Adjuvant Aromatase Inhibitor Therapy Research Articles

Bone recurrence in early breast cancer patients: The paradox of aromatase inhibitors induced bone resorption.

Despite the increase in chances of cure for early breast cancer (EBC) patients, approximately 20-45% of them will experience a disease recurrence, particularly bone metastases in 60-80% of cases, which occur more frequently in luminal subtypes. Endocrine therapy (ET) has always been the milestone of adjuvant treatment for hormone receptor-positive EBC patients, leading to indubitable reduction of disease recurrence risk. However, adjuvant aromatase inhibitors (AIs) therapy may promote a progressive decrease in bone mineral density (BMD), which can lead to osteoporosis. The increased bone resorption associated with osteoporosis may provide fertile soil for cancer growth and accelerate the development of bone metastases. In this single-institution cohort study, we performed a retrospective analysis of "luminal-like" EBC patients who experienced bone recurrence after a subsequent disease free interval. The aim of the study was to evaluate the median time to skeletal recurrence (TSkR). 143 patients experienced bone recurrence. Median TSkR was 54 months (95%CI: 45-65). Among patients who received adjuvant AIs median TSkR was 35 months (95%CI: 25-54), while among patients who did not was 61 months (95%CI: 50-80) (HR = 1.45 [95%CI: 0.97-2.17], p =0.0644). After adjusting for TNM stage (AJCC 8th edition), adjuvant AIs treatment was significantly related to a shorter TSkR (HR = 1.60 [95%CI: 1.06-2.42], p =0.0244). Adjuvant Tamoxifen, adjuvant AIs/Tamoxifen and no-treatment did not revealed to be associated to TSkR. In this cohort of EBC patients with bone recurrence, AIs treatment seems to be related to a shorter TSkR. AIs-induced bone resorption might represent the underlying mechanism.

Extended adjuvant aromatase inhibitor therapy: less is more

Adjuvant endocrine therapy has transformed outcomes for patients with early-stage, hormone receptor-positive, HER2-negative breast cancer; however, the optimal duration remains undefined. In a recent issue of The New England Journal of Medicine, Gnant etal. report the results of the ABCSG-16/SALSA trial that investigated the optimal duration of extended adjuvant aromatase inhibition and found that 5 years was not more beneficial than a 2-year extension.1.

Endocrine Treatment and Targeted Therapy for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: ASCO Guideline Update.

To update recommendations of the ASCO systemic therapy for hormone receptor (HR)-positive metastatic breast cancer (MBC) guideline. An Expert Panel conducted a systematic review to identify new, potentially practice-changing data. Fifty-one articles met eligibility criteria and form the evidentiary basis for the recommendations. Alpelisib in combination with endocrine therapy (ET) should be offered to postmenopausal patients, and to male patients, with HR-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, ABC, or MBC following prior endocrine therapy with or without a cyclin-dependent kinase (CDK) 4/6 inhibitor. Clinicians should use next-generation sequencing in tumor tissue or cell-free DNA in plasma to detect PIK3CA mutations. If no mutation is found in cell-free DNA, testing in tumor tissue, if available, should be used as this will detect a small number of additional patients with PIK3CA mutations. There are insufficient data at present to recommend routine testing for ESR1 mutations to guide therapy for HR-positive, HER2-negative MBC. For BRCA1 or BRCA2 mutation carriers with metastatic HER2-negative breast cancer, olaparib or talazoparib should be offered in the 1st-line through 3rd-line setting. A nonsteroidal aromatase inhibitor (AI) and a CDK4/6 inhibitor should be offered to postmenopausal women with treatment-naïve HR-positive MBC. Fulvestrant and a CDK4/6 inhibitor should be offered to patients with progressive disease during treatment with AIs (or who develop a recurrence within 1 year of adjuvant AI therapy) with or without one line of prior chemotherapy for metastatic disease, or as first-line therapy. Treatment should be limited to those without prior exposure to CDK4/6 inhibitors in the metastatic setting.Additional information can be found at www.asco.org/breast-cancer-guidelines.

SERENA-4: A phase 3 comparison of AZD9833 (camizestrant) plus palbociclib, versus anastrozole plus palbociclib, for patients with ER-positive, HER2-negative advanced breast cancer who have not previously received systemic treatment for advanced disease.

TPS1101 Background: More than two thirds of patients with advanced breast cancer (ABC) have estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2−) tumors. Current standard-of-care first-line treatments include an aromatase inhibitor (AI) or fulvestrant, a selective ER degrader (SERD), combined with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Concurrent use of luteinizing hormone-releasing hormone (LHRH) agonists is recommended for men and premenopausal women with ABC. Nevertheless, almost all ABCs eventually become resistant to endocrine therapy (ET) and the disease is incurable. New therapies are needed to combat ET resistance, maintain patient quality of life (QoL), and delay the need for chemotherapy. AZD9833 (camizestrant) is an orally bioavailable, highly potent, next-generation SERD that demonstrated anti-cancer properties across a range of preclinical models, including those with ER-activating mutations (Scott et al, 2020). A phase I study (SERENA-1) has demonstrated that AZD9833 is well tolerated and has a promising antitumor profile when administered alone or in combination with palbociclib, a CDK4/6 inhibitor (Baird et al, SABCS 2020). SERENA-4 (NCT04711252) is a randomized, multicenter, double-blind, phase III trial to evaluate the safety and efficacy of AZD9833 in combination with palbociclib for patients with ER+ HER2− ABC who have not received any systemic treatment in the advanced disease setting. Methods: SERENA-4 will enroll 1,342 patients with de novo or recurrent ER+ HER2– ABC who have not previously received systemic treatment for their locoregionally recurrent or metastatic disease. Patients with recurrent disease must have received adjuvant AI or tamoxifen therapy for at least 24 months without relapse. Patients will be randomized 1:1 to receive orally either (a) AZD9833 (75 mg, once daily), palbociclib (125 mg, once daily for 21 days followed by 7 days off treatment) and anastrozole-matching placebo (once daily) or (b) anastrozole (1 mg, once daily), palbociclib (same as active arm), and AZD9833-matching placebo (once daily). Premenopausal women and men will also receive LHRH agonists. The primary endpoint will be progression-free survival (PFS; up to 5 years). Secondary endpoints will include overall survival (up to 8 years), length of second PFS period, objective response, time to chemotherapy, and changes in QoL measures. Enrollment began in January 2021. Acknowledgments: We thank Rose Goodchild, PhD, of Oxford PharmaGenesis, UK, for providing medical writing assistance. Funding: The SERENA-4 trial is funded and overseen by AstraZeneca. Clinical trial information: NCT04711252 .

Associations between preexisting nociplastic pain and early discontinuation of aromatase inhibitor therapy in breast cancer.

12068 Background: Aromatase inhibitors (AI) are recommended for at least five years to reduce risk of breast cancer recurrence in postmenopausal women with hormone receptor-positive disease. Despite the potential benefit, up to 50% of patients discontinue AI early, primarily because of musculoskeletal side effects. Some patients, including those with fibromyalgia and other chronic pain conditions, have preexisting pain that arises from altered nociception without clear evidence of tissue or peripheral nerve damage, called nociplastic or centralized pain. We hypothesized that preexisting nociplastic pain is associated with early discontinuation of AI therapy due to toxicity. Methods: Patients diagnosed with breast cancer between 2012-19 and who enrolled in the Michigan Genomics Initiative (MGI) were identified. Patients who were female, had hormone receptor-positive breast cancer, had not received neoadjuvant therapy, and who initiated adjuvant AI therapy were included in the analysis. Prior to breast cancer surgery patients completed surveys about pain in the affected breast and overall worst pain (Brief Pain Inventory [BPI]), nociplastic pain (2011 Fibromyalgia Survey [FS], which assesses widespread pain plus somatic symptom severity), and anxiety (PROMIS Anxiety 4a v.1). Demographics, cancer characteristics, and treatment history, including date and reason for discontinuation of AI therapy, were abstracted from the medical record. Patients were censored at date of last oncology follow-up. Univariate and multivariable analyses were conducted to assess relationship between age, BMI, surgical site pain, overall worst pain, FS score, anxiety, and time to discontinuation of initial AI medication. Results: Of 207 analyzed patients, the average age was 61 years, average BMI was 30.3 kg/m2, 181 (87%) were postmenopausal at the time of breast cancer diagnosis, and 31% received chemotherapy. The majority were prescribed anastrozole (n=196); 6 took letrozole and 5 took exemestane. Average scores prior to surgery were 1.5/10 for worst pain, 0.2/10 for surgical site pain, 4.2/31 for FS score, and 54.1/100 for anxiety. On univariate analysis, only use of exemestane (HR 5.55, p<.001) and use of letrozole (HR 3.11, p<.001) were associated with shorter time to ET discontinuation; age, BMI, surgical site pain, worst pain, FS score, and anxiety were not statistically significantly associated with time to AI discontinuation. On multivariable analysis, only higher FS score was statistically significantly associated with time to AI discontinuation (HR 1.11, p=.021). Conclusions: Greater pre-existing nociplastic pain was associated with early discontinuation of AI therapy. For these patients, early interventions that target centralized pain, or treatment with tamoxifen instead of AI therapy, may be appropriate in order to reduce risk of nonpersistence with AI therapy.

Abstract PS5-25: Association of OPG rs2073618 and aromatase inhibitor induced musculoskeletal symptoms

Abstract Background: Adjuvant aromatase inhibitors (AI) reduce recurrence and mortality after early stage hormone receptor-positive (HR+) breast cancer (BC). Treatment-related toxicities, including AI-induced musculoskeletal symptoms (AIMSS), are common during adjuvant AI therapy. Prior work suggests the risk of AIMSS is associated with inherited germline genetic polymorphisms in several genes, such as TCL1A, CYP19A1, OPG, and VDR. These pharmacogenetic associations require replication in independent cohorts prior to clinical translation to identify patients at risk for AIMSS. The objective of this retrospective pharmacogenetic analysis was to replicate previously reported associations for candidate germline genetic polymorphisms with AIMSS. Methods: Women with stage 0-III HR+ BC initiating adjuvant endocrine therapy (ET) with tamoxifen or an AI were enrolled in a prospective clinic-based observational cohort. The type of ET was selected by the provider. A baseline (BL) blood sample was collected for isolation of germline DNA for pharmacogenetic analysis. AIMSS were assessed by patient-reported outcomes (PRO). Participants completed PROMIS pain interference (PI), PROMIS physical function (PF) and Functional Assessment of Cancer Therapy - Endocrine Symptoms (FACT-ES) measures at BL and after 3, 6, 9, 12, 24, 48 and 60 months (mo). The FACT-ES includes one question about joint pain, rated on a 5-point scale (“not at all” to “very much”). This secondary retrospective pharmacogenetic analysis was conducted in participants receiving AI therapy for whom blood samples and PRO scores at BL and 3 and/or 6 mo were available. For the primary analysis, we defined AIMSS as a ≥4 point increase in PI T score from BL to 3 and/or 6 mo. For secondary analyses, we evaluated alternate definitions of AIMSS including a ≥4 point decrease in PF T score and a ≥1 category increase on the FACT-ES joint pain question from BL to 3 and/or 6 mo. The primary hypothesis was that TCL1A rs11849538 is associated with AIMSS. Twelve other germline variants in CYP19A1, VDR, PIRC66, OPG, ESR1, CYP27B1, CYP17A1, and RANKL previously reported to be associated with AIMSS were also analyzed. We assumed a dominant genetic effect and pre-specified the direction of effect on AIMSS for each variant. We conducted univariate logistic regression to evaluate associations between each definition of AIMSS and candidate polymorphism using an unadjusted α=0.05. Significant univariate associations in the expected direction were adjusted for age, race, body mass index (BMI), prior taxane and type of AI using multivariable logistic regression. Results: Of 182 participants on AI, 143 with PRO and genetic data available were included in this analysis. Median age was 67, 85% were white, median BMI was 27.8 and 27% had prior taxane. 78% received anastrozole, 20% letrozole and 2% exemestane. On primary analysis, participants carrying TCL1A rs11849538 were not more likely to develop AIMSS as defined by increase in PI T score by ≥4 (OR=1.29, 95% CI: 0.55-3.07, p=0.56). None of the other polymorphisms was associated with increase in PI T score by ≥4. On secondary analysis, OPG rs2073618 was associated with AIMSS, as defined by an increase on the FACT-ES joint pain question ≥1 (OR=3.33, 95% CI: 1.48-7.49, p=0.004) and this association maintained significance after covariate adjustment (OR=3.98, 95% CI: 1.61-9.84, p=0.003). Age, race, BMI, prior taxane and type of AI were not associated with AIMSS on multivariate analysis. No other polymorphisms were associated with AIMSS on secondary analyses. Conclusions: Carriers of OPG rs2073618 may be at increased risk of AIMSS. If confirmed in other cohorts, OPG genotyping may be able to identify individuals with HR+ early BC at increased risk for AIMSS during AI therapy. Alternate ET or interventions to reduce musculoskeletal symptoms may be needed for this population. Citation Format: Daniel L Hertz, Karen Lisa Smith, Yuhua Zong, Christina L Gersch, Andrea Pesch, Arti Patel, Jennifer Lehman, N. Lynn Henry, Kelley M Kidwell, James M Rae, Vered Stearns. Association of OPG rs2073618 and aromatase inhibitor induced musculoskeletal symptoms [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 PS5-25.

Steroid Hormone Receptor and Infiltrating Immune Cell Status Reveals Therapeutic Vulnerabilities of ESR1-Mutant Breast Cancer.

Mutations in ESR1 that confer constitutive estrogen receptor alpha (ER) activity in the absence of ligand are acquired by ≥40% of metastatic breast cancers (MBC) resistant to adjuvant aromatase inhibitor (AI) therapy. To identify targetable vulnerabilities in MBC, we examined steroid hormone receptors and tumor-infiltrating immune cells in metastatic lesions with or without ER mutations. ER and progesterone receptor (PR) were significantly lower in metastases with wild-type (WT) ER compared with those with mutant ER, suggesting that metastases that evade AI therapy by mechanism(s) other than acquiring ER mutations lose dependency on ER and PR. Metastases with mutant ER had significantly higher T regulatory and Th cells, total macrophages, and programmed death ligand-1 (PD-L1)-positive immune-suppressive macrophages than those with WT ER. Breast cancer cells with CRISPR-Cas9-edited ER (D538G, Y537S, or WT) and patient-derived xenografts harboring mutant or WT ER revealed genes and proteins elevated in mutant ER cells, including androgen receptor (AR), chitinase-3-like protein 1 (CHI3L1), and IFN-stimulated genes (ISG). Targeting these proteins blunted the selective advantage of ER-mutant tumor cells to survive estrogen deprivation, anchorage independence, and invasion. Thus, patients with mutant ER MBC might respond to standard-of-care fulvestrant or other selective ER degraders when combined with AR or CHI3L1 inhibition, perhaps with the addition of immunotherapy. SIGNIFICANCE: Targetable alterations in MBC, including AR, CHI3L1, and ISG, arise following estrogen-deprivation, and ER-mutant metastases may respond to immunotherapies due to elevated PD-L1+ macrophages.See related article by Arnesen et al., p. 539.

When cardiomyopathy, cancer, and COVID‐19 collide: A case report

Malignancy has historically prohibited solid organ transplant; however, patients with effectively treated, favorable‐risk cancers should not necessarily be eliminated as transplant candidates. These cases require careful review by a multidisciplinary team. Here, we report the case of a woman with end‐stage heart failure undergoing heart transplant evaluation during the COVID pandemic who was found to have early‐stage, hormone receptor‐positive breast cancer. Given her favorable cancer‐related prognosis, a multidisciplinary committee recommended lumpectomy, accelerated partial breast irradiation, and adjuvant aromatase inhibitor therapy for definitive treatment to allow for consideration of orthotopic heart transplant.

Sexual Dysfunction in Postmenopausal Women with Breast Cancer on Adjuvant Aromatase Inhibitor Therapy

Introduction: The aim of this study was to investigate whether postmenopausal women with breast cancer (BC) on adjuvant aromatase inhibitor (AI) therapy have a higher prevalence of female sexual dysfunction (FSD). Second, the aim was to determine the quality of life (QoL) and level of anxiety depending on whether or not they are AI users. Methods: A prospective cross-sectional study involving 168 patients was performed. Three questionnaires were carried out: sexual functioning was evaluated with the Female Sexual Function Index (FSFI), while the EORTC QLQ-BR23 measures to study QoL in patients with BC and the State-Trait Anxiety Inventory (STAI) questionnaire (trait and status) were used to assess anxiety status in patients under treatment with AIs or not. Results: 47.6% (80/168) of the postmenopausal BC survivors were not sexually active (mean time after surgery: 48.6 months) despite a relatively low mean age (56.43 years). Postmenopausal AI-treated women had significantly worse sexual function as measured by the FSFI (23.40 ± 5.26 vs. 30.16 ± 2.24; p = 0.000). There were significant differences between both groups in all domains, except orgasm. The QoL score was 37.67 ± 7.38 in AI users versus 39.00 ± 1.44 among nonusers (p = 0.053). Patients under endocrine treatment also presented STAI scores significantly higher (25.83 ± 4.99 vs. 19.00 ± 7.12; p = 0.000). Trait anxiety was high in both groups, but this was not statistically significant. Conclusions: We observed a high prevalence of sexual inactivity among BC survivors regardless of AI use. Patients with AI use presented significantly higher prevalence of FSD, worse QoL, and greater anxiety.

Statin use and breast cancer recurrence in postmenopausal women treated with adjuvant aromatase inhibitors: a Danish population-based cohort study

PurposeTo examine the association between statin use and risk of breast cancer recurrence in a national Danish cohort of postmenopausal breast cancer patients receiving aromatase inhibitors (AI) in the adjuvant setting.Patients and methodsWe enrolled all postmenopausal patients diagnosed with stage I–III estrogen receptor positive breast cancer during the years 2007–2017, assigned adjuvant AI treatment, and registered in both the Danish Breast Cancer Group database and the Danish Cancer Registry. We ascertained incident statin exposure (≥ 1 prescription post-diagnosis) from the Danish National Prescription Registry and modeled statins as a time-varying exposure lagged by 6 months. Follow-up began 7 months after diagnosis and continued to the first event of recurrence, death, emigration, 5 years elapsed, or 25th September 2018. We estimated incidence rates of recurrence at 5 years and used Cox regression models to compute crude and adjusted hazard ratios (HRs) with 95% confidence intervals (95% CI), comparing statin exposure with non-exposure.ResultsWe enrolled 14,773 eligible patients. During the 5 years of follow-up, there were 32 recurrences in 3163 person-years of follow-up among statin-exposed patients, and 612 recurrences in 45,655 person-years among unexposed patients (incidence rate per 1000 person-years: 10.12 [95% CI 6.92–14.28] and 13.40 [95% CI 12.36–14.51], respectively). In multivariable models, any statin exposure was associated with a reduced rate of 5-year breast cancer recurrence (adjusted HR 0.72 [95% CI 0.50–1.04]). Considering only lipophilic statins as exposure the results were similar (adjusted HR 0.70 [95% CI 0.48–1.02]).ConclusionsStatin use was associated with a reduced risk of breast cancer recurrence among postmenopausal patients diagnosed with early stage breast cancer who received adjuvant AI therapy.

Early-stage breast cancer (BC) patients: Factors associated with aromatase inhibitor-induced musculoskeletal symptoms.

525 Background: Hormone receptor positive (HR+) breast cancer comprises the largest subgroup of breast cancer. Aromatase Inhibitors (AI) are a key treatment for HR+ BC patients (pts) and reduce mortality. Aromatase Inhibitor-Associated Musculoskeletal Symptoms (AIMSS), defined as myalgias, arthralgias, or joint stiffness, occur in up to 50% of pts leading to low adherence to and often discontinuation of therapy. Little is known of the mechanism of AIMSS or its predisposing risk factors. This study aims to identify risk factors associated with AIMSS development in BC patients on AI therapy. Methods: We conducted a medical record review of pts with non-metastatic HR+ BC on adjuvant AI therapy between January 2009 and June 2017 at the University of Maryland Comprehensive Cancer Center. This study included 194 ptswho were free of arthralgia prior to AI therapy. We analyzed pts’ demographics, lifestyle factors, reproductive history, tumor characteristics, medications, cancer treatment, co-morbidities, AI type, onset and severity of AIMSS. Severe AIMSS was defined as requiring change in AI therapy or discontinuation. Multivariable-adjusted logistic regression was used to identify risk factors for severe AIMSS. Results: The mean age of participants was 61. The mean BMI at diagnosis was 30 kg/m2. 41% of pts were White, 40% were Black, 7% other and 12% unknown. Most (79%) did not have a history of tamoxifen and 16% were on GnRH agonists. Most (71%) used letrozole as initial AI therapy; 18% anastrozole; and 11% exemestane. 56% experienced AIMSS while on AI therapy and 20% required change or hold of AI therapy. 4% permanently discontinued AI due to AIMSS severity. BMI at diagnosis was significantly positively associated with risk of AIMSS. Multivariate odds ratio (95% confidence intervals) comparing the highest to lowest tertile of body mass index (BMI) at diagnosis was 4.01 (1.07-10.90; Ptrend: 0.05). There were no significant associations with race, smoking, reproductive factors, type of AI therapy, tamoxifen use prior to AI therapy, medication use, experience of other cancer treatments, and tumor characteristics. Conclusions: 56% of BC pts on adjuvant AI therapy experienced AIMSS. 24% of these changed, held or discontinued AI regimen due to severe AIMSS. Higher BMI at diagnosis was associated with a higher risk of AIMSS. Our results confirm clinical significance of AIMSS among BC pts on AI therapy and suggest BMI as a modifiable factor for AIMSS. A larger study is warranted to replicate our findings and seek other possible risk factors for AIMSS.

Randomized Trial of Text Messaging to Reduce Early Discontinuation of Adjuvant Aromatase Inhibitor Therapy in Women With Early-Stage Breast Cancer: SWOG S1105.

Nonadherence to aromatase inhibitors (AIs) for breast cancer is common and increases the risk of recurrence. Text messaging increases adherence to medications for chronic conditions. We conducted a randomized clinical trial of text messaging (TM) versus no text messaging (No-TM) at 40 sites in the United States. Eligible patients were postmenopausal women with early-stage breast cancer taking an AI for > 30 days with a planned duration of ≥ 36 months. Test messages were sent twice a week over 36 months. Content themes focused on overcoming barriers to medication adherence and included cues to action, statements related to medication efficacy, and reinforcements of the recommendation to take AIs. Both groups were assessed every 3 months. The primary outcome was time to adherence failure (AF), where AF was defined as urine AI metabolite assay results satisfying one of the following: < 10 ng/mL, undetectable, or no submitted specimen. A stratified log-rank test was conducted. Multiple sensitivity analyses were performed. In total, 724 patients were registered between May 2012 and September 2013, among whom,702 patients (348 in the text-messaging arm and 354 in the no-text-messaging arm) were eligible at baseline. Observed adherence at 36 months was 55.5% for TM and 55.4% for No-TM. The primary analysis showed no difference in time to AF by arm (3-year AF: 81.9% TM v 85.6% No-TM; HR, 0.89 [95% CI, 0.76 to 1.05]; P = .18). Multiple time to AF sensitivity analyses showed similar nonsignificant results. Three-year self-reported time to AF (10.4% v 10.3%; HR, 1.16 [95% CI, 0.69 to 1.98]; P = .57) and site-reported time to AF (21.9% v 18.9%; HR, 1.31 [95% CI, 0.86 to 2.01]; P = .21) also did not differ by arm. To our knowledge, this was the first large, long-term, randomized trial of an intervention directed at improving AI adherence. We found high rates of AI AF. Twice-weekly text reminders did not improve adherence to AIs. Improving long-term adherence will likely require personalized and sustained behavioral interventions.

Abstract P5-12-12: Prospective evaluation of adherence to adjuvant aromatase inhibitor (AI) therapy among Hispanic/Latino women with breast cancer (BC) living in the border city of El Paso, Texas

Abstract Background: Adjuvant therapy with AI improve survival and is recommended to all postmenopausal women with hormone receptor-positive BC. A typical duration of the therapy is from 5 to 10 years. Despite clinically proven efficacy early discontinuation rate approaching 10% per year. The purpose of this study was to determine the adherence level through the Morisky Medication Adherence Scale (MMAS-8) among women with breast cancer treated at Texas Tech University Health Sciences Center El Paso (TTUHSC EP). Methods: Institutional review board approval was obtained prior to initiating this prospective study. 133 postmenopausal women were consented and participated in this study. Patients seen at the TTUHSC EP who was diagnosed with stage I-III breast cancer and who were on adjuvant AIs, were given the MMAS-8 questionnaire, and a demographics questionnaire. In order to identify reasons for non-adherence to AIs, all patients were also asked to identify the reason why they did not take their medication if applicable.Results: One hundred thirty-three patients were enrolled, median age 64 (range 41 - 89), 110 (90.2%) identified themselves as Hispanic/Latino. 58.2% have an income of 15K or less. 39% completed eighth grade or less, 34.5% completed high school, and 12% obtained a technical degree. Mean duration of AI therapy was 6.5 years. The majority of patients have high or intermediate levels of adherence 88%. Only 12 % had a low level of adherence. 7 (5.6%) patients scored two or below in the intentional adherence scale, and 18 (13.5%) scored two or below in the unintentional adherence scale (maximum scale is four). Conclusions: Our results indicate that the majority of patients treated at TTUHSC EP have a high or intermediate level of adherence to AI therapy. The main reason listed for non-adherence were mostly unintentional: forgetfulness and missing getting refills on time. Citation Format: Alexander Philipovskiy, Aleli Campbell, Brenda Castillo, Rosalinda Heydarian, Sumit Gaur, Alok Dwivedi, Zeina Nahleh. Prospective evaluation of adherence to adjuvant aromatase inhibitor (AI) therapy among Hispanic/Latino women with breast cancer (BC) living in the border city of El Paso, Texas [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 P5-12-12.

Abstract P5-12-13: Factors associated with aromatase inhibitor associated musculoskeletal symptoms in early stage breast cancer patients

Abstract Introduction: Aromatase Inhibitors (AI) are a mainstay of treatment for hormone receptor positive breast cancer (BC) in postmenopausal women. However, patients under AI treatment often suffer from Aromatase Inhibitor-Associated Musculoskeletal Symptoms (AIMSS), defined as myalgias, arthralgias, or joint stiffness in hands, fingers, knees, hips and feet, which may limit treatment and subsequently increase BC mortality. The depletion of estrogen following AI initiation has been postulated to cause AIMSS. However, it has not yet been fully established about the clinical significance of AIMSS and its risk factors and the underlying mechanisms. The aim of this study is to identify epidemiologic risk factors associated with the development of AIMSS in BC patients on adjuvant AI therapy. Methods: We conducted a retrospective review of medical records among 111 stages 0-III hormone receptor positive BC patients who received adjuvant AI therapy, including anastrozole, letrozole or exemestane, between January 2009 and June 2017, at the University of Maryland Greenebaum Comprehensive Cancer Center. To be eligible, women had to be either postmenopausal or premenopausal, on a GnRH analog for at least 3 months, and report of no AIMSS before the AI initiation. We collected patients’ data on demographics, lifestyle factors, reproductive histories, tumor characteristics, types of AI and cancer treatment, co-morbidities, use of medications, length of AI therapy, and onset and severity of AIMSS. We defined severe AIMSS as AIMSS requiring the change of AI therapy or discontinuation of AI. The demographics and clinicopathological characteristics of patients on AI therapy and frequencies of AIMSS onset during AI treatment was characterized with means (SDs) or percentages. To estimate the association of severe AIMSS with epidemiologic risk factors, odds ratios (ORs) and 95% confidence intervals were calculated using multivariable-adjusted logistic regression. Results: This study included 111 BC patients with a mean age of 64 years. Their mean BMI at time of BC diagnosis was 30.8 kg/m2, and 41% of patients were White, 39% were Black, 4% were Asian/Pacific Islander, and 16% were other. Majority of patients (77%) had no prior experience of tamoxifen use and used letrozole as an initial AI therapy (70.3%); 15.3% used anastrozole, and 14.4% used exemestane. We found that 52.6% of patients experienced any degree of AIMSS while on AI therapy. In particular, 19.8% of patients required change or holding AI therapy, and 3.6% permanently discontinued AI because of AIMSS. We observed that older age at AI therapy initiation and higher levels of circulating vitamin D-25OH were significantly associated with lower odds of severe AIMSS. Multivariate ORs (95% Cis) comparing the highest to the lowest tertile of age and vitamin D levels at AI initiation were 0.18 (0.05-0.71) and 0.10 (0.02-0.49), respectively (all P-trend: ≤ 0.04). There were no significant association between race, body mass index, smoking, alcohol use, reproductive factors, type of AI therapy, and tamoxifen use prior to AI therapy. Conclusions: In our study, nearly 52.6% of BC patients on adjuvant AI therapy experienced AIMSS. Of those, 23.4% changed or discontinued AI regimen due to severe AIMSS. Older age and higher circulating levels of vitamin D-25OH at the initiation of adjuvant AI therapy were associated with lower risk of developing severe AIMSS. The study results support the clinical significance of AIMSS in BC patients leading to decreased adherence to AI therapy. The replication of our association with age and vitamin D levels in a larger study is warranted as it may provide a greater insight into etiologies of AIMSS. Citation Format: Yamin Sun, Simran Elder, Seungyoun Jung, Candace Mainor, Shruti Murali, Paula Rosenblatt, Katherine Tkaczuk. Factors associated with aromatase inhibitor associated musculoskeletal symptoms in early stage breast cancer patients [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 P5-12-13.

Abstract P2-10-07: Cardiovascular disease risk and statin use among women with breast cancer treated with adjuvant aromatase inhibitor therapy

Abstract Background: Patients with early-stage breast cancer are more likely to die from cardiovascular disease (CVD) than breast cancer. Aromatase inhibitors (AI) are used as adjuvant therapy in postmenopausal women with hormone receptor-positive breast cancer to improve survival rates, however, AI use has numerous adverse effects including increasing the risk of CVD due to negative effects on blood pressure and cholesterol levels. The American College of Cardiology/American Heart Association 2019 guidelines recommend that all patients at intermediate or high risk for CVD based on 10-year atherosclerotic cardiovascular disease (ASCVD) risk score be on a statin. We aimed to evaluate CVD risk and statin use among racially/ethnically diverse women with breast cancer on adjuvant AI therapy. Methods: We evaluated postmenopausal women with stage I-III breast cancer treated with AIs between 2007 and 2018 at Columbia University Irving Medical Center in New York, NY. Ten-year ASCVD risk score was calculated at breast cancer diagnosis from age (20-79 years), gender (female only), race (white/black/other), serum total cholesterol (130-320 mg/dL) and HDL cholesterol (20-100 mg/dL), systolic blood pressure (90-200 mm Hg), hypertension treatment (yes/no), diabetes (yes/no), and smoking status (current/former/never). Individuals were categorized based upon their 10-year ASCVD risk as low (&amp;lt;5%), borderline (5-7.5%), intermediate (7.5-20%), or high risk (&amp;gt;20%). We used descriptive statistics and multivariable logistic regression to determine predictors of statin use among patients with intermediate or high risk ASCVD risk scores. Results: Of 363 evaluable patients, median age at diagnosis was 64 years (range, 50-80) and 35.8% were non-Hispanic white, 32.5% Hispanic, 23.4% non-Hispanic black, and 8.3% other races. Overall, the proportion of women with low risk ASCVD risk was 25.6%, borderline risk was 8.0%, intermediate risk was 37.7%, and high risk was 28.7%. Mean 10-year ASCVD risk scores were 13.7% for black women, 11.5% Hispanics, and 11.0% for white women and other races (p=0.082). The percentage of patients on statins was 50% in the intermediate risk category and 77% in the high risk category. Among those with intermediate or high ASCVD risk scores (N=240), statin use was associated with higher ASCVD risk, higher total cholesterol and systolic blood pressure, and a diagnosis of hypercholesterolemia. Conclusions: Among women with early-stage breast cancer starting adjuvant AI therapy, there is a high prevalence with intermediate and high ASCVD risk. Given the effects of AI therapy on CVD risk factors, these patients should be screened for ASCVD risk and started on statin therapy when indicated. Citation Format: Monica F Chen, Morgan Manger, Katherine D Crew. Cardiovascular disease risk and statin use among women with breast cancer treated with adjuvant aromatase inhibitor 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 P2-10-07.

Adherence to Adjuvant Aromatase Inhibitor Therapy Among Postmenopausal Hispanic/Latino Women With Breast Cancer.

The purpose of this study was to determine the level of adherence to adjuvant aromatase inhibitor (AI) therapy and factors associated with non-adherence among Hispanic/Latino women with hormonal receptor-positive breast cancer (BC) treated at an academic center at the American-Mexican border city of El Paso, TX. Institutional Review Board approval was obtained in this cross-sectional study using the validated Morisky Medication Adherence Scale to assess patient adherence to AI therapy. Patients diagnosed with stage I-III hormonal receptor-positive, human epidermal growth factor receptor 2-negative BC who were on adjuvant AIs therapy were recruited from the Texas Tech University Health Sciences Center El Paso breast clinic. Between September 2017 and August 2018, 122 consecutive patients were enrolled; 119 were analyzed, three were lost to follow up. The mean age was 61.6±9.4 years, and 109 (91.6%) self-identified as Hispanic/Latino. A total of 58% reported an annual income of $15,000 or less. Overall, 40.3% had completed eighth grade or less education, 31.9% high school, and 12% had obtained a technical degree. The majority of patients (56%) had either a medium (45%) or a low level of adherence (11%). High adherence was noted in 44% of participants. Seven (5.6%) patients scored 2 or below on a 4-point scale for intentional adherence, and 18 (13.5%) scored 2 or below on a 4-point scale for unintentional adherence. These data suggest that the majority of Hispanic/Latino women with breast cancer have medium or low levels of adherence to therapy with AIs. Factors associated with medium and low adherence were unintentional (forgetfulness), but also included intentional factors, such as avoidance of adverse effects and delays with obtaining refills (cost-related nonadherence).

Exercise therapies for preventing or treating aromatase inhibitor-induced musculoskeletal symptoms in early breast cancer.

Survival for stage I to III, hormone receptor-positive, breast cancer has substantially improved over time due to advances in screening, surgery and adjuvant therapy. However many adjuvant therapies have significant treatment-related toxicities, which worsen quality of life for breast cancer survivors. Postmenopausal women with hormone receptor-positive breast cancer are now prescribed aromatase inhibitors (AI) as standard, with longer durations of therapy, up to 10 years, being considered for certain women. AI treatment is associated with a high incidence of AI-induced musculoskeletal symptoms (AIMSS), often described as symmetrical pain and soreness in the joints, musculoskeletal pain and joint stiffness. AIMSS reduces compliance with AI therapy in up to one half of women undergoing adjuvant AI therapy, potentially compromising breast cancer outcomes. Exercise has been investigated for the prevention and treatment of AIMSS but the effect of this intervention remains unclear. To assess the effects of exercise therapies on the prevention or management of aromatase inhibitor-induced musculoskeletal symptoms (AIMSS) in women with stage I to III hormone receptor-positive breast cancer. We searched Cochrane Breast Cancer's Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases up to 13 December 2018. We also searched two conference proceedings portals and two clinical trials registries for ongoing studies or unpublished trials, or both, in August 2019. We also reviewed reference lists of the included studies. We included randomised controlled trials that compared exercise versus a comparator arm. We did not impose any restriction on the comparator arm, which could include an alternative type of exercise, no exercise or a waiting list control. Both published and non-peer-reviewed studies were eligible. Two review authors independently extracted data, assessed risk of bias and certainty of the evidence using the GRADE approach. The outcomes investigated were pain, joint stiffness, grip strength, health-related quality of life, cancer-specific quality of life, adherence to AI therapy, adverse events, incidence of AIMSS, breast cancer-specific survival and overall survival. For continuous outcomes that were assessed with the same instrument, we used the mean difference (MD); for those outcomes that used different instruments, we used the standardised mean difference (SMD) for the analysis. For dichotomous outcomes, we reported outcomes as an odds ratio (OR). We included seven studies with 400 randomised participants; one study assessed exercise for preventing AIMSS and six studies assessed treating AIMSS. For preventing AIMSS, the single study reported no difference in pain scores, grip strength or compliance to taking AI medication between groups. Data values were not provided in the study and no other outcomes were reported. For managing AIMSS, we found that the evidence for the effect of exercise therapies on overall change in worst pain scores was very uncertain (SMD -0.23, 95% confidence interval (CI) -0.78 to 0.32; 4 studies, 284 women; very low-certainty evidence). The evidence suggested that exercise therapies result in little to no difference in overall change in stiffness scores (Western Ontario McMasters Universities Osteoarthritis Index (WOMAC) stiffness score MD -0.76, 95% CI -1.67 to 0.15 and Visual Analogues Scale (VAS) stiffness score MD -0.42, 95% CI -2.10 to 1.26; 1 study, 53 women; low-certainty evidence). The evidence was very uncertain for the outcomes of overall change in grip strength (MD 0.30, 95% CI -0.55 to 1.15; 1 study, 83 women; very low-certainty evidence); overall change in health-related quality of life (subscales of SF-36 tool ranged from least benefit of MD 1.88, 95% CI -2.69 to 6.45 to most benefit of MD 9.70, 95% CI 1.67 to 17.73; 2 studies, 123 women, very low-certainty evidence); overall change in cancer-specific quality of life (MD 4.58, 95% CI -0.61 to 9.78; 2 studies, 136 women; very low-certainty evidence); and adherence to aromatase inhibitors (OR 2.43, 95% CI 0.41 to 14.63; 2 studies, 224 women; very low-certainty evidence). There were no adverse events identified across four studies in either arm (0 events reported; 4 studies; 331 participants; low-certainty evidence). There were no data reported on incidence of AIMSS, breast cancer-specific survival or overall survival. Given the wide-ranging benefits of exercise for people affected by cancer, it was surprising that this review provided no clear evidence of benefit for exercise therapies in women with early breast cancer with AIMSS. This review only yielded seven eligible studies with 400 participants, which is likely to have underpowered the findings. The meta-analysis was challenging due to the considerable heterogeneity amongst the trials, with a wide range of exercise regimens and follow-up periods. Despite these inconclusive findings, exercise needs to be part of routine care for women with breast cancer due to its wide-ranging benefits. Future research in this area would be enhanced with further understanding of the mechanism of AIMSS, a single clear definition of the condition, and phase III randomised controlled trials that are adequately powered to test targeted exercise interventions on the key clinical outcomes in this condition.

Predicting the Benefit of Adjuvant Aromatase Inhibitor Therapy in Postmenopausal Breast Cancer Patients with Phosphorylated S6K1 Expression Status.

PurposePhosphorylated ribosomal S6 kinase 1 (pS6K1) is a major downstream regulator of the mammalian target of rapamycin (mTOR) pathway. Recent studies have addressed the role of S6K1 in adipogenesis. pS6K1 may affect the outcome of estrogen depletion therapy in patients with hormone-sensitive breast cancer due to its association with adipogenesis and increased local estrogen levels. This study aimed to investigate the potential of pS6K1 as a predictive marker of adjuvant aromatase inhibitor (AI) therapy outcome in postmenopausal or ovarian function-suppressed patients with hormone-sensitive breast cancer.MethodsMedical records were retrospectively reviewed in postmenopausal or ovarian function-suppressed patients with estrogen receptor-positive and node-positive primary breast cancer. pS6K1 expression status was scored on a scale from 0 (negative) to 3+ (positive) based on immunohistochemical analysis.ResultsA total of 428 patients were eligible. The median follow-up duration was 44 months (range, 1–90). In patients with positive pS6K1 expression, AIs significantly improved disease-free survival (DFS) compared to selective estrogen receptor modulators (SERMs) (5 year-DFS: 83.5% vs. 50.7%, p = 0.016). However, there was no benefit of AIs on DFS in the pS6K1 negative group (5 year-DFS 87.6% vs. 91.4%, p = 0.630). On multivariate analysis, AI therapy remained a significant predictor for DFS in the pS6K1 positive group (hazard ratio, 0.39; 95% confidence interval, 0.16–0.96; p = 0.041). pS6K1 was more effective in predicting the benefit of AI therapy in patients with ages < 50 (p = 0.021) compared to those with ages ≥ 50 (p = 0.188).ConclusionpS6K1 expression may predict AI therapy outcomes and serve as a potential predictive marker for adjuvant endocrine therapy in postmenopausal and ovarian function-suppressed patients with hormone-sensitive breast cancer. AIs may be more effective in patients with pS6K1 positive tumors, while SERM could be considered an alternative option for patients with pS6K1 negative tumors.

Effect of Vitamin D on Bone Mineral Density Changes in Patients with Breast Cancer Receiving Adjuvant Aromatase Inhibitor Therapy

Effect of Vitamin D on Bone Mineral Density Changes in Patients with Breast Cancer Receiving Adjuvant Aromatase Inhibitor Therapy

Efficacy and toxicity of extended aromatase inhibitors after adjuvant aromatase inhibitors-containing therapy for hormone-receptor-positive breast cancer: a literature-based meta-analysis of randomized trials

Endocrine therapy with aromatase inhibitors (AIs) is the cornerstone of adjuvant systemic treatment for postmenopausal patients with hormone receptor-positive breast cancer. It has become clear that hormone receptor-positive breast cancer carries a consistent risk of relapse up to 15 years after diagnosis. Extended duration of adjuvant AIs therapy after completing initial standard adjuvant AIs-containing therapy may prevent late recurrence and death. We performed a meta-analysis to assess the real impact of the extended adjuvant therapy with AIs. A literature-based meta-analysis of the randomized controlled trials (RCTs) was undertaken. Relevant publications from PubMed, Embase, Cochrane Library, and abstracts from American Society of Clinical Oncology (ASCO) and San Antonio Breast Cancer (SABCS) symposia were searched. The endpoints were disease-free survival (DFS), overall survival (OS), local recurrence, distant recurrence, contralateral breast cancer, non-breast cancer-related death, and toxicity. Eight trials comprising 15,966 patients met the inclusion criteria. The pooled analysis revealed a significant improvement in DFS (RR = 0.79; 95% CI 0.68-0.91), distant recurrence (RR = 0.75; 95% CI 0.58-0.96), and contralateral breast cancer (RR = 0.53; 95% CI 0.40-0.70) in the extended AIs group. While there was not significant improvement in OS (RR = 1.00, 95% CI 0.99-1.01), non-breast cancer-related death (RR = 1.16, 95% CI 0.96-1.41), and local recurrence (RR = 0.82; 95% CI 0.64-1.06), the subgroup analysis showed that the patient with tumor size > 2cm (HR = 0.74, RD = - 0.31, P = 0.05 vs. HR = 0.85, RD = - 0.16, P = 0.20), node positive status (HR = 0.77, RD = - 0.27, P = < 0.0001 vs. HR = 0.89, RD = -0.12, P = 0.19) and previous chemotherapy use (HR = 0.75, RD = - 0.29, P = 0.003 vs. HR = 0.91, RD = -0.10, P = 0.44) would get a greater DFS benefit with extended AIs. Longer treatment with AIs was associated with an increased risk ratio of bone pain (RR = 1.26, RD = 0.04, P = 0.003), bone fractures (RR = 1.59, RD = 0.02, P = 0.002), osteoporosis (RR = 1.53, RD = 0.07, P = 0.005), myalgia (RR = 1.26, RD = 0.04, P = 0.02), and treatment discontinuation for adverse events (RR = 1.51, RD = 0.06, P = 0.0009). After initial standard AIs-containing adjuvant therapy, extended AIs therapy could further bring a DFS benefit for postmenopausal patients with early breast cancer, especially in the patients with high-risk characteristics.