Efficacy Of Aromatase Inhibitors Research Articles

Factors that impact aromatase inhibitor adherence in early-stage hormone receptor positive breast cancer.

e12524 Background: Despite efficacy of aromatase inhibitors (AI) in improving survival for patients with hormone receptor positive (HR+) breast cancer, adherence to AI remains suboptimal. The aim of this study is to evaluate factors that may affect patient adherence to first-line AI. Methods: We retrospectively reviewed records of 195 female patients with HR+, HER2 negative early-stage breast cancer who were started on first-line adjuvant AI between 2011-2020 at our academic institution. We collected information on recurrence risk (defined by Oncotype score, with low risk ≤ 15, moderate risk 16-25, high risk ≥ 26), AI-related side effects, supportive therapy use for side effects, and socioeconomic demographics (i.e. income, insurance type, and race). We linked median family income with zip codes based on national census data and sorted them based on the Pew Research Center categorization. The primary end point was the rate of first-line AI adherence at 4 years. The Kruskal-Wallis rank sum test, Fisher’s exact test, and Pearson’s chi-squared test were used to compare AI adherence when varying patient profiles. Results: In our cohort, 50% (n=98) were adherent to first-line AI at 4 years, 9% (n=17) were still taking first-line AI but have not yet reached 4 years, and 41% (n=80) discontinued first-line AI early. Of those who discontinued first-line AI early, 68% (n=54) switched to an alternate endocrine treatment due to side effects, 4% (n=3) stopped all endocrine treatment, and 28% (n=23) were lost to follow up. AI-related side effects were common; 83% (n=162) reported AI-related side effects, yet only 27% of those patients received supportive therapy. Supportive therapy use was not significantly different when varying patients’ recurrence risk and socioeconomic demographics. In addition, adherence did not differ based on side effect frequency or supportive therapy use. The population’s Oncotypes included 36% (n=70) low risk, 36% (n=70) moderate risk and 12% (n=24) high risk; the remaining had no Oncotype sent. There was no significant difference in adherence among the risk groups. In evaluating demographics, the cohort’s median age was 62 and it included 9% Asian, 13% Black, 5% Hispanic, 54% White, and 19% Other/Unknown. The majority (62%) of patients were of middle income ($52,000-145,000), followed by 29% in upper and 9% in lower income. The minority (22%) of patients were on Medicaid. Those with a lower discontinuation rate were older (64 vs. 61, p=0.019), while there was no significant difference based on race, income, or insurance. Conclusions: Despite the small sample, it is reassuring that at our institution, long term adherence to first-line AI and supportive therapy use did not vary among socioeconomic demographics. However, a gap persists between the prevalence of AI-related side effects and usage of proven supportive treatments. Further study on strategies to enhance AI tolerance and adherence is needed.

Implications and Efficacy of Aromatase Inhibitors in Combination and Monotherapy for the Treatment of Lung Cancer.

Lung tumors express high levels of aromatase enzyme compared to surrounding normal tissue. Inhibition of aromatase has emerged as a recent therapeutic approach for the treatment of breast cancer. However, the role of aromatase inhibition in lung cancer treatment requires further investigation. The anti-proliferative effects of aromatase inhibitors were evaluated by MTT assay. Cell migration was assessed using a wound healing assay. The mechanism of cell death was determined using the annexin VFITC/ propidium iodide staining flow cytometry method. The soft agar colony formation assay evaluated cells' capability to form colonies. Exemestane and curcumin significantly inhibited the growth of lung cancer cell lines in a dose- and timedependent manner. The IC50 values after 48 hours of treatment with exemestane were 176, 180, and 120 μM in A549, H661, and H1299, respectively. Curcumin IC50 values after 48 hours were 80, 43, and 68 μM in A549, H661, and H1299, respectively. The combined treatment of exemestane or curcumin with cisplatin, raloxifene, and celecoxib resulted in a synergistic effect in the A549 lung cell line with a combination index of less than 1, suggesting synergism. Exemestane resulted in approximately 96% inhibition of wound closure at 100 μM, while curcumin resulted in approximately 63% inhibition of wound closure at 50 μM. Exemestane and curcumin inhibited the formation of cell colonies by reducing the number and size of formed colonies of A549, H661, and H1299 cell lines in a concentration dependent manner. Exemestane and curcumin had significantly induced apoptosis in A549 cells compared to control of untreated cells. Aromatase inhibition by exemestane or curcumin had significantly inhibited the growth of lung cancer cell lines, synergized with cisplatin, raloxifene, and celecoxib, suppressed lung cancer cell migratory potential, induced apoptosis, and reduced colony formation of lung cancer cells.

Effect of progesterone receptor status on efficacy of aromatase inhibitors and survival time in patients with advanced breast cancer

To investigate the effect of progesterone receptor (PR) on the efficacy of first-line aromatase inhibitor (AI) endocrine therapy and progression-free survival (PFS) in patients with estrogen receptor (ER) positive HER-2 negative advanced breast cancer. The clinical data of 198 patients with advanced breast cancer treated in Henan Cancer Hospital from January 2014 to October 2019 were collected. The Chi-square test was used to compare the difference between the two groups, and the Cox regression model was used to analyze the related prognostic factors. The median progression-free survival time ((PFS)) of PR+and PR- patients were 12.5 months and 9.0 months, respectively, and the difference was statistically significant (P=0.004). The clinical benefit rate (CBR) was 81.1% and 63.1%, respectively, and the difference was not statistically significant (P<0.001). PR is an independent prognostic factor of first-line AI endocrine therapy in ER-positive HER-2-negative patients. PR+type breast cancer has a better response to first-line AI endocrine therapy and longer PFS time than PR- type advanced breast cancer.

Abstract P1-17-06: Impact of body mass index on the efficacy of aromatase inhibitors in patients with metastatic breast cancer

Abstract Background: Aromatase inhibitors (AIs) are part of standard endocrine therapy for hormone receptor (HR)-positive breast cancer (BC) and are used in both adjuvant and metastatic settings. Since AIs work by inhibiting the conversion of androgens to estrogen in peripheral adipose tissue, the higher levels of estrogen in obese patients may lead to incomplete inhibition by AIs and influence their efficacy. A retrospective analysis of the ABCSG-12 trial found that overweight premenopausal patients with early-stage BC treated with anastrozole had a 60% increased risk of disease recurrence and more than doubling in risk of death compared with normal weight patients on anastrozole. Similarly, an exploratory analysis from the ATAC trial found that in post-menopausal women with early-stage BC, overall recurrence rates were lower in patients randomized to anastrozole versus tamoxifen but in women with body mass index (BMI) &amp;gt; 30, there was no significant difference in disease recurrence between anastrozole and tamoxifen. While these findings raise concern for the efficacy of adjuvant AI therapy in obese patients with early-stage BC, this has not yet been demonstrated in the metastatic setting. The aim of this study was to determine the impact of BMI on efficacy of AIs in patients with metastatic HR-positive BC. Methods: We performed a retrospective chart review of all female patients with metastatic HR-positive BC on an AI in first- or second-line settings and seen at our academic institution between 2001-2020. The primary endpoint was progression-free survival (PFS), defined as the time from start of AI to disease progression or death from any cause. PFS was compared across BMI groups using Kaplan-Meier curves and log-rank tests. Cox proportional hazards regression model was used for univariate and multivariate analyses. Results: We identified 219 patients who had received an AI in the first- or second-line settings for metastatic HR-positive BC and with documented information on BMI. The median age was 59 with 45% of patients White, 29% African American, 16% Hispanic/Latino, 5.5% Asian and remainder other/unknown. 32% (71) had HER-2 positive disease. 82% (179) were on an AI in the first-line setting. Overall, 53% were on letrozole, 42% on anastrozole and 5.5% on exemestane. Of the 219 patients, 56% (123) had a low BMI (defined as &amp;lt; 27 kg/m2) and 44% (96) had a high BMI (≥ 27 kg/m2; based on the Breast Cancer Weight Loss [BWEL] trial). The median PFS was 21.9 months (95% CI, 14.5 to 28.4) in the low BMI group versus 20.2 months (95% CI, 14.3 to 27.5) in the high BMI group with no statistically significant difference (p =0.73). There were 8 (6.5%) deaths in the low BMI group and 7 (7.3%) deaths in the high BMI group. Multivariate cox regression model did not demonstrate any significant impact of BMI on PFS when adjusting for age, race/ethnicity, HER2 status, type of AI, line of therapy, drug partner and type of metastatic disease (HR =0.91, 95% CI =0.64 to 1.30, p =0.6 for high BMI group). Subgroup analysis of patients on an AI in the first line setting also did not show a significant difference in PFS with median PFS 19.3 and 18 months in the low and high BMI groups, respectively. Conclusions: In patients on an AI for metastatic HR-positive breast cancer, there was no statistically significant difference in PFS in patients with low versus high BMI. While BMI influences efficacy of AIs in the adjuvant setting, our results demonstrate that in the metastatic setting, BMI does not significantly impact the efficacy of AIs among our patient population. This discrepancy could be due to other differences in disease characteristics that make complete aromatase inhibition more important in the adjuvant setting when disease burden is the lowest. Additional larger studies are needed to confirm this finding. Citation Format: Rima Patel, Zhiqiang Li, Brittney S. Zimmerman, Marc Y. Fink, Jason D. Wells, Xiang Zhou, Kristin L. Ayers, Arielle Redfern, Scott Newman, Rong Chen, William K. Oh, Amy Tiersten. Impact of body mass index on the efficacy of aromatase inhibitors in patients with metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-17-06.

Impact of body mass index on the efficacy of aromatase inhibitors in patients with metastatic breast cancer.

Higher levels of estrogen in obese patients may lead to incomplete inhibition by aromatase inhibitors (AIs). The aim of this study was to determine the impact of body mass index (BMI) on efficacy of AIs in patients with metastatic hormone receptor (HR)-positive breast cancer (BC). We performed a retrospective chart review of all female patients with metastatic HR-positive BC on an AI in first- or second-line settings and seen at our academic institution between 2001 and 2020. The primary endpoint was progression-free survival (PFS), defined as the time from start of AI to disease progression or death from any cause. We identified 219 patients who had received an AI in the first- or second-line settings for metastatic HR-positive BC and with documented information on BMI. Of the 219 patients, 56% (123) had a low BMI (defined as < 27kg/m2) and 44% (96) had a high BMI (≥ 27kg/m2). The median PFS was 21.9months (95% CI 14.5 to 28.4) in the low BMI group versus 20.2months (95% CI 14.3 to 27.5) in the high BMI group (p = 0.73). While BMI influences efficacy of AIs in the adjuvant setting, our results suggest that in the metastatic setting, BMI may not impact the efficacy of AIs. This discrepancy could be due to other differences in disease characteristics that make complete aromatase inhibition more important in the adjuvant setting when disease burden is the lowest.

Predictive role of HER2-status on the effectiveness of endocrine adjuvant treatment in postmenopausal breast cancer patients: a population-based cohort study

PurposeThere are conflicting results on the potential role of HER2-status on the efficacy of aromatase inhibitors (AIs) and tamoxifen (TAM) in patients with hormone receptor (HR)-positive breast cancer (BC). The purpose of this population-based cohort study was to investigate the potential benefit of AIs compared to TAM as adjuvant therapy in postmenopausal BC patients by HER2-status in the era of modern therapy with HER2-blockade.MethodsA population-based cohort study was performed including all postmenopausal women diagnosed with HR-positive BC without distant metastasis between 2007 and 2012 in three healthcare regions in Sweden. We analyzed the breast cancer-specific survival (BCSS) and overall survival (OS) in two distinct cohorts (HER2-negative, HER2-positive) based on the type of endocrine therapy (ET) used. A propensity score matching was performed separately in the HER2-negative and HER2-positive cohorts, respectively.ResultsAfter propensity score matching, 4368 patients with HER2-negative and 214 patients with HER2-positive BC were available for analysis. In the HER2-negative cohort, an improved BCSS [Hazard Ratio (HR): 0.51; 95% confidence interval (CI): 0.34–0.77, p value < 0.001] and a trend toward improved OS (HR: 0.66; 95% CI: 0.41–1.08, p value = 0.093) in favor of AI-based therapy was observed. In the HER2-positive cohort, no statistically significant difference between AI-based ET and TAM was found in terms of either BCSS or OS, although the direction of HR was similar as in the HER2-negative cohort (HR for BCSS: 0.84; 95% CI: 0.14–5.04, p = 0.849; HR for OS: 0.62; 95% CI: 0.10–3.38, p = 0.345).ConclusionOur study results, based on propensity-matched cohorts, did not support any predictive value of HER2-status on endocrine therapy in postmenopausal BC patients. AI-based ET remains the treatment of choice for postmenopausal BC patients with HR-positive disease in the modern era of HER2-directed therapy irrespective of HER2-status.

Use of androgens and aromatase inhibitors in poor responders undergoing in vitro fertilization

Hypothesis/aims of study. Poor ovarian response is still considered one of the most challenging tasks in reproductive medicine. Poor responders have decreased circulating androgens during spontaneous cycles. Androgens are known to play an important role in follicular growth and development. Hence, the use of various androgens and androgen inhibitors in poor responders undergoing ovarian stimulation for IVF has been proposed to improve efficacy of treatment. This study was aimed to examine the efficacy of aromatase inhibitors and androgens in infertility treatment in patients with poor response.&#x0D; Study design, materials and methods. This prospective cohort-controlled clinical trial included 204 patients under 42 years of age with infertility and poor response to ovarian stimulation. In vitro fertilization treatment with an antagonist FSH/hMG protocol with letrozole (5 mg/day) was administered in the first group of patients (n = 26) during the first 5 days of stimulation. Patients of the second group (n = 38) were applied testosterone (25 mg/day) transdermally, starting from the 5th day of the menstrual cycle preceding controlled ovarian stimulation for in vitro fertilization. The third group of patients (n = 18) was administered dehydroepiandrosterone (100 mg/day) for 3 months prior to controlled ovarian stimulation for in vitro fertilization.&#x0D; Results. Improved response to FSH stimulation with letrozole co-treatment was evidenced, with parameters of stimulation efficacy and embryo development being better in the testosterone group. No significant improvement in ovarian response markers, ovarian response to gonadotrophin stimulation and in vitro fertilization outcomes were found in poor responders receiving pre-treatment dehydroepiandrosterone.&#x0D; Conclusion. Further studies are necessary to improve approaches of testosterone and aromatase inhibitors use in poor responders undergoing in vitro fertilization.

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.

Aromatase inhibitor therapy for endometrial stromal sarcoma - two-centre experience.

Endocrine therapy is the recommended systemic treatment for steroid receptor positive endometrial stromal sarcoma (ESS). There is no current consensus on the optimal hormonal therapy for ESS. The literature offers several reports on advanced/recurrent/metastatic ESS patients treated with progestins, whereas data on the efficacy of aromatase inhibitors are scarce. We retrospectively identified cases treated for ESS with aromatase inhibitors at our institutions. There were five patients with advanced or unresectable recurrent estrogen, progesterone and androgen receptor-positive ESS, treated with aromatase inhibitors: letrozole or anastrozole (at a daily dose of 2.5 mg and 1 mg, respectively), as first-line endocrine therapy in all but one case treated following progression with megestrol acetate. Disease stabilization was achieved in four cases (80%), including two with long-term progression-free survival for up to 10 years attained under letrozole treatment, and one case after prior progestin treatment. During therapy, no substantial toxicity was observed. Aromatase inhibitors as first- or second-line endocrine treatment achieve disease control in most steroid receptor positive ESS. Our series of cases is evidence of aromatase inhibitors efficacy as long-term endocrine treatment option for ESS patients.

A Comparison of Efficacy Of Aromatase Inhibitors (Letrozole), Clomiphene Citrate And Recombinant F.S.H In Induction Of Ovulation In Polycystic Overian Syndrome

Background: Polycystic ovarian syndrome is also called hyper-androgenic anovulation syndrome.It is a set of symptoms due to elevated male hormone in women. The major features of PCOS include menstrual dysfunction, anovulation and signs of hyperandrogens Other signs and symptoms of PCOS include hirsutism, infertility, obesity, metabolic syndrome, diabetes and obstructive sleep apnea. On examination, finding in women with PCOS may include virilizing signs, acanthosis nigricans, hypertension and enlarged ovaries (may or may not present).Ovulation induction in women with PCOS suffering from anovulatory infertility includes the use of antioestrogen, insulin sensitisers, aromatase inhibitors (Letrozole), gonadotropin (FSH) and surgical treatment. Objective: The present study aimed at comparing between the efficacy of aromatase inhibitors(letrizole), clomiphene citrate and recombinant (FSH) on induction of ovulation in polycystic ovarian syndrome. Patients and Methods: the present study was conducted on 150 patients with polycystic ovarian syndrome according to the Rotterdam criteria for polycystic ovarian syndrome with history of menstrual disturbance and whose age ranged between 18-37 years. In the current study, patients were allocated into 3 equal groups: group A (Clomiphene citrate), group B (Letrizole) and group C (Recombinant FSH). Results: Clomiphene citrate, letrizole and recombinant (FSH)were the common to be used for induction of ovulation in polycystic ovarian syndrome.In our study we proved that recombinant (FSH) is the most effective of these drugs,followed by letrizole and the least is clomiphene citrate. Conclusion: PCOS is a major cause of infertility in women.Medical treatment (induction of ovulation) is one of the major methods of management of PCOS. Recombinant (FSH) has the higest efficacy in our study.

A Comparison of Efficacy Of Aromatase Inhibitors (Letrozole), Clomiphene Citrate And Recombinant F.S.H In Induction Of Ovulation In Polycystic Overian Syndrome

Background: Polycystic ovarian syndrome is also called hyper-androgenic anovulation syndrome.It is a set of symptoms due to elevated male hormone in women. The major features of PCOS include menstrual dysfunction, anovulation and signs of hyperandrogens Other signs and symptoms of PCOS include hirsutism, infertility, obesity, metabolic syndrome, diabetes and obstructive sleep apnea. On examination, finding in women with PCOS may include virilizing signs, acanthosis nigricans, hypertension and enlarged ovaries (may or may not present).Ovulation induction in women with PCOS suffering from anovulatory infertility includes the use of antioestrogen, insulin sensitisers, aromatase inhibitors (Letrozole), gonadotropin (FSH) and surgical treatment. Objective: The present study aimed at comparing between the efficacy of aromatase inhibitors(letrizole), clomiphene citrate and recombinant (FSH) on induction of ovulation in polycystic ovarian syndrome. Patients and Methods: the present study was conducted on 150 patients with polycystic ovarian syndrome according to the Rotterdam criteria for polycystic ovarian syndrome with history of menstrual disturbance and whose age ranged between 18-37 years. In the current study, patients were allocated into 3 equal groups: group A (Clomiphene citrate), group B (Letrizole) and group C (Recombinant FSH). Results: Clomiphene citrate, letrizole and recombinant (FSH)were the common to be used for induction of ovulation in polycystic ovarian syndrome.In our study we proved that recombinant (FSH) is the most effective of these drugs,followed by letrizole and the least is clomiphene citrate. Conclusion: PCOS is a major cause of infertility in women.Medical treatment (induction of ovulation) is one of the major methods of management of PCOS. Recombinant (FSH) has the higest efficacy in our study.

Abstract OT3-06-06: A phase I/II study of preoperative letrozole, everolimus, and TRC105 in women with newly diagnosed local or locally advanced potentially resectable hormone-Receptor positive and Her2 negative breast cancer

Abstract Hypothesis: Pharmacologic inhibition of angiogenesis and mTOR pathway blockade will enhance the efficacy of aromatase inhibitors in the neoadjuvant setting in women with hormone receptor-positive and Her2-negative (HR+/Her2-) breast cancer. Background: In non-metastatic HR+/Her2- breast cancer, downstaging to stage I or 0 in the neoadjuvant setting has been associated with favorable prognosis. With chemotherapy yielding similar benefits with endocrine therapy, aromatase inhibitors have become the agents of choice in postmenopausal women. The elucidation of pathways that are operational in luminal breast cancer and compromise the efficacy of hormonal therapy along with preclinical and clinical evidence of successful combinations of endocrine therapy with targeted agents set the stage for more rational, effective, and equally well tolerated regimens. Proangiogenic signaling has been strongly associated with accelerated hormone-independent growth and resistance to endocrine therapies. Breast cancer cells with upregulated PI3K/AKT/mTOR pathway are resistant to hormonal therapy and this resistance has been restored by everolimus. Inhibiting mTOR, a downstream signaling node where multiple pathways converge has the potential to abrogate primary and escape signaling cascades that mediate resistance to endocrine therapies. Study Design: Phase I dose escalation: follows a 3+3 design. During the phase I, the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) will be determined. Letrozole will be kept the same for all cohorts (2.5 mg PO qd). Everolimus will be escalated from 5 mg (cohort 1) to 10 mg PO qd (cohort 2). TRC105 will be 15 mg/kg q2 weeks (cohorts 1 and 2). Premenopausal women at the time of enrollment will receive goserelin 3.6 mg SC q4 weeks to achieve ovarian suppression. Duration of treatment is 24 weeks. Phase II dose expansion: will be initiated once the MTD and RP2D have been determined. Phase II follows a Gehan's two-stage design: 10 patients will enroll first, and if no patient has achieved downstaging, the study will close since it is unlikely (p=0.1) that 0/10 responses would occur if true response rate were &amp;gt;20%. If at least one patient has downstaging, 10 additional patients will enroll (total, 20). Primary Objectives Phase I: Determine the tolerability and feasibility of letrozole, everolimus, and TRC105 in women with newly diagnosed stage 2 and 3 HR+/Her2- breast cancer. Phase II: in the same patient population determine the efficacy, pharmacokinetic, and pharmacodynamic parameters of the combination. Correlative Studies: Immunohistochemistry for pAKT and PTEN, CD105, CD31/CD34, NG2, MCAM/CD146 on diagnostic tissue, research biopsy, and final surgical specimen. Surgical specimens that meet criteria for next-generation sequencing will undergo ribosome profiling Key Eligibility Criteria: Recent diagnosis of HR+Her2- breast cancer Stage 2 and 3 breast cancer Any histological grade No prior treatment specific for breast cancer Pre- and perimenopausal women are eligible if ovarian suppression is achieved with goserelin. Current Status: Cohort 1 of the Phase 1 complete. Cohort 2 of Phase 1 actively enrolling. Citation Format: Vaklavas C, Lamaster KV, Stringer EM, Falkson CI, Li Y, Forero A. A phase I/II study of preoperative letrozole, everolimus, and TRC105 in women with newly diagnosed local or locally advanced potentially resectable hormone-Receptor positive and Her2 negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-06-06.

Role of Aromatase Inhibitor in Endometriosis

Endometriosis is a chronic estrogen-dependent inflammatory disease which caused substantial impact on the quality of life in women of childbearing age and in some postmenopausal women. Surgical intervention is available but the high recurrence rate after surgery leads to extensive study on medical treatment in treating endometriosis. Currently there are various medical treatments available such as combined oral contraceptive agents, progestins and gonadotrophin-releasing hormone (GnRH) agonists. However, these medical therapies only alleviate the symptoms of endometriosis to certain extent without curing the disease. In recent years, aromatase inhibitors emerged in clinical use due to its ability to suppress aromatase which in turn reduced the production of estrogen. Several studies have been done focusing on the efficacy of aromatase inhibitor in controlling the pain symptoms and endometriosis-associated infertility. This new group of drug has also shown efficacy in symptomatic relief in postmenopausal endometriosis. Aromatase inhibitors showed comparable efficacy with other medical therapeutic modalities with a slight edge in providing both symptomatic relief and fertility treatment in endometriosis. The adverse effects of bone density might be of concern however combination with Vitamin D and calcium supplements can make the long term therapy of this drug seem possible.

Abstract P5-14-06: Lapatinib reverses endocrine resistance in select patients with HER2 negative, hormone positive metastatic breast cancer

Abstract Introduction: A significant proportion of breast cancer (BC) patients show primary or acquired resistance to endocrine therapy (ET). The cross-talk between estrogen receptor and other growth factor receptor (GFR) families is suggested to play a crucial role in the development of endocrine resistance and dual targeting of these pathways can potentially reverse endocrine resistance. Lapatinib (Lap) is an oral, dual inhibitor of EGFR/HER2 and preclinical studies have demonstrated combination of Lap and ET to be effective in setting of endocrine resistance. Aims: 1) To evaluate if Lap can restore efficacy of aromatase inhibitor (AI) or fulvestrant(F) in metastatic BC, 2) Study blood/tissue response biomarkers. Methods: Eligible patients with HER2 negative (IHC and FISH) hormone positive metastatic BC who had progression of disease while on AI or Fulvestrant (+/-AI), or developed metastatic disease on adjuvant AI were enrolled on an IRB approved phase II study. Study treatment included continuation of same dose and schedule ET on which last progression was noted with the addition of Lapatinib 1500 mg PO/QD. Patients could have unlimited prior ET. The study end points included clinical benefit rate (CBR) at 16wks (CBR16), CBR at 24 wks (CBR24) and PFS. Correlative studies included blood markers (HER2/ECD, CTC, CTC HER2 phenotyping) and tumor next generation sequencing (NGS) (315 cancer-related genes, Foundation Medicine, Inc). Results: Between 2009 and 2014, thirty-two patients were enrolled. Median age: 61.5 yrs, median number of prior endocrine regimens: 2 (range 1-4), 72% had visceral disease, 28% had bone only disease, 67% were considered to be responsive to the last ET. For 28 patients evaluable for efficacy the ET was AI =29%, F= 32%, AI+F=39%. The CBR16 was 25% (7/28) and the CBR24 was 14%(4/28). Median PFS for the entire cohort was 2.1 mths and the median PFS for patients with CB at 16 weeks was 7.4 mths. 12% of patients had Grade 3/4 AE (Diarrhea: 6%, Vomiting: 6%, Rash: 3%). Serum HER2/ECD was elevated in 43%, &amp;gt;1 CTC detected in 57%, HER2 positive CTC noted in 18%. HER2/ECD and HER2 positive CTC did not correlate with CBR16. Tumor NGS done on partial sample set (n=7, patients without early progression) demonstrate PI3K pathway activating mutations in 55% (4/7) of patients (PIK3CA mutations=3, AKT3 amplification &amp; PTEN homozygous deletion=1). No ESR1 alterations were observed. All 4 patients with PIK3CA pathway mutations demonstrate CB at 16 wks, and 3/4 demonstrate CB at 24 wks. Conclusion: Addition of Lap restored sensitivity to ET (AI/Fulvestrant) in 25% of patients with HER 2 negative BC. Response was independent of HER 2 positive CTC and HER2/ECD levels. Genomic profiling suggests a relationship between PIK3CA mutation and benefit from this approach. NGS of the entire study cohort is in process and will be reported. HER2-negative breast cancers harboring PIK3CA mutations may rely more on GFR/PI3K signaling than on estrogen for growth; thus, blocking GFR signaling with lap might restore hormonal sensitivity. A randomized study of lap + ET in selected patients with HER2 negative BC is warranted and biomarker results from this study may help identify subgroups that should be targeted in a larger study. Citation Format: Sharma P, Kimler BF, Ward C, Wang K, Ali S, Balasubramanian S, O'Dea AP, Madhusudhana S, Baccaray S, Fabian CJ, Schmitt SB, Godwin AK, Khan QJ. Lapatinib reverses endocrine resistance in select patients with HER2 negative, hormone positive metastatic breast cancer. [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 P5-14-06.

Study of the impact of Charlson comorbidity index on the efficacy of aromatase inhibitors in patients with hormone-receptor-positive postmenopausal breast cancer.

e11565 Background: The risk of breast cancer (BC) increases with age, so BC patients often have comorbid diseases at the time of diagnosis. Owing to the better disease-free survival (DFS) rate and ...

Should We Embrace or Ablate Our Urge to (Ovarian) Suppress?

The quest to define optimal endocrine therapy for premenopausal women with early-stage breast cancer began more than 50 years ago but is still unfulfilled. Multiple strategies have emerged, including tamoxifen, ovarian function suppression (OFS) by surgery, luteinizing hormone–releasing hormone agonist or radiation, and combination strategies such as tamoxifen plus OFS or aromatase inhibitor plus OFS. An added confounder is that these strategies have frequently been assessed in the context of adjuvant chemotherapy, which is commonly used in premenopausal women and may have indirect endocrine effects because of chemotherapy-induced menopause. This complex landscape was reviewed in a 2011 American Society of Clinical Oncology (ASCO) endorsement of the 2010 Cancer Care Ontario guideline recommending against the routine use of OFS in addition to tamoxifen or chemotherapy and a 2014 ASCO guideline endorsing consideration of 10 years of tamoxifen for these young women with hormone-responsive disease. Against this backdrop, in the article that accompanies this editorial, Tevaarwerk et al report the final results of a phase III Eastern Cooperative Oncology Group trial (E-3193, INT-0142) in which 345 premenopausal women with lymph node–negative, hormone receptor–positive breast cancer measuring 3 cm were randomly assigned from 1994-1997 to receive 5 years of tamoxifen alone or 5 years of tamoxifen plus OFS; no chemotherapy was permitted. With a median follow-up of almost 10 years, there were no significant differences in the primary end points of disease-free survival (DFS; 87.9% v 89.7% P .62) or overall survival (95.2% v 97.6%; P .67). Secondary end points included toxicity and several patient-reported outcomes (PROs) including menopausal symptoms, sexual function, and health-related quality of life. These results suggest that tamoxifen plus OFS leads to increased toxicity, more menopausal symptoms, and reduced sexual function, peaking around year 3 and then diminishing over time. The strengths of this study include the importance of the question, the clean design that enabled the testing of hormone therapies in the absence of chemotherapy, the focus on hormone-responsive tumors, the balance between the arms, the long follow-up, and the assessment of PROs. The major limitation is, of course, that the study’s early closure as a result of poor accrual left it vastly underpowered for its primary end points; this trial fell victim to the 1997 report of National Surgical Adjuvant Breast and Bowel Project (NSABP) B20, which recommended the use of chemotherapy in addition to tamoxifen for women with axillary lymph node–negative, hormoneresponsive breast cancer, especially women younger than 50 years of age. However, E-3193 was a success in its collection of detailed PROs, and it is noteworthy that it met the prespecified target accrual for these secondary end points. Given the exceptional outcomes for patients enrolled onto this trial, which had greater than 95% overall survival in the absence of chemotherapy, such patient-reported data are valuable contributions to the discussion between physicians and patients about the risks and benefits of individual therapies. Several crucial questions remain. Given the statistical limitations of this trial, might the combination of OFS plus tamoxifen actually be better than tamoxifen? What about the combination of OFS plus an aromatase inhibitor, given the efficacy of aromatase inhibitors in postmenopausal hormone receptor–positive breast cancer? Three large trials are helping to address these two questions: ABCSG-12 (Austrian Breast and Colorectal Cancer Study Group trial 12), SOFT (Suppression of Ovarian Function Trial), and TEXT (Tamoxifen and Exemestane Trial). A lingering concern is how we can integrate the results of all of these trials that use 3 to 5 years of adjuvant endocrine therapy with the findings of the ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) and aTTom (Adjuvant Tamoxifen—To Offer More?) trials, which support the use of 10 years of tamoxifen. In the SOFT trial, 3,066 premenopausal women with hormoneresponsive breast cancer were randomly assigned to 5 years of tamoxifen, tamoxifen plus OFS, or exemestane plus OFS; (neo)adjuvant chemotherapy was permitted as long as patients remained premenopausal at its completion. In the TEXT trial, 2,672 premenopausal patients with hormone-responsive breast cancer were randomly assigned to receive 5 years of tamoxifen plus OFS or exemestane plus OFS; endocrine therapy was started concurrently with chemotherapy if chemotherapy was planned. Because of lower than expected event rates, the statistical plans for these two trials were revised some years ago to enable a joint analysis of 4,690 women receiving tamoxifen plus OFS versus exemestane plus OFS. In contrast to E-3193, 42% of these women were lymph node positive, and 57% received some type of chemotherapy. At a median follow-up of 68 months, a significantly improved DFS was seen with exemestane plus OFS (91.1% v 87.3%; HR, 0.72; 95% CI, JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 35 DECEMBER 1

Effect of obesity on aromatase inhibitor efficacy in postmenopausal, hormone receptor-positive breast cancer: a systematic review.

Aromatase inhibitors (AIs) decrease the production of oestrogen, decreasing stimulation of hormone receptor-positive breast cancer. Theoretically, AIs may be less effective in obese women, due to the greater quantity of aromatase in peripheral fatty tissue. We performed a systematic review to assess the effect of obesity on AI efficacy in breast cancer treatment. The review followed PRISMA guidelines. Studies included were interventional or observational studies with comparison groups, of postmenopausal women with hormone receptor-positive breast cancer on treatment with an AI, alone or in combination with other drugs, in which body mass index or another measure of obesity was recorded. Studies in all languages were included; if published as an abstract only, authors were contacted for further information. Outcome measures included overall survival, disease-free survival or time to progressive disease, survival from the start of therapy, mortality measures, local or distant recurrence of primary cancer and time to recurrence. Of 2,344 citations identified from five databases, eight studies met the criteria for inclusion; three randomised controlled trials and five retrospective cohort studies. Due to variability in study factors, it was not possible to perform a quantitative meta-analysis. However, the systematic review showed a trend towards a negative effect of obesity on AI efficacy. There is evidence of a negative effect of obesity on AI efficacy in postmenopausal hormone receptor-positive breast cancer, but the size of the effect cannot be assessed. More information is needed before clinical recommendations are made.

Norethisterone acetate versus norethisterone acetate combined with letrozole for the treatment of ovarian endometriotic cysts: a patient preference study

ObjectiveTo compare the efficacy of norethisterone acetate (NETA; group N) or letrozole combined with NETA (group L) in treating endometriotic ovarian cysts. Study designThis patient-preference study included 20 patients in group N and 20 patients in group L. The primary aim of the study was to compare the volume of the endometriomas during and after treatment. The secondary outcome was the evaluation of the changes in pain symptoms during and after treatment. ResultsAfter six months of treatment, the volume of the endometriomas significantly decreased compared with baseline in both study groups; it was smaller in group L than in group N (p=0.026). The rate of satisfied patients at six months of treatment was similar between the study groups (p=0.451). No significant difference was reported between the two study groups in the amelioration of pain symptoms and in the incidence of adverse events. ConclusionsLetrozole combined with NETA is more efficacious than NETA alone in reducing the volume of endometriotic cysts but in none of the 40 patients included in the study did the endometriomas disappear. The efficacy of aromatase inhibitors, however, should be balanced with the need to administer long-term treatment.

Comparison of the efficacy of adjuvant letrozole and anastrozole in hormone-receptor positive postmenopausal breast cancer patients.

e11554 Background: In the adjuvant hormonal treatment of postmenopausal breast cancer patients, most of the trials have showed the superiority of aromatase inhibitors over tamoxifen. However, there are limited data in the literature comparing the efficacy of aromatase inhibitors in postmenopausal women. Thus, the aim of this study is to compare the efficacy of letrozole and anastrozole in hormone-receptor positive postmenopausal breast cancer patients. Methods: Newly diagnosed breast cancer patients from 2001 to 2012 in our clinic were retrospectively analyzed. A total 566 hormone receptor-positive postmenopausal breast cancer patients were analyzed. The patients were divided into two group; anastrozole group (n=235) and letrozole patients (n=331). Kaplan–Meier survival analysis was carried out for disease free survival (DFS) and overall survival (OS). The log-rank test was used to examine the statistical significance of the differences observed between the groups. Results: The mean age was 59.2±8.5 in anastrozole group, and 60.1±8.4 in letrozole arm (P = 0.19). The mean BMI was 29.4±5.1 kg/m2 and 29.3±5.3 kg/m2 of anastrozole and letrozole arm, respectively (P =0.84). The median follow-up time for this analysis was 25.1 months. The histology of the primary tumor and type of surgery was similar and not statistically significant in both groups. Also in both arms the incidence of lymphovascular invasion, perineural invasion, HER2 positivity and histological grade were similar and not statistically significant. There were no apparent differences in baseline nodal status (P = 0.43), tumor size (P = 0.58) and tumor stage (P = 0.15) between two treatment arms. In anastrozole arm DFS rate was 93.7%, 81.3% and 66.0% whereas in letrozole arm DFS rate was 90.6%, 78.7% and 68.5% in the first, third and fifth years respectively. Median OS could not be obtained due to low events in both groups. Three year survival rate in anastrozole group was 98.8%, whereas in letrozole arm was 96.7% (P=0.84). Conclusions: In this retrospective study, the efficacy of letrozole and anastrozole was similar in hormone-receptor positive postmenopausal breast cancer patients.

Efficacy of tamoxifen±aminoglutethimide in normal weight and overweight postmenopausal patients with hormone receptor-positive breast cancer: an analysis of 1509 patients of the ABCSG-06 trial

Background:There exists evidence that body mass index (BMI) impacts on the efficacy of aromatase inhibitors in patients with breast cancer. The relationship between BMI and the efficacy of tamoxifen is conflicting. We investigated the impact of BMI on the efficacy of single tamoxifen and tamoxifen plus an aromatase inhibitor in the well-defined prospective study population of the ABCSG-06 trial.Methods:ABCSG-06 investigated the efficacy of tamoxifen vs tamoxifen plus aminoglutethimide in postmenopausal women with hormone receptor-positive breast cancer. Taking BMI at baseline, patients were classified as normal weight (BMI=18.5–24.9 kg m−2), overweight (BMI=25–29.9 kg m−2), and obese (30 kg m−2) according to WHO criteria.Results:Overweight+obese patients had an increased risk for distant recurrences (hazard ratio (HR): 1.51; Cox P=0·018) and a worse overall survival (OS; HR: 1·49; Cox P=0·052) compared with normal weight patients. Analysing patients treated with single tamoxifen only, no difference between overweight+obese patients and normal weight patients regarding distant recurrence-free survival (HR: 1.35; Cox P=0·24) and OS (HR: 0.99; Cox P=0·97) could be observed. In contrast, in the group of patients treated with the combination of tamoxifen plus aminoglutethimide, overweight+obese patients had an increased risk for distant recurrences (1.67; Cox P=0·03) and a worse OS (1.47; Cox P=0·11) compared with normal weight patients.Conclusion:BMI impacts on the efficacy of aromatase inhibitor-based treatment but not single tamoxifen.