteria. Patients who discontinued everolimus/placebo due to toxicity continued fulvestrant until PD. The primary endpoint was progression-free survival (PFS), defined as time from start of treatment until progression or death. With accrual of 130 patients (120 eligible), the trial had 90% power to detect an improvement in median PFS from 5.4 months to 9.2 months (1-sided stratified log-rank test, type I error rate10%), with analysis planned after 98 PFS events. Results: Of 130 patients treated (64 everolimus, 66 placebo), median age was 61 years (range 35-92), and treatment arms were balanced for stratification factors used in randomization, including ECOG PS 0 vs. 1 (59%/41%), measurable disease (66%), and prior chemotherapy for metastasis (17%). Grade 3/4 AEs were more common in the everolimus arm (53%/3% vs. 23%3%), including hyperglycemia (16%/0% vs. 0%), stomatitis (11%/0% vs. 0%), hypertriglyceridemia (9%/2% vs. 0%), lymphopenia (9%/0% vs. 0%), and pneumonitis (6%/2% vs. 0%). There were 3 grade 5 events (2 everolimus, 1 placebo arm), none of which were attributed to therapy. Selected grade 2 events of interest included fatigue (17% vs. 6%), hyperglycemia (6% vs. 0%), and stomatitis (6% vs. 0%). Everolimus/placebo was discontinued for adverse events, patient withdrawal, or physician discretion in 39% in the everolimus arm and 21% in the placebo arm. After 98 PFS events, median PFS was 10.4 months in the everolimus arm versus 5.1 months in the placebo arm (hazard ratio: 0.61, 95% C.I. 0.40 – 0.92; stratified logrank p= 0.02). Conclusions: The addition of everolimus to fulvestrant significantly improved PFS in post-menopausal women with AI-resistant MBC. Everolimus used without prophylactic corticosteroid mouthwash exhibited a similar rate of oral mucositis and overall AE profile when combined with fulvestrant as when combined with exemestane. Keywords: advanced breast cancer, PrECOG 0102, endocrine resistance, everolimus, exemestane, hormone receptor-positive, mTOR inhibitor, postmenopausal. Citation Format: Kornblum NS, Manola J, Klein P, Ramaswamy B, Brufsky A, Stella PJ, Burnette B, Telli M, Makower DF, Leach J, Truica CI, Wolff AC, Soori GS, Haley B, Nagarajan A, Wassenaar TR, Goldstein L, Miller KD, Sparano JA. PrECOG 0102: A randomized, double-blind, phase II trial of fulvestrant plus everolimus or placebo in post-menopausal women with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (MBC) resistant to aromatase inhibitor (AI) therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S1-02.

Abstract P3-04-11: ER is required for mTORC1 inhibitor-induced feedback activation of PI3K/AKT in ER+ breast cancer cells and patients' tumors

Abstract The mTORC1 inhibitor everolimus (afinitor) is approved for the treatment of patients with advanced/metastatic ER+/HER2- breast cancer in combination with the steroidal aromatase inhibitor exemestane following progression on a non-steroidal aromatase inhibitor. The BOLERO-2 and TAMRAD studies demonstrated that combined everolimus/anti-estrogen therapy provided longer PFS compared to anti-estrogen alone. However, it has not been clarified whether continued treatment with an anti-estrogen backbone is beneficial in the setting of mTORC1 inhibition. Upon activation by mTORC1, p70S6K phosphorylates the insulin-like growth factor-1 receptor (IGF-1R)/insulin receptor (InsR) effector IRS-1 to promote IRS-1 degradation, which in turn decreases activation of phosphatidylinositol 3-kinase (PI3K), AKT, and mTORC1. IGF1R, IRS1, and IRS2 are ER-inducible genes, and crosstalk between the ER and IGF-1R pathways has been described. We hypothesized that mTORC1 inhibition with everolimus will upregulate IGF-1R/InsR/IRS-1/2 signaling to activate PI3K/AKT and promote cancer cell survival, while combined inhibition of ER and mTORC1 will block PI3K/AKT activation by decreasing IGF-1R and IRS-1/2, providing rationale for combined targeting of ER and mTORC1. In 3 ER+ breast cancer cell lines, everolimus treatment increased phospho-AKT levels. ER inhibition with fulvestrant suppressed the induction of P-AKT by everolimus. IGF-1R/InsR inhibition with OSI-906, and RNAi-mediated knockdown of IGF-1R, InsR, or IRS-1/2, decreased everolimus-induced P-AKT. Everolimus sensitized IGF-1R/InsR to IGF-1 that was suppressed by fulvestrant but enhanced by 17b-estradiol. Although fulvestrant decreased IGF-1R and InsR protein levels, phospho-receptor tyrosine kinase profiling showed that fulvestrant increased P-IGF-1R and P-InsR. Acting downstream of IGF-1R/InsR, fulvestrant prevented everolimus-induced PI3K/AKT activation by blocking binding between the p85 regulatory subunit of PI3K and IRS-1, possibly by decreasing IRS-1/2 levels. In summary, everolimus-induced activation of PI3K/AKT requires IGF-1R/InsR/IRS-1/2 signaling facilitated by ER. Combined treatment with fulvestrant and everolimus synergistically inhibited growth in 4 ER+ cell lines. To determine whether ER promotes PI3K/AKT activation induced by mTORC1 inhibition in patients' tumors without exposing patients to everolimus, we analyzed live tumor tissues from post-menopausal patients with ER+/HER2- breast cancer treated +/- letrozole for 10-21 d before surgical tumor resection. Tumor cores (1 mm diameter) were used for ex vivo culture in DMEM +/- everolimus +/- OSI-906 for 1 h, and lysates were analyzed by immunoblot. Everolimus significantly increased P-AKT in tumors from untreated patients (n=10). OSI-906 did not affect P-AKT, but OSI-906 suppressed everolimus-induced P-AKT. In tumors from letrozole-treated patients (n=7), neither everolimus nor OSI-906 affected P-AKT. These data collectively suggest that ER activation is required for activation of PI3K/AKT induced by mTORC1 inhibition, and provide rationale for therapeutic combinations of anti-estrogens and mTORC1 inhibitors. Citation Format: Yang W, Chen VS, Schwartz GN, Marotti JD, Rosenkranz KM, Gui J, Miller TW. ER is required for mTORC1 inhibitor-induced feedback activation of PI3K/AKT in ER+ breast cancer cells and patients' tumors [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-04-11.

Differential profile of letrozole and exemestane on bone turnover markers in vinylcyclohexene diepoxide treated ovotoxic female mice.

The third generation aromatase inhibitors are currently the drugs of choice for the treatment of early and advanced breast cancer in postmenopausal women. One of the significant limiting factor during therapy is their negative impact on bone health. In this study, we compared the effects of a nonsteroidal (letrozole) and a steroidal aromatase inhibitor (exemestane) on bone mineral density and markers of bone turnover including alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP), hydroxyproline (HxP), receptor activator of nuclear factor kappa B ligand (RANKL), sclerostin, and dickkopf-1 (DKK-1) in vinylcyclohexene diepoxide (VCD)-induced ovotoxic female mice. VCD administration for 15 days mimicked a postmenopausal state with reduced serum estradiol levels. Ovotoxicity was accompanied by reduced ALP, HxP and enhanced TRAP, sclerostin and DKK-1 activity in femoral epiphysis and lumbar vertebrae of mice. While letrozole (1 mg/kg) administration for 1 month enhanced bone turnover in ovotoxic mice, exemestane (3.25 mg/kg) was devoid of such effects in both normal and ovotoxic mice. The latter, however, reduced ALP in femoral epiphysis of ovotoxic mice. Letrozole depleted estradiol levels in ovotoxic mice and enhanced RANKL activity while exemestane neither affected estradiol nor RANKL in both normal and ovotoxic mice, and enhanced sclerostin and DKK-1 in femoral epiphysis only. The study indicates that the two aromatase inhibitors possesses differential profile in terms of their effects on bone and that exemestane could be a better option for the treatment of breast cancer in postmenopausal women at least in terms of its effects on bone.

Abstract OT2-01-04: E2112: Randomized phase III trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer. A trial of the ECOG-ACRIN cancer research group

Abstract Background: A potential mechanism of resistance to endocrine therapy in breast cancer involves changes in gene expression secondary to epigenetic modifications, which might be modulated with the use of histone deacetylase (HDAC) inhibitors such as entinostat. ENCORE 301, a phase II study evaluating the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in patients with hormone receptor (HR)-positive advanced breast cancer who had experienced disease progression after a non-steroidal AI (NSAI), showed a significant improvement in progression-free survival (PFS), and overall survival (OS). Entinostat has been designated a Breakthrough Therapy by the FDA. Methods: E2112 is a multicenter randomized double-blind placebo-controlled phase III study (NCT02115282) enrolling patients with advanced HR-positive, HER2-negative breast cancer with prior disease progression on a NSAI (n=600). Patients receive exemestane 25mg po daily and entinostat/placebo 5mg po every week. Eligibility: Postmenopausal women and men, ECOG 0-1, locally advanced/metastatic invasive adenocarcinoma of the breast: ER/PR-positive, HER2-negative, measurable or non-measurable (20% cap) disease. Disease progression after NSAI use in the metastatic setting OR relapse while on or within ≤ 12 months of end of adjuvant NSAI therapy. Statistics: Both PFS (central review) and OS are primary endpoints, and the study is designed to show an improvement in either PFS or OS. Secondary endpoints include: Safety and tolerability, objective response rate, changes in lysine acetylation status in peripheral blood mononuclear cells, patient-reported symptom burden and treatment toxicities, adherence. One-sided type 1 error 0.025 split between two hypotheses tests: 0.001 for PFS test and 0.024 for OS. PFS is tested in the first 360 pts, 88.5% power to detect 42% reduction in the hazard of PFS failure (median PFS 4.1 to 7.1 months); OS is tested in all 600 pts, 80% power to detect 25% reduction in the hazard of death (median OS 22 to 29.3 months). E2112 was activated in March 2014 and accrual is anticipated to complete in 40 months. Citation Format: Connolly R, Zhao F, Miller K, Tevaarwerk A, Wagner L, Lee M, Murray J, Gray R, Piekarz R, Zujewski JA, Sparano J. E2112: Randomized phase III trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer. A trial of the ECOG-ACRIN cancer research group. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-01-04.

Abstract P2-11-11: Phase II trial of exemestane with immunomodulatory oral cyclophosphamide in metastatic hormone receptor (HR)-positive breast cancer: Prolonged progression-free survival (PFS) in patients with distinct T regulatory cell (Treg) profile

Abstract Background: Resistance to endocrine therapies in HR-positive breast cancer is a significant challenge. The steroidal aromatase inhibitor (AI) exemestane (EXE) has demonstrated short-term efficacy in metastatic HR-positive HER2-negative breast cancer (mHR+BC) that has progressed during treatment with a non-steroidal AI. Combination strategies have not shown a survival benefit. Immunotherapy represents a promising approach as it may increase durability of responses. Low dose cyclophosphamide (CTX) has demonstrated efficacy in combination with neoadjuvant letrozole in HR+BC, conceivably by enhancing anti-tumor immune responses. Here we investigated whether EXE combined with immunomodulatory CTX could provide durable responses in heavily pretreated patients and assessed immunological profiles (NCT01963481). Methods: Phase II trial of EXE (25mg PO daily) with CTX (50 mg PO daily) enrolled postmenopausal women (n=23) with mHR+BC who had progressed on prior endocrine therapy (including nonsteroidal AI, tamoxifen, and/or fulvestrant); prior chemotherapy was allowed. The primary endpoint was PFS (per RECIST 1.1) at 3 months; secondary endpoints were response rate, tolerability, and immune correlates. Detailed functional immune profiling of peripheral T cell subsets were performed by flow cytometry at baseline, 1, 3, 6, 9 & 12 months, with healthy donors available as controls. Results: All 23 patients have been enrolled, and 21 are evaluable for response. Median age was 54 (range 31-77), median prior lines of endocrine therapy was 2 (1-3) and chemotherapy was 1 (0-5). The majority (15/23) had visceral organ involvement. Combination treatment was well tolerated with one grade 3 urinary tract infection but no grade 4 or 5 toxicity. An objective response was observed in 19% of patients (4/21, 1 CR and 3 PR) and an additional 33% (7/21) had SD, resulting in a 3-month-PFS of 48.5% (95% CI, 30.5-77.1). Responses were durable in all patients, lasting =/> 9 months and included patients with liver metastases. Comparison of peripheral immune cell subsets of patients (n=16) at baseline to age/sex-matched healthy controls demonstrated an increased proportion of CD4+ memory T cells with central memory phenotype (CD45RO+CD27+, p<0.0001). When patients were stratified based on PFS at 3 months, the proportion of naïve Tregs (CD4+CD45RO-FOXP3+Helios+) at baseline was significantly lower (p=0.003) in the non-progressor group compared to patients with progression. Remarkably, when these patient groups were compared for changes in T cell subsets during treatment, the proportion of both naïve and memory Treg subsets increased from baseline to 3 months (p<0.01), but only in the non-progressor patient group. While preliminary, these findings are possibly indicative of novel predictive biomarkers. Conclusion: EXE and CTX had a favorable safety profile with evidence of clinical activity in patients with heavily pretreated mHR+BC, including durable responses in liver and bone. Correlative studies are ongoing to identify potential biomarkers of response or resistance to therapy. Citation Format: Kwa M, Novik Y, Oratz R, Jhaveri K, Wu J, Gu P, Meyers M, Muggia F, Bonakdar M, Abidoglu C, Kozhaya L, Li X, Joseph B, Iwano A, Friedman K, Goldberg JD, Unutmaz D, Adams S. Phase II trial of exemestane with immunomodulatory oral cyclophosphamide in metastatic hormone receptor (HR)-positive breast cancer: Prolonged progression-free survival (PFS) in patients with distinct T regulatory cell (Treg) profile. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-11-11.

Palbociclib for the treatment of postmenopausal breast cancer – an update

ABSTRACTIntroductionBreast cancer is a heterogeneous disease comprising different biological subtypes. In two thirds of tumours, expression of steroid-receptors is present, allowing for targeted treatment with endocrine therapy. In metastatic breast cancer, sequential administration of different non-cross resistant drugs offers a chance to delay cytotoxic chemotherapy. Activity of endocrine therapy, however, decreases with time as indicated by a shorter progression-free survival interval with every further treatment line, suggesting onset of resistance. Current research therefore focuses on prevention or delay of resistance by combining endocrine therapy with other targeted treatment approaches such as small-molecule pathway-inhibitors. Indeed, combining the steroidal aromatase-inhibitor exemestane with the mTor-inhibitor everolimus doubles activity of endocrine therapy in a pretreated population albeit at the price of increased toxicity.Data from several clinical trials suggest that inhibitors of the cycline-dependent kinases (CDK) 4 and 6 are able to delay or reverse resistance to endocrine therapy as well, while tolerability may be superior.Areas CoveredThis review provides a summary of clinical data on CDK 4/6 inhibitors, summarizes the biological rational for their use and provides an outlook to future developments in this field. A systematic literature search was performed in order to identify publications concerning the use of CDK 4/6 inhibitors in breast cancer. The search included original research articles, abstracts from major conferences and reviews published from 2005 to 2015 and was limited to English-language publications.Expert opinionBased upon available data regarding activity and tolerability, it is believed that CDK 4/6 inhibitors will evolve to become a valuable addition to the therapeutic options in metastatic breast cancer.

Associations between genetic variants and the effect of letrozole and exemestane on bone mass and bone turnover

Adjuvant therapy for hormone receptor (HR) positive postmenopausal breast cancer patients includes aromatase inhibitors (AI). While both the non-steroidal AI letrozole and the steroidal AI exemestane decrease serum estrogen concentrations, there is evidence that exemestane may be less detrimental to bone. We hypothesized that single nucleotide polymorphisms (SNP) predict effects of AIs on bone turnover. Early stage HR-positive breast cancer patients were enrolled in a randomized trial of exemestane versus letrozole. Effects of AI on bone mineral density (BMD) and bone turnover markers (BTM), and associations between SNPs in 24 candidate genes and changes in BMD or BTM were determined. Of the 503 enrolled patients, paired BMD data were available for 123 and 101 patients treated with letrozole and exemestane, respectively, and paired BTM data were available for 175 and 173 patients, respectively. The mean change in lumbar spine BMD was significantly greater for letrozole-treated (-3.2%) compared to exemestane-treated patients (-1.0%) (p=0.0016). Urine N-telopeptide was significantly increased in patients treated with exemestane (p=0.001) but not letrozole. Two SNPs (rs4870061 and rs9322335) in ESR1 and one SNP (rs10140457) in ESR2 were associated with decreased BMD in letrozole-treated patients. In the exemestane-treated patients, SNPs in ESR1 (Rs2813543) and CYP19A1 (Rs6493497) were associated with decreased bone density. Exemestane had a less negative impact on bone density compared to letrozole, and the effects of AI therapy on bone may be impacted by genetic variants in the ER pathway.

Abstract OT2-1-06: E2112: A randomized phase III trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer

Abstract Background: Epigenetic alterations in the genome, including abnormal DNA methylation and histone hypoacetylation, initiate and promote cancerous changes. A potential mechanism of resistance to endocrine therapy in breast cancer involves changes in gene expression secondary to epigenetic modifications, which might be modulated with the use of histone deacetylase (HDAC) inhibitors such as entinostat. Results from ENCORE 301, a phase II study evaluating the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in patients with hormone receptor (HR)-positive advanced breast cancer who had experienced disease progression on a non-steroidal AI (NSAI), showed a significant improvement in progression-free survival (PFS), the primary endpoint, and overall survival (OS), an exploratory endpoint. Based on the OS results, entinostat has been designated a Breakthrough Therapy by the FDA when used in combination with exemestane in HR-positive advanced breast cancer. Trial design: E2112 is a multicenter randomized double-blind placebo-controlled phase III study (NCT02115282) enrolling patients with advanced HR-positive, HER2-negative breast cancer who have experienced disease progression on a NSAI (n=600). Patients will receive exemestane 25mg po daily and entinostat/placebo 5mg po every week (28 day cycle). Staging every 12 weeks. Eligibility Criteria: Postmenopausal women and men (≥ 18 years), ECOG performance status 0-1, locally advanced/metastatic invasive adenocarcinoma of the breast: ER/PR-positive, HER2-negative, measurable or non-measurable (20% cap) disease. Disease progression after NSAI use in the metastatic setting OR relapse while on or within ≤ 12 months of end of adjuvant NSAI therapy. Prior CDK inhibitor or everolimus permitted, but not exemestane or fulvestrant. One prior chemo permitted in metastatic setting. Specific Aims: Both PFS (defined by central review) and OS are primary endpoints, and the study is designed to show an improvement in either PFS or OS. Secondary endpoints include: Safety and tolerability, objective response rate, changes in lysine acetylation status in peripheral blood mononuclear cells, patient-reported symptom burden and treatment toxicities, adherence. Statistical Methods: One-sided type 1 error 0.025 split between two hypotheses tests: 0.001 for PFS test and 0.024 for OS. PFS is tested in the first 360 pts, 88.5% power to detect 42% reduction in the hazard of PFS failure (median PFS 4.1 to 7.1 months); OS is tested in all 600 pts, 80% power to detect 25% reduction in the hazard of death (median OS 22 to 29.3 months) Present and Targeted Accrual: This study was activated in March 2014 and accrual is anticipated to complete in 40 months. Contact Person: Dr. Roisin Connolly, Email: rconnol2@jhmi.edu Funding: ECOG-ACRIN Cancer Research Group (ECOG-ACRIN), Cancer Therapy Evaluation Program (CTEP) at the National Cancer Institute, and Syndax Pharmaceuticals. Citation Format: Roisin M Connolly, Fengmin Zhao, Kathy D Miller, Amye J Tevaarwerk, Lynne I Wagner, Min-Jung Lee, Judy Murray, Robert Gray, Richard L Piekarz, Jo Anne A Zujewski, Joseph A Sparano. E2112: A randomized phase III trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT2-1-06.

MTOR Inhibitors in Breast Cancer: Not the Answer for All

The recent FDA approval of the mTOR inhibitor everolimus for use in conjunction with the steroidal aromatase inhibitor (AI) exemestane for advanced breast cancer was based on data from the BOLERO-2 trial (N Engl J Med 2012 Feb 9; 366: 520), which showed that the two-agent combination conferred a significant improvement in progression-free survival (PFS) over exemestane alone in patients with metastatic disease that progressed …

Abstract P2-14-01: Fulvestrant vs exemestane for treatment of metastatic breast cancer in patients with acquired resistance to non-steroidal aromatase inhibitors – a meta-analysis of EFECT and SoFEA (CRUKE/03/021 & CRUK/09/007)

Abstract Background: Optimal endocrine treatment (trt) for post-menopausal women with ER+ advanced breast cancer (ABC) progressing on or following a non-steroidal (NS) aromatase inhibitor (AI) is unclear. The EFECT study showed no difference in efficacy between the steroidal antiestrogen fulvestrant (F) & steroidal AI exemestane (E) in this setting (HR = 0.96, 95%CI: 0.82, 1.13; p = 0.65). Pre-clinical data suggest F may be more effective in a low estrogen environment. SoFEA investigated F combined with anastrozole (F+A) in patients (pts) with acquired resistance to previous AI compared with F alone & F alone vs. E. The combination of F+A was no better than F (HR = 1.00, 95%CI: 0.83, 1.21; p = 0.98) nor F alone better than E (HR = 0.95, 95%CI: 0.79, 1.14; p = 0.56); the lack of added benefit for F+A is consistent with previous 1st-line studies that have assessed this combination versus A alone (FACT & SWOG-S0226). Methods: SoFEA is a multi-center partially blinded randomized phase III study postmenopausal women were allocated to F plus A (F+A n=243), F plus placebo (n = 231) or E (n = 249). Similarly, EFECT is a randomized, double-blind, placebo controlled, multi-center phase III trial of F (n = 351) versus E (n = 342) in postmenopausal women (see table). However, given the differences in prior endocrine therapy/responsiveness within SoFEA & EFECT populations, an individual pt meta-analysis combining data from SoFEA & EFECT will be conducted enabling exploration of putative effects within specific pt subgroups to establish evidence in support, or not, of a pt subgroup sensitive to F at the dose used in these trials. Subgroups to be analysed include receptor status, visceral involvement, AI sensitivity, age, NSAI setting & time on NSAI. Results: 723 pts (480 in F & E) were enrolled from 82 UK & 4 South Korean centers (03/2004-04/2010) in SoFEA. 693 pts were enrolled from 138 centers worldwide (08/2003-11/2005) in EFECT. Trt was well tolerated in both trials; serious adverse events were rare. The meta-analysis will be conducted in July 2012 & results presented. Conclusion: Combining individual pt data from SoFEA & EFECT via meta-analysis will provide definitive clinical information on pt's response to F at the dose used in these studies, in particular whether certain pts with acquired resistance to NSAI do experience benefit of use of this antiestrogen as opposed to E. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-14-01.

Everolimus for postmenopausal women with advanced breast cancer: Updated results of the BOLERO-2 phase III trial.

99 Background: Current treatment options for postmenopausal patients with estrogen-receptor–positive breast cancer (BC) who relapse or progress on a nonsteroidal aromatase inhibitor (NSAI) are limited. The BOLERO-2 trial supports the activity of everolimus (EVE; an oral mammalian target of rapamycin [mTOR] inhibitor) added to the steroidal aromatase inhibitor exemestane (EXE) to prolong progression-free survival (PFS) in this patient population. Long-term PFS and survival data are awaited. Methods: BOLERO-2 is a phase 3, double-blind, randomized, international trial comparing EVE (10 mg once daily) + EXE (25 mg once daily) vs. placebo (PBO) + EXE in postmenopausal women with advanced estrogen-receptor–positive BC progressing or recurring after NSAIs (letrozole or anastrozole). Patients were randomized (2:1) to EVE + EXE or PBO + EXE. The primary endpoint was PFS by local investigator assessment. Main secondary endpoints included centrally assessed PFS, overall survival (OS), safety, bone turnover, and overall response rate. Results: Baseline disease characteristics including tumor burden and prior cancer therapy were well balanced between treatment arms (N = 724). Median PFS was doubled and response rates were consistently improved with EVE + EXE (n = 485) vs PBO + EXE (n = 239) in interim analyses. Median PFS by local assessment was ~3 mo with PBO + EXE vs 6.9 mo (hazard ratio [HR], 0.43; P < .0001) and 7.4 mo (HR, 0.44; P < .0001) with EVE + EXE at 7.5 mo and 12.5 mo follow-up, respectively. Fewer deaths were reported with EVE + EXE (17.2%) vs PBO + EXE (22.7%) at 12.5 mo follow-up. Safety profiles were consistent with previous reports for mTOR inhibitors. PFS data including 528 events (protocol-specified final analysis), and updated OS and safety data will be presented. Conclusions: Adding EVE to EXE markedly prolonged PFS in patients with NSAI-refractory advanced estrogen-receptor–positive BC. There were fewer deaths among patients receiving EVE, and further follow-up will evaluate the effect of EVE on OS.

Everolimus for postmenopausal women with advanced breast cancer: Updated results of the BOLERO-2 phase III trial.

559 Background: Current treatment options for postmenopausal patients with estrogen-receptor–positive (ER+) breast cancer (BC) who relapse or progress on a nonsteroidal aromatase inhibitor (NSAI) are limited. The BOLERO-2 trial supports the activity of everolimus (EVE; an oral mammalian target of rapamycin [mTOR] inhibitor) added to the steroidal aromatase inhibitor exemestane (EXE) to prolong progression-free survival (PFS) in this patient population. Long-term PFS and survival data are awaited. Methods: BOLERO-2 is a phase III double-blind, randomized, international trial comparing EVE (10 mg once daily) plus EXE (25 mg once daily) versus placebo (PBO) plus EXE in postmenopausal women with advanced ER+ BC progressing or recurring after NSAIs (letrozole or anastrozole). Patients were randomized (2:1) to EVE + EXE or PBO + EXE. The primary endpoint was PFS by local investigator assessment. Main secondary endpoints included centrally assessed PFS, overall survival (OS), safety, bone turnover, and overall response rate (ORR). Results: Baseline disease characteristics including tumor burden and prior cancer therapy were well balanced between treatment arms (N = 724). Median PFS was doubled and response rates were consistently improved with EVE + EXE (n = 485) vs PBO + EXE (n = 239) in interim analyses. Median PFS by local assessment was ~3 mo with PBO + EXE vs 6.9 mo (hazard ratio [HR] = 0.43; P < .0001) and 7.4 mo (HR = 0.44; P < .0001) with EVE + EXE at 7.5 mo and 12.5 mo follow-up, respectively. Fewer deaths were reported with EVE + EXE (17.2%) vs PBO + EXE (22.7%) at 12.5 mo follow-up. Safety profiles were consistent with previous reports for mTOR inhibitors. PFS data including 528 events (protocol-specified final analysis), and updated OS and safety data will be presented. Conclusions: Adding EVE to EXE markedly prolonged PFS in patients with NSAI-refractory advanced ER+ BC. There were fewer deaths among patients receiving EVE, and further follow-up will evaluate the effect of EVE on OS.

Effects of estrogen depletion on angiogenesis in estrogen-receptor-positive breast carcinoma – an immunohistochemical study of vasohibin-1 and CD31 with correlation to pathobiological response of the patients in neoadjuvant aromatase inhibitor therapy

Objectives: Tumor–stroma interactions, including angiogenesis, are pivotal in breast cancer. Changes of angiogenesis during endocrine therapy have not been reported in breast cancer patients. Vasohibin-1 (VASH-1) is a recently identified endothelium-derived negative feedback regulator of angiogenesis. Vasohibin-1 positive ratio (VPR) is proposed as an indicator of neovascularization of the tissues.Methods: The status of neovascularization, based on VPR before and after steroidal aromatase inhibitor (AI) exemestane (EXE) treatment, was evaluated in 54 post-menopausal Asian patients. VPR changes were correlated with the pathobiological response of the patients using Ki67 labeling index (LI) changes.Results: When using a decrement of more than 40% in post-treatment Ki67 LI as the definition of response, significant inverse correlation was detected between Ki67 LI and VPR changes in responders. Significant increment in neovascularization, as demonstrated by elevated VPR, was only detected in responders (p = 0.039). Increased angiogenesis detected in responders to neoadjuvant therapy may represent a stromal response to dying/dead cells, as part of tumor–stroma interaction following estrogen depletion.Conclusions: VPR could be a potential surrogate marker for predicting neoadjuvant endocrine therapy response, incorporating features of both carcinoma and stromal cells, in the early stage of neoadjuvant endocrine therapy before any discernible clinical and/or histopathological changes became apparent.

Carpal tunnel syndrome and musculoskeletal symptoms in postmenopausal women with early breast cancer treated with exemestane or tamoxifen after 2–3 years of tamoxifen: a retrospective analysis of the Intergroup Exemestane Study

Aromatase inhibitors are more effective than is tamoxifen in prevention of breast-cancer recurrence, but at the expense of increased musculoskeletal side-effects, such as carpal tunnel syndrome. The aim of this study was to assess risk factors and the prognostic value of musculoskeletal symptoms during treatment with the steroidal aromatase inhibitor exemestane or with tamoxifen after 2-3 years of tamoxifen. In the Intergroup Exemestane Study, postmenopausal women treated for early invasive breast cancer who remained disease free and on treatment after 2-3 years of tamoxifen were randomised to switch to exemestane or to continue tamoxifen for the remainder of the 5-year period of endocrine treatment. The primary endpoint for this retrospective analysis was occurrence of carpal tunnel syndrome and any musculoskeletal events, analysed in the safety population, which consisted of all patients who had received any trial treatment. As well as case-report forms, questionnaires were distributed retrospectively to gain more details of cases of carpal tunnel syndrome. The relation between musculoskeletal symptoms reported by 6 months from randomisation and survival from 9 months onwards was assessed by Cox proportional hazards models. The trial is registered, number ISRCTN11883920. It has completed accrual and follow-up is continuing for enrolled participants. After a median follow-up of 91·0 months (IQR 83·0-99·2), carpal tunnel syndrome had been reported for 66 (2·8%) of 2319 patients in the exemestane group compared with 13 (0·6%) of 2338 in the tamoxifen group (odds ratio [OR] 5·23, 99% CI 2·39-11·49; p<0·0001). More events occurred during treatment in the exemestane group than in the tamoxifen group (66 [2·8%] vs seven [0·3%], adjusted OR 9·90, 99% CI 3·52-27·82; p<0·0001). There was no significant difference between groups in events in the post-treatment period (ten with exemestane [0·4%] vs seven with tamoxifen [0·3%]; p=0·46). More patients in the exemestane group (1082 of 2319 patients, 46·7%) had musculoskeletal symptoms than in the tamoxifen group (901 of 2338, 38·5%; OR 1·48, 99% CI 1·32-1·67, p<0·0001). More events occurred during treatment in the exemestane group than in the tamoxifen group (984 [42·4%] vs 776 [33·2%], adjusted OR 1·59, 99% CI 1·32-1·91; p<0·0001), with this difference persisting to some extent in the post-treatment period (449 [19·4%] vs 390 [16·7%]; p=0·017). Of 73 on-treatment cases of carpal tunnel syndrome, 58 (79·5%) completed questionnaires were available. 27 patients (46·6%) had bilateral carpal tunnel syndrome and 31 (53·4%) had unilateral disease; 40 (69·0%) underwent surgical release. The disorder greatly affected daily-life activities in 21 (36·2%) cases. Occurrence of musculoskeletal symptoms, including carpal tunnel syndrome, was associated with improved disease-free survival in unadjusted analysis (p=0·023), but not with overall survival (p=0·36). However, after adjustment for possible confounding factors, musculoskeletal symptoms were not associated with disease-free survival (hazard ratio [HR] 0·96, 95% CI 0·82-1·14, p=0·67) or overall survival (HR 1·02, 95% CI 0·84-1·25, p=0·82). Occurrence of carpal tunnel syndrome is higher in patients with breast cancer given exemestane than in those treated with tamoxifen, and surgical release might be necessary in most cases. Development of musculoskeletal symptoms in the first 6 months of treatment is not an independent biomarker of improved disease outcome. Further investigation is warranted into the relation between treatment-emergent musculoskeletal symptoms and clinical outcome in patients with breast cancer receiving hormonal therapy. Pfizer.

P1-16-01: A Randomized, Double-Blinded, Controlled Study of Exemestane vs. Anastrozole for the First-Line Treatment of Postmenopausal Japanese Women with Hormone Receptor Positive Advanced Breast Cancer.

Abstract Background The steroidal irreversible aromatase inhibitor (AI) exemestane (E), the non-steroidal reversible AI anastrozole (A) and tamoxifen (T) are approved for the first-line treatment of the postmenopausal women with hormone receptor (HR) positive advanced breast cancer (ABC) in Japan. Although there are some studies which compare the efficacy and safety of AIs and T in the first-line disease setting, the number of studies that compare efficacy and safety of AIs is limited. We conducted this multicenter, randomized, double-blinded non-inferiority study, to evaluate the time to progression (TTP) in HR positive ABC randomized to therapy with E or A. Methods Patients (pts) who were ≥20 years [yrs], postmenopausal, ECOG PS ≤1 and had HR positive ABC that recurred after the adjuvant therapy or metastatic disease settings were eligible and randomized (1:1) to 25 mg/day of E or to 1 mg/day of A. Data were evaluated for non-inferiority of E compared to A defined as the upper limit of a two-sided 95% confidence interval (CI) of the hazard ratio (HR) of TTP being less than or equal to 1.25. The primary endpoint was TTP assessed by the independent radiological images review committee (RIRC). Secondary endpoints included TTP by investigator, time to treatment failure, overall survival (OS), objective response rate (ORR), clinical benefit rate, and safety. Results A total of 298 pts from 58 sites were randomized to E (n=149; mean age: 63.4 yrs) or A (n=149; mean age: 64.0 yrs). The mean BMI for the E and A arms were 23.0 kg/m2 and 23.6 kg/m2, respectively. Six pts (2 pts in E arm, 4 pts in A arm) were excluded from the full analysis set due to lack of evaluation for anti-tumor response after study medication started. Median TTP (as per RIRC) was 13.8 months (M) vs. 11.1 M for E vs. A, respectively (HR 1.007; 95% CI: 0.771−1.317). Median TTP (Investigator) was 13.8 M vs. 13.7 M for E vs. A, respectively (HR 1.059; 95% CI: 0.816−1.374). The median OS for A treated pts was 60.1 M, OS for E was not reached (as of data cut-off: December 8, 2010). ORR for E was 43.9% (95% CI: 35.3−52.8) and 39.1% (95% CI: 30.6−18.1) for A. Other analyses, including sub-population analyses are ongoing. The incidence of treatment related adverse events (AEs) in E arm was 71.1% (n=106) and in A arm 59.7% (n=89); the AEs were mostly grade 1 and 2 in 61.7% (n=92) and 53.7% (n=80) of pts respectively. They were expected and manageable. Treatment related SAEs were similar in both groups: 6 (4.0%) in E arm and 5 (3.4%) in A arm. The most common AEs for E were hot flushes (22.1%), arthralgias (16.8%), musculoskeletal stiffness (11.4%) and γ-GTP increased (10.1%); in A arm, hot flushes (14.8%) and arthralgia (16.8%) were observed in &amp;gt;10% pts. Conclusions Although median TTP (RIRC) of E is slightly improved compared with that of A, the result of TTP did not meet the non-inferiority criteria. There were no significant differences found between E and A in ORR. Although AEs in E were numerically higher, the observed AE profiles were similar to those previously reported for E and A. This study shows that E is comparable to A in efficacy and safety. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-16-01.

Ki67 index changes, pathological response and clinical benefits in primary breast cancer patients treated with 24 weeks of aromatase inhibition

Aromatase inhibitor shows efficacy for hormone receptor positive postmenopausal breast cancer. We evaluated the activity of 24 weeks of aromatase inhibition with exemestane for primary breast cancer in a neoadjuvant setting. Patients with stage II/IIIA invasive breast cancer with estrogen receptor (ER) and/or progesterone receptor (PgR)-positive status were eligible. Primary endpoints were objective response rate (ORR) and safety. A steroidal aromatase inhibitor exemestane of 25 mg/day was administered for 16 weeks with an 8-week extension. Secondary endpoints were rates of breast-conserving surgery (BCS), and change of Ki67 index and ER/PgR expression in central laboratory analyses. Between March 2006 and December 2007, 116 patients were enrolled. Among those, 102 patients completed 24 weeks of administration. The ORR was 47% (55/116) at Week 16 and 51% (59/116) at Week 24, respectively. No serious toxicity was seen. ORR was associated with ER Allred scores but not with PgR scores. The significant reduction in Ki67 index was confirmed. No progression was experienced in tumors with less than 15% Ki67 index. Pathological response was observed in 28 (30%) of 94 evaluated cases. No statistical correlation between pre-treatment Ki67 index and pathological response was detected; however, a trend of correlation was found between the post-treatment preoperative endocrine prognostic index (PEPI), a prognostic score and the pathological response. At diagnosis, 59 patients (51%) would have required mastectomy but 40 patients were converted to BCS, showing an increase in the rate of BCS (77%). The 24-week aromatase inhibition provided preferable clinical benefits with significant reduction in Ki67 index. More precise mechanisms of the response need to be investigated.