Treatment Of Hormone-sensitive Breast Cancer Research Articles

The role of CDK4/6 inhibitors in older and younger patients with breast cancer: A systematic review and meta-analysis.

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have an extremely important impact on the treatment of hormone-sensitive breast cancer (BC) and have radically changed the first-line treatment for metastatic disease with increased rates of treatment response, overall survival (OS), and progression-free survival (PFS). We performed a pooled analysis of randomized trials to validate or refute the hypothesis that there is a significant survival benefit of adding anti-CDK4/6 inhibitors to standard endocrine therapy (ET) in older patients with advanced BC. We selected only English-language phase II/III randomized controlled trials that compared ET alone with ET with anti-CDK4/6 inhibitors in the treatment of advanced BC, with subgroups reporting the outcomes of elderly patients (usually at least 65 years). The primary endpoint was OS. The review process led to the inclusion of 12 articles and two meeting abstracts, including a total of 10 trials. The addition of CDK4/6 inhibitors to ET (letrozole or fulvestrant) significantly reduced mortality risk by 20% in younger patients (fixed-effect model; HR 0.80; 95% CI 0.72-0.9; p<0.01) and 21% in older BC patients (HR 0.79; 95% CI 0.69-0.91; p<0.01). No OS data were available for patients ≥70 years. This large, pooled analysis is the first to demonstrate that CDK4/6 inhibitors confer OS and PFS benefits in elderly patients (those aged ≥65 years) with advanced ER+BC and to indicate that it should be discussed with and offered to all patients after geriatric assessment and according to the toxicity profile.

The impact of endoxifen-guided tamoxifen dose reductions on endocrine side-effects in patients with primary breast cancer

Tamoxifen is important in the adjuvant treatment of hormone-sensitive breast cancer and substantially reduces recurrence; however, almost 50% of patients are non-compliant mainly due to side-effects. The aim of this study was to investigate whether endoxifen-guided tamoxifen dose reduction could lead to fewer side-effects. Effects of tamoxifen dose reduction were investigated in patients with bothersome side-effects and endoxifen levels ≥32 nM and compared to patients with side-effects who remained on tamoxifen 20 mg. Endocrine symptoms and health-related quality of life (HR-QOL) were assessed after 3 months with the Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES) questionnaire. Tamoxifen dose was reduced in 20 patients, 17 of whom were assessable for side-effect analyses. A clinically relevant improvement of >6 points was observed in endocrine symptoms and HR-QOL in 41% and 65% of the patients, respectively. In total, there was a significant and clinically relevant improvement in endocrine symptoms [5.7, 95% confidence interval (CI)-0.5-11.5] and HR-QOL (8.2, 95% CI 0.9-15.4) after dose reduction. This was not seen in patients whose doses were not reduced (n= 60). In 21% of patients, endoxifen dropped slightly below the 16-nM threshold (12.8, 15.5, 15.8, 15.9 nM). Endoxifen-guided dose reduction of tamoxifen significantly improved tamoxifen-related side-effects and HR-QOL. Nearly 80% of patients remained above the most conservative endoxifen threshold.

Expression and Function of StAR in Cancerous and Non-Cancerous Human and Mouse Breast Tissues: New Insights into Diagnosis and Treatment of Hormone-Sensitive Breast Cancer.

Breast cancer (BC) is primarily triggered by estrogens, especially 17β-estradiol (E2), which are synthesized by the aromatase enzyme. While all steroid hormones are derived from cholesterol, the rate-limiting step in steroid biosynthesis is mediated by the steroidogenic acute regulatory (StAR) protein. Herein, we demonstrate that StAR mRNA expression was aberrantly high in human hormone-dependent BC (MCF7, MDA-MB-361, and T-47D), modest in hormone-independent triple negative BC (TNBC; MDA-MB-468, BT-549, and MDA-MB-231), and had little to none in non-cancerous mammary epithelial (HMEC, MCF10A, and MCF12F) cells. In contrast, these cell lines showed abundant expression of aromatase (CYP19A1) mRNA. Immunofluorescence displayed qualitatively similar patterns of both StAR and aromatase expression in various breast cells. Additionally, three different transgenic (Tg) mouse models of spontaneous breast tumors, i.e., MMTV-Neu, MMTV-HRAS, and MMTV-PyMT, demonstrated markedly higher expression of StAR mRNA/protein in breast tumors than in normal mammary tissue. While breast tumors in these mouse models exhibited higher expression of ERα, ERβ, and PR mRNAs, their levels were undetected in TNBC tumors. Accumulation of E2 in plasma and breast tissues, from MMTV-PyMT and non-cancerous Tg mice, correlated with StAR, but not with aromatase, signifying the importance of StAR in governing E2 biosynthesis in mammary tissue. Treatment with a variety of histone deacetylase inhibitors (HDACIs) in primary cultures of enriched breast tumor epithelial cells, from MMTV-PyMT mice, resulted in suppression of StAR and E2 levels. Importantly, inhibition of StAR, concomitant with E2 synthesis, by various HDACIs, at clinical and preclinical doses, in MCF7 cells, indicated therapeutic relevance of StAR in hormone-dependent BCs. These findings provide insights into the molecular events underlying the differential expression of StAR in human and mouse cancerous and non-cancerous breast cells/tissues, highlighting StAR could serve not only as a novel diagnostic maker but also as a therapeutic target for the most prevalent hormone-sensitive BCs.

Comparison of Acupuncture vs Sham Acupuncture or Waiting List Control in the Treatment of Aromatase Inhibitor–Related Joint Pain

Aromatase inhibitors (AIs) have proven efficacy for the treatment of hormone-sensitive breast cancer; however, arthralgias (pain and stiffness) contribute to nonadherence with therapy for more than 50% of patients. To examine the effect of acupuncture in reducing AI-related joint pain through 52 weeks. A randomized clinical trial was conducted at 11 sites in the US from May 1, 2012, to February 29, 2016, with a scheduled final date of follow-up of September 5, 2017, to compare true acupuncture (TA) with sham acupuncture (SA) or waiting list control (WC). Women with early-stage breast cancer were eligible if they were taking an AI and scored 3 or higher on the Brief Pain Inventory Worst Pain (BPI-WP) item (score range, 0-10; higher scores indicate greater pain). Analysis was conducted for data received through May 3, 2021. Participants were randomized 2:1:1 to the TA (n = 110), SA (n = 59), or WC (n = 57) group. The TA and SA protocols were composed of 6 weeks of intervention at 2 sessions per week (12 sessions overall), followed by 6 additional weeks of intervention with 1 session per week. Participants randomized to WC received no intervention. All participants were offered 10 acupuncture sessions to be used between weeks 24 and 52. In this long-term evaluation, the primary end point was the 52-week BPI-WP score, compared by study group using linear regression, adjusted for baseline pain and stratification factors. Among 226 randomized women (mean [SD] age, 60.7 [8.6] years; 87.7% White; mean [SD] baseline BPI-WP score, 6.7 [1.5]), 191 (84.5%) completed the trial. In a linear regression, 52-week mean BPI-WP scores were 1.08 (95% CI, 0.24-1.91) points lower in the TA compared with the SA group (P = .01) and were 0.99 (95% CI, 0.12-1.86) points lower in the TA compared with the WC group (P = .03). In addition, 52-week BPI pain interference scores were statistically significantly lower in the TA compared with the SA group (difference, 0.58; 95% CI, 0.00-1.16; P = .05). Between 24 and 52 weeks, 12 (13.2%) of TA, 6 (11.3%) of SA, and 5 (10.6%) of WC patients reported receipt of acupuncture. In this randomized clinical trial, women with AI-related joint pain receiving 12 weeks of TA had reduced pain at 52 weeks compared with controls, suggesting long-term benefits of this therapy. ClinicalTrials.gov Identifier: NCT01535066.

Sensing of Letrozole Drug by Pure and Doped Boron Nitride Nanoclusters: Density Functional Theory Calculation

Background: Letrozole is a non-steroidal drug utilized as a treatment of hormone-sensitive breast cancer. It has been shown that letrozole has harmful side effects. Therefore, it seems necessary to design a letrozole drug sensor. In this work, we scrutinized the sensing properties of the B30N30, AlB29N30, and GaB29N30 nanoclusters toward the letrozole drug in various adsorption sites. Methods: Investigations were done using the density functional theory (DFT) calculation with the B3PW91/6-311G(d, p) level of theory. The time-dependent density functional theory (TD-DFT) calculations were used to investigate Ultraviolet-visible (UV-vis) spectrums with the same level of theory. Results: The adsorption energy of B30N30, AlB29N30, and GaB29N30 in the most stable complexes were calculated at -16.81, -34.62, and -27.41 kcal mol-1, respectively. The results obtained from the study of electronic properties showed a high sensitivity for the detection of letrozole in B30N30 compared to AlB29N30 and GaB29N30. The calculated recovery time for the B30N30 is 0.13 × 10-5 s, which indicates a very short recovery time. The UV-vis spectrums showed that the letrozole/B30N30 exhibits shift toward the higher wavelengths (red shift). Conclusion: Therefore, these results showed that the B30N30 is a good candidate for identifying letrozole. Further, B30N30 would be more effective than AlB29N30 and GaB29N30 due to the simple synthesis.

Abstract ES8-3: Everything Comes at a Price - Toxicity, Cost and Adherence to Endocrine Therapy

Abstract Despite the proven efficacy of aromatase inhibitors (AIs) for the treatment of hormone-sensitive breast cancer (BC) adherence to therapy for the full duration of 5-years is suboptimal. Adherence is likely even lower for extended adjuvant therapy for up to 10-years. Issues related to non-adherence are increasingly important, as analyses from prospective randomized trials show compliance to endocrine therapy is associated with improved disease-free survival. The reasons for non-adherence to hormonal therapy are multifactorial. Barriers to compliance include patient, physician, medication and system related variables and poor compliance is usually associated with a combination of these factors. Characteristics associated with non-adherence include very high and low age, minority race, being single, increased number of comorbidities, lack of knowledge about efficacy of AI therapy, history of non-adherence to other chronic medications, limited insurance status, and higher out of pocket costs. Side effects from hormonal therapy is the most common reason for early discontinuation. AI arthralgia has been estimated to affect 45-60% of patients, many of whom report severe or continuous pain. One study reported an overall AI discontinuation rate of 32.4% within 2 years due to adverse effects, 24.3% specifically due to musculoskeletal symptoms, which was the primary reason for discontinuation. There is no consensus on the best treatment for AI arthralgia. The most commonly used therapy is NSAIDs, although there are no formal data testing their efficacy for AI arthralgia, and they are associated with potentially severe adverse effects. Randomized controlled trials have shown benefits from exercise (aerobic and strength training exercises), acupuncture, omega-3-fatty acids and duloxetine compared to placebo for AI arthralgia. Studies have also demonstrated improvement in symptoms over time even among patients receiving placebo. Various educational interventions have also been studied to improve adherence. A systematic review of behavioral interventions to enhance adherence to hormone therapy found five articles that met inclusion criteria and none reported the interventions significantly enhanced adherence compared to usual care. All evaluated educational interventions with or without reminders or navigation. In addition, a multicenter randomized clinical trial of patients with early stage breast cancer on AI’s found that bi-weekly unidirectional text messages for 36 months focused on overcoming potential barriers to medication adherence did not result in improved adherence to hormonal therapy. It is likely that improving long-term adherence will likely require sustained behavioral interventions and support. Citation Format: DL Hershman. Everything Comes at a Price - Toxicity, Cost and Adherence to Endocrine Therapy [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 ES8-3.

Pharmacokinetic evaluation of a transdermal anastrozole-in-adhesive formulation.

Background and objectiveAnastrozole is a well-established active pharmaceutical ingredient (API) used for the treatment of hormone-sensitive breast cancer (BC) in postmenopausal women. However, treatment with the only available oral formulation is often associated with concentration-dependent serious side effects such as hot flashes, fatigue, muscle and joint pain, nausea, diarrhea, headache, and others. In contrast, a sustained-release system for the local application of anastrozole should minimize these serious adverse drug reactions.MethodsAnastrozole-in-adhesive transdermal drug delivery systems (TDDS) were developed offering efficient loading, avoidance of inhomogeneity or crystallization of the drug, the desired controlled release kinetics, storage stability, easy handling, mechanical stability, and sufficient stickiness on the skin. In vitro continuous anastrozole release profiles were studied in Franz diffusion cells. In vivo, consecutive drug plasma kinetics from the final anastrozole transdermal system was tested in beagle dogs. For drug analysis, a specific validated liquid chromatography– mass spectrometry method using fragment ion detection was developed and validated.ResultsAfter efficient drug loading, a linear and sustained 65% drug release from the TDDS over 48 h was obtained. In vivo data showed a favorable anastrozole plasma concentration–time course, avoiding side effect-associated peak concentrations as obtained after oral administration but matching therapeutic plasma levels up to 72 h.ConclusionThese results provide the basis for establishing the transdermal application of anastrozole with improved pharmacokinetics and drug safety as novel therapeutic approach and promising option to treat human BC by decreasing the high burden of unwanted side effects.

Surgical Oophorectomy is Ineffective Therapy in Women with Hormone-Receptor Positive Breast Cancer Who are in Historical, but Low-Progesterone Luteal Phase

The hormonal biology of the menstrual cycle has major relevance in the treatment of hormone-sensitive breast cancer. There are 500,000 new cases of hormone-receptor positive breast cancer in premenopausal women annually; 80% of these are among women in low- and middle-income countries. Surgical oophorectomy should play a major role in the treatment of these women. New data from two phase III clinical trials show that women who are in historical luteal phase, but have low progesterone levels at the times of their oophorectomy surgeries benefit little from this intervention. The unique sequence of hormonal signaling to micro-metastases which occurs in this situation offers a logical explanation for this observation. Because surgical oophorectomy is a safe and widely practical and affordable intervention, this new observation and explanation deserves the attention of the practicing global surgical community. Universal application of surgical oophorectomy treatment could save 100,000 lives of young women with breast cancer each year.

Abstract OT3-02-04: A randomized controlled trial comparing acupuncture versus usual care for the treatment of aromatase inhibitor-induced arthralgia (AIIA) in women with early-stage breast cancer

Abstract BACKGROUND: The increase in breast cancer (BC) survival is largely due to the benefits of hormonal therapy, such as tamoxifen and aromatase inhibitors (AIs), for the treatment of hormone-sensitive breast cancer. Recent clinical trials have demonstrated that AIs are more effective than tamoxifen at reducing BC recurrences. However, BC patients receiving AIs have a higher incidence of osteoporosis, bone fractures, and musculoskeletal symptoms, particularly joint pain and stiffness. The incidence of AIIA in the ATAC trial was 27.8% in patients taking anastrozole versus (vs) 21% in patients taking tamoxifen (Baum M, Lancet 2002). The arthralgia associated with AIs can be so debilitating that it contributes to a significant percentage of non-compliance and discontinuation of systemic treatment. Patients with cancer often show interest in complementary and integrative modalities for symptom management (Vickers AJ, Lancet 2001), of which Acupuncture (Ac) is one of the most utilized therapies. ELIGIBILITY: Subjects must be female ≥18 years, have undergone mastectomy or breast-sparing surgery, and must have recovered from all pain-related effects of the surgery and radiotherapy with a minimum washout period of 30 days prior to registration. Patients should have ER and PR positive BC and be actively taking a 3rd-generation AI (Anastrozole, Letrozole, or Exemestane) for at least the 30 days prior to registration and plan to continue for at least one year after registration. ECOG PS &amp;lt;2 and platelets counts &amp;gt; 50,000/uL. Patients must not have received topical analgesic with exception of oral NSAIDS drugs ≤14 days to registration. TRIAL DESIGN: This is a 12-week, two arm randomized (1:1) trial evaluating the benefit of Ac in BC patients experiencing AIIA. AIMS: The aim of this study is to investigate the effectiveness of an integrative approach using Ac vs usual care (UC) treatment consisting of NSAIDs for the management of the AIIA.Primary endpoint is to compare the difference of Brief Pain Inventory-Short Form (BPI-SF) score at baseline vs week 8 between Ac and UC groups. Secondary endpoints are a) to compare the difference of BPI-SF score at baseline vs week 12 between Ac and UC groups, b) to compare the difference in AI adherence between Ac and UC groups and c) to compare the difference in patient initiated AI discontinuation between Ac and UC groups. STATS/TARGET ACCRUAL: This is a randomized controlled phase II study with the goal to compare reduction in BPI-SF score for patients treated with Ac vs UC alone. Patients are randomized 1:1 between the two arms. Prior work has indicated a 2-point BPI-SF score reduction as clinically meaningful. A sample size of 56 patients yields a study with 90% power and a one-sided significance level of 0.025 to determine a difference in pain reduction ≥2. These calculations are based on the assumptions of normal distribution of the improvement in BPI-SF score and a standard deviation that is conservatively calculated to be 2.3. An additional 6 patients will be accrued to account for attrition. Citation Format: Frank HS, Bendinger GM, Ensor Jr. JE, Neufeld N, Nixon D, Randolph K, McGuire E, Rados K, McNight JE, Pabbathi H, Panicker R, Johnson AT, Lammersfeld C, Alvarez R. A randomized controlled trial comparing acupuncture versus usual care for the treatment of aromatase inhibitor-induced arthralgia (AIIA) in women with early-stage breast cancer [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 OT3-02-04.

Evolution of systemic treatment for hormone-sensitive breast cancer: from sequential use of single agents to the upfront administration of drug combinations

Current standards of treatment of endocrine-dependent cancers (breast cancer (BC), prostate cancer) imply sequential use of endocrine therapy and cytotoxic agents: it is believed, that steroid hormone antagonists cease the division of transformed cells and therefore make them resistant to other therapeutic modalities. It is important to recognize that conceptual investigations in this field were carried out dozens of years ago, and often involved relatively non-efficient drugs, imperfect laboratory tests, etc. There are several recent examples of combined use of endocrine therapy and other compounds. The addition of docetaxel (6 cycles) to androgen deprivation resulted in significant improvement of overall survival in men with metastatic prostate cancer. Clinical trial involving the combined use of exemestane and everolimus demonstrated promising results. There are ongoing studies on inhibitors of cycline-dependent kinases. Use of these drugs in the beginning of endocrine therapy may significantly delay resistance to the antagonists of estrogen signaling.

Clinical utility of exemestane in the treatment of breast cancer.

Breast cancer is the most prevalent cancer in women, causing a significant mortality worldwide. Different endocrine strategies are available for the treatment of hormone-sensitive breast cancer, including antiestrogen tamoxifen and fulvestrant, as well as third-generation aromatase inhibitors (AIs), such as letrozole, anastrozole, and exemestane. In this review, we will focus on exemestane, its clinical use, and its side effects. Exemestane is a steroidal third-generation AI now used in all treatment settings for breast cancer. In the metastatic disease, it has been extensively investigated as the first-, second-, and further-line treatment and it is now registered for the treatment of postmenopausal women with advanced estrogen-receptor-positive breast cancer whose disease has progressed following antiestrogen therapy. A potential lack of cross-resistance with nonsteroidal AIs has been described, giving additional therapeutic opportunities in sequences of endocrine agents. Exemestane is also approved for the adjuvant treatment of postmenopausal early breast cancer, either as upfront monotherapy for 5 years, as a switch following 2–3 years of tamoxifen, or as extended therapy beyond 5 years of adjuvant treatment. New promising data also showed a beneficial effect in young premenopausal early breast cancer patients, when administered together with ovarian suppression. Interesting results have also emerged when exemestane has been investigated as neodjuvant treatment as well as preventive agent in healthy women at high risk for breast cancer. Exemestane is generally well tolerated, with a side effect profile similar to that of other AIs, including menopausal symptoms, arthralgia, and bone loss. In conclusion, exemestane can be considered an effective and well-tolerated endocrine treatment option for all stages of breast cancer.

Abstract P5-15-03: Baseline joint pain predicts severity of subsequent joint symptoms in women initiating aromatase inhibitors for early stage breast cancer

Abstract Background: Aromatase inhibitors (AIs) are the standard adjuvant treatment of hormone-sensitive breast cancer (BC) in postmenopausal women. However, these therapies are associated with musculoskeletal complaints which may lead to non-adherence and early discontinuation. The aim of this study was to characterize the natural history of the AI-induced arthralgia. Methods: Postmenopausal women with stage I-III BC were prospectively enrolled at the onset of adjuvant AI therapy. Subjects completed the Brief Pain Inventory (BPI) questionnaire at baseline, 3, 6, 9, and 12 months. BPI worst pain scores were categorized as 0-3, 4-6 and 7-8. Multiple logistic regression analysis was used to evaluate the association between baseline factors and having a 2-point worsening in BPI worst pain score. A Cox-proportional hazards model was used to evaluate factors that influenced the time to first 2-point worsening in pain score. Clinically significant change was defined as ≥2-point increase from baseline. Those with a baseline BPI worst pain score of ≥9 were removed from analysis. Results: Among 180 consented subjects, 1 was found to be ineligible due to being perimenopausal, 42 subjects were lost to follow up, 17 subjects came off their AI and 8 subjects dropped out. Mean age was 61; 60% were white, 32% Black, 10%, Asian and 31% were Hispanic; 86% started on anastrazole; 24% had a change in AI. At baseline, 76 women had a BPI worst pain score between 0-3; 28 between 4-6; and 18 had 7+. Seventy subjects (64%) experienced at least a 2-point worsening of BPI from baseline and women who developed a 2-point worsening had a lower mean baseline BPI (2.57 vs. 3.75) compared to those who did not. Those experiencing an initial worsening in the first 6 months of therapy improved over time; while the patients experiencing BPI worsening at 9 months, continued to have progressive increase in BPI. In a multiple logistic regression model adjusting for AI switching, BMI, age, baseline score, prior chemotherapy, osteoarthritis, and prior hormone replacement therapy, those who had a baseline worst pain score between 4-6 (p=0.04) or 7+ (p=0.005) were less likely to develop a 2-point worsening in BPI at 12 months from baseline. Similarly, those with a baseline worst pain categorization of 7+ had a hazard ratio of 0.34 for time to 2-point worsening. Conclusions: Women with low baseline BPI score are more likely to develop worsening BPI score over time. Women who develop symptoms later in the course of their therapy are at greatest risk for persistent symptoms. This has implications for studies evaluating interventions for prevention of AI arthralgias. BPI mean scorePatients with &amp;gt;2 point increase in BPI at any timePatients with &amp;gt;2 point increase in BPI at 3 monthsPatients with &amp;gt;2 point increase in BPI at 6 monthsPatients with &amp;gt;2 point increase in BPI at 9 monthsPatients with &amp;gt;2 point increase in BPI at 12 monthsBaseline score3.752.57*2.592.302.11*1.85*Three month score4.254.526.08*4.684.133.87Six month score4.504.83*5.32*6.37*5.074.22Nine month score4.005.105.115.135.75*5.04Twelve month score4.255.37*5.484.865.666.21**p value &amp;lt;0.05 compared to baseline Citation Format: Lea Baer, Katherine D Crew, Danielle Awad, Kevin Kalinsky, Matt Maurer, Dawn L Hershman. Baseline joint pain predicts severity of subsequent joint symptoms in women initiating aromatase inhibitors for early stage 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 P5-15-03.

Abstract A146: Preclinical models relevant to the treatment of post-menopausal breast cancer.

Abstract The past decades have witnessed immense progress in the treatment of hormone-sensitive breast cancer. However, despite the success of agents targeting estrogen activity, a significant proportion of patients will experience relapse due to endocrine therapy resistance. In order to better understand the underlying causes and enable successful targeting of implicated pathways, preclinical models that recapitulate the post-menopausal setting are essential. To this end, we have developed a panel of estrogen receptor (ER+) models with varying senstivity to endocrine therapies. Our panel includes models of long-term estrogen-deprivation (LTED), a surrogate for longterm exposure and relapse on aromatase inhibitors. Using both xenograft (MCF7LTED, HCC1428LTED) and primary tumor models (BR0555fLTED and CTC-174LTED), we have utilized them to benchmark standard of care treatments and test the efficacy of novel agents. Importantly, we demonstrate that these models closely mimick the post-menopausal hormonal millieu found in patients and recapitulate pharmacodynamic responses observed in the clinic. As such, these are instrumental tools to uncovering endocrine resistance mechanisms and provide a potentially predictive platform for clinical efficacy. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A146. Citation Format: Ermira Pazolli, Anne Marie Mazzola, Jon Curwen, Hazel Weir, Casey Kiessel, Michael Grondine, Celina D'Cruz, Mike Zinda. Preclinical models relevant to the treatment of post-menopausal breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A146.

Abstract P2-12-01: Prospective Evaluation of Joint Symptoms in Postmenopausal Women Initiating Aromatase Inhibitors for Early Stage Breast Cancer

Abstract Background: Aromatase inhibitors (AIs) are widely prescribed to postmenopausal women for the adjuvant treatment of hormone-sensitive breast cancer (BC). However, musculoskeletal complaints can lead to nonadherence and early discontinuation. The aim of this study was to characterize the natural history of the AI-induced arthralgia syndrome and determine predictors of worsening symptoms. Methods: Postmenopausal women with stage I-III BC initiating adjuvant AI therapy were enrolled. All patients completed the following questionnaires at baseline and every 3 months for a year: Modified Brief Pain Inventory-Short Form (BPI-SF), Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index and the Modified Assessment of Chronic Rheumatoid Affections of the Hands (M-SACRAH). Higher scores reflect worse symptoms. Quality of life was assessed using the Functional Assessment of Cancer Therapy-Endocrine Subscale (FACT-ES). Hand grip strength was measured at each visit with a Martin dynamometer. Paired t-tests were performed to compare follow-up evaluations to baseline. Linear Regression was performed to evaluate the association between baseline symptoms and change in symptoms. Results: A total of 169 patients have been consented, 3-month data is available on 102; 6-month data on 85. Median age: 63 (42–89); White/Black/Asian/Hispanic: 61.48/30.33/3.28/25.6; median BMI (kg/m2): 28 (12–50). Compared to baseline, there was a statistically significant increase in BPI pain severity and endocrine related symptoms on the FACT-ES at 3 and 6 months. Significant changes in the BPI pain interference, M-SACRAH pain and stiffness, WOMAC function, physical well-being on the FACT-ES, trial outcome index and pinch grip strength were seen at 3 months; however these changes did not remain significant at 6 months. Logistic regression models evaluating predictors of patient reported outcome measures and grip strength were performed. Baseline score was the strongest predictor of worsening symptoms (p &amp;lt; 0.01) after correcting for age, prior chemotherapy and baseline joint conditions. Conclusions: Treatment with adjuvant AI therapy is associated with significant worsening of joint pain and stiffness which is most prominent at the 3 months evaluation. Patients with baseline joint symptoms are at greatest risk for worsening symptoms on AIs. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-12-01.

OT2-07-02: SWOG S0927: A Randomized Double Blind Placebo-Controlled Trial of Omega-3-Fatty Acid for the Control of Aromatase Inhibitor (AI)-Induced Musculoskeletal Pain in Women with Early Stage Breast Cancer.

Abstract Background: Despite the well-proven efficacy of aromatase inhibitors(AIs) for the treatment of hormone-sensitive breast cancer, a significant number of women suffer from musculoskeletal side-effects which can result in early discontinuation of this important medication. Given the proposed anti-inflammatory effects of omega-3-fatty acid and the paucity of therapeutic options for AI-induced arthralgia, it is therefore reasonable to test the efficacy of omega-3-fatty acid in women with breast cancer who have developed moderate to severe joint symptoms after initiating AIs. Specific aims: To assess if omega-3-fatty acid as compared to placebo causes a reduction in worst joint pain/stiffness in women with AI-associated arthralgias at 12weeks as measured by the modified Brief Pain Inventory (BPI). Additional measures will include the WOMAC, M-SACRAH, FACT-ES and global rating of change, which will be assessed at baseline, 6, 12 and 24 weeks. We will evaluate fasting lipids, hormone levels, serum inflammatory markers (TNF, IL2, CRP), and markers of joint destruction (CTX-II) at baseline, 12 and 24 weeks. Eligibility criteria:Pts. must have histologically-confirmed stages I-III breast cancer, with no evidence of metastatic disease and undergone definitive breast cancer surgery. Pts must be post-menopausal and currently be taking a third-generation AI —anastrazole(Arimidex®), letrozole (Femara®), or exemestane (Aromasin®) for at least the previous 90 days prior to registration with plans to continue for at least an additional 180 days after registration.The patient must have a worse joint pain/stiffness score of 5 or greater on the 10-point scale of the BPI which started or increased after initiation of AI. Pts must not have taken omega-3-fatty acid supplements within the past 3 months prior to registration.Pts will be randomized to receive 6 capsules daily (at 1,000 mg each; ∼600mg combination of ethyl esters EPA/DHA) of omega-3-fattyacid or matching placebo daily for 24 weeks. Statistical methods:We stipulate an alpha=.05 two-sided test, with an estimated 5% non-adherenceand 20% dropout rate at the primary endpoint evaluation time of 12 weeks after randomization. For a two point difference in worst joint pain/stiffness and a 3.5 point SD at 12 weeks, 222 eligible patients would be required for 90% power under a two-arm normal design. To allow ineligibility rate of 10%, 246 total pts will be enrolled. The study should be activated September 2011. Funding: Supported by National Cancer Institute grant CA037429 Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT2-07-02.

Insight into the Enzyme-Inhibitor Interactions of the First Experimentally Determined Human Aromatase

Aromatase is an important pharmacological target in the anti-cancer therapy as the intratumoral aromatase is the source of local estrogen production in breast cancer tissues. Suppression of estrogen biosynthesis by aromatase inhibition represents an effective approach for the treatment of hormone-sensitive breast cancer. Because of the membrane-bound character and heme-binding instability, no crystal structure of aromatase was reported for a long time, until recently when crystal structure of human placental aromatase cytochrome P450 in complex with androstenedione was deposited in PDB. The present study is towards understanding the structural and functional characteristics of aromatase to address unsolved mysteries about this enzyme and elucidate the exact mode of binding of aromatase inhibitors. We have performed molecular docking simulation with twelve different inhibitors (ligands), which includes four FDA approved drugs; two flavonoids; three herbal compounds and three compounds having biphenyl motif with known IC50 values into the active site of the human aromatase enzyme. All ligands showed favorable interactions and most of them seemed to interact to hydrophobic amino acids Ile133, Phe134, Phe221, Trp224, Ala306, Val370, Val373, Met374 and Leu477 and hydrophilic Arg115 and neutral Thr310 residues. The elucidation of the actual structure-function relationship of aromatase and the exact binding mode described in this study will be of significant interest as its inhibitors have shown great promise in fighting breast cancer.

Tamoxifen Induces Triacylglycerol Accumulation in the Mouse Liver by Activation of Fatty Acid Synthesis

Tamoxifen is an anti-estrogen drug widely used for the treatment of hormone-sensitive breast cancer. Approximately 43% of breast cancer patients treated with tamoxifen develop hepatic steatosis. The mechanism or mechanisms by which tamoxifen may induce lipid accumulation in the liver are unclear. Mice were injected with tamoxifen or vehicle (sesame oil containing 1% benzyl alcohol) for 5 consecutive days. In comparison with the vehicle, tamoxifen increased hepatic triacylglycerol levels by 72%. The levels of plasma triacylglycerol were similar between the tamoxifen-treated and control groups. We found increased radiolabeling of triacylglycerol and phospholipids from [(3)H]acetate (∼50%) but not [(14)C]oleate in hepatocytes from tamoxifen-treated mice versus control mice. Fatty acid uptake, triacylglycerol secretion, and fatty acid oxidation remained unchanged in isolated hepatocytes after tamoxifen treatment. The apparent increase in fatty acid synthesis was explained by a marked decrease in the phosphorylation of acetyl coenzyme A carboxylase, which resulted in its activation. Our data suggest that increased de novo fatty acid synthesis is the primary event leading to tamoxifen-induced steatosis in the mouse liver. Inhibition of fatty acid synthesis might, therefore, ameliorate steatosis/steatohepatitis in breast cancer patients treated with tamoxifen.

Does Adjuvant Antiestrogen Therapy Affect Cognitive Function in Women with Hormone-Sensitive Breast Cancer?

Adjuvant endocrine therapy with tamoxifen or aromatase inhibitors (AIs) is widely prescribed after initial treatment for hormone-sensitive breast cancer — but we know little about the effects of such antiestrogen therapy on cognitive function. Researchers performed neuropsychological assessments in 179 postmenopausal Dutch women (mean age, 68) with estrogen- or progesterone-receptor–positive breast cancer who were enrolled in an international …

Zoledronic Acid Once-yearly: What Role in the Prevention of Non-vertebral Osteoporotic Fractures?

Osteoporosis is the most common bone disease. Low levels of oestrogens or testosterone are risk factors for primary osteoporosis. The most common cause of secondary osteoporosis is glucocorticoid treatment, but there are many other secondary causes of osteoporosis. Osteoporosis can be secondary to anti-oestrogen treatment for hormone-sensitive breast cancer and to androgen-deprivation therapy for prostate cancer. Zoledronic acid is the most potent bisphosphonate at inhibiting bone resorption. In osteoporosis, zoledronic acid increases bone mineral density for at least a year after a single intravenous administration. The efficacy and safety of extended release (once-yearly) zoledronic acid in the treatment of osteoporosis is reviewed.

Adding Zoledronic Acid to Endocrine Therapy in the Adjuvant Treatment of Hormone-Sensitive Breast Cancer in Premenopausal Women: A New Care Standard or a Provocative Idea?

The optimum adjuvant treatment of hormone receptorpositive breast cancer in premenopausal women has been the subject of controversy between American and European physicians for some time. In many European countries, the standard of care consists of ovarian suppression alone or in addition to tamoxifen therapy. The use of chemotherapy, although considered the standard by most American oncologists, is not considered by many European oncologists. Although there seems to be little question that ovarian suppression, with or without tamoxifen, is therapeutically equivalent to chemotherapy alone, the equivalence of ovarian suppression plus tamoxifen to chemotherapy plus tamoxifen remains a persistent, unanswered research question. In this setting, if one assumes that ovarian suppression plus hormonal therapy is an acceptable form of treatment, two issues come to mind. First, if aromatase inhibitors are superior to tamoxifen in reducing the risk of recurrence of breast cancer in postmenopausal women, will the same superiority translate into a premenopausal age group who are rendered menopausal through ovarian suppression? Second, will the addition of zoledronic acid to the treatment regimen also reduce the risk of recurrence? Zoledronic acid, although used primarily in medical oncology to reduce morbidity from skeletal-related events in patients with established bone metastases from breast cancer, is believed, based on preclinical data, to have inherent antitumor properties that may render it useful in the treatment of early-stage breast cancer.