Adjuvant Aromatase Inhibitor Therapy Research Articles

Bone mineral density fall during aromatase inhibitor treatment may predict lower breast cancer recurrence.

Aromatase inhibitors (AIs) are associated with reduction in bone mineral density (BMD). The use of bone strengthening agents zoledronic acid and denosumab are associated with improved breast cancer outcomes for post-menopausal patients treated with AIs. This study investigates whether change in BMD with AI therapy is associated with breast cancer recurrence. A cohort of patients treated at a single institution diagnosed with hormone receptor-positive breast cancer with baseline BMD and subsequent BMD test while receiving adjuvant aromatase inhibitor therapy were studied. Demographic, treatment and outcome data was obtained. Simple and multiple linear regression analysis was performed to investigate predictors of annual percent BMD change at the LS and hip. Univariate and multivariate Cox proportional hazards modelling were undertaken to investigate predictors of breast cancer recurrence. 353 patients eligible patients were identified. In multivariate analysis of lumbar spine BMD change, the difference between those in quartile 1, which showed the greatest reduction in BMD, and quartile 3, with substantially less reduction, was significant (HR = 3.02, 95% CI 1.15-7.90 p = 0.025). Hip BMD reduction was also not significantly associated with breast cancer recurrence. The two quartiles with the least reduction in hip BMD showing a non-significant reduced risk of recurrence relative to the quartile with the greatest (p = 0.10). The findings suggest an association may exist between lumbar spine BMD change and breast cancer recurrence for patients treated with adjuvant AI. Further research is required to determine whether BMD change can be utilised as a biomarker.

OP70 Treating Patients With Hormone-Sensitive Cancer On Endocrine Therapy With Denosumab (Prolia®): A Systematic Review And Network Meta-Analysis

IntroductionPatients receiving endocrine therapy for hormone-sensitive cancers, such as men with prostate cancer (MPC) on hormone ablation therapy (HAT) and women with breast cancer (WBC) on adjuvant aromatase inhibitor therapy (AAIT), have an increased risk of developing osteoporosis. The aim of this study was to compare the safety and effectiveness of denosumab (Prolia®) with selective estrogen receptor modulators (SERMs) (raloxifene and bazedoxifene), bisphosphonates (zoledronate, ibandronate, alendronate, and risedronate), and placebo for the treatment of osteoporosis in patients receiving endocrine therapy for hormone-sensitive cancer.MethodsSystematic literature searches were conducted in three biomedical databases (PubMed, the Cochrane Library, and Embase) to identify randomized controlled trials (RCTs). Only RCTs that investigated MPC on HAT or WBC on AAIT allocated to denosumab, SERMs, bisphosphonates, or placebo were included. RCTs were appraised using the Cochrane Risk of Bias 2.0 tool. Frequentist network and pairwise meta-analyses were performed on predetermined outcomes of vertebral or nonvertebral fractures, treatment-related adverse events (AEs), bone mineral density (BMD), mortality, withdrawal due to treatment-related AEs, and serious AEs.ResultsA total of 14 RCTs (15 publications, 6,463 participants) were included. Relative to placebo, denosumab was found to prevent vertebral fractures in cancer patients receiving endocrine therapy. Moreover, denosumab, alendronate, and zoledronate increased femoral neck (FN) and lumbar spine (LS) BMD in MPC on HAT, compared with placebo, whereas denosumab, risedronate, and ibandronate improved LS and total hip BMD in WBC on AAIT. Similarly, denosumab and risedronate increased trochanteric BMD in WBC on AAIT, compared with placebo. In WBC on AAIT, only denosumab increased FN BMD relative to placebo.ConclusionsDenosumab was more effective than placebo in preventing vertebral fractures and improving BMD at the LS and FN in MPC on HAT, and in preventing vertebral fractures and improving FN, trochanteric, total hip, and LS BMD in WBC on AAIT. From a policy perspective, the continued reimbursement of denosumab needs to be reviewed.

277P Fat body mass independently predicts incident vertebral fractures in breast cancer patients given adjuvant aromatase inhibitor therapy and denosumab

277P Fat body mass independently predicts incident vertebral fractures in breast cancer patients given adjuvant aromatase inhibitor therapy and denosumab

Effects of Non-Ablative Solid-State Vaginal Laser (SSVL) for the Treatment of Vulvovaginal Atrophy in Breast Cancer Survivors after Adjuvant Aromatase Inhibitor Therapy: Preliminary Results.

One of the side effects of anti-estrogen treatments in breast cancer survivors (BCSs), especially with aromatase inhibitor (AI) treatment, is the frequent appearance of vulvo-vaginal atrophy (VVA). We aim to evaluate the efficacy, safety and feasibility of a new type of non-ablative Solid-State Vaginal Laser (SSVL) treatment in BCSs with VVA. A total of 30 BCSs with a history of AI use and symptoms of VVA were treated with a non-ablative SSVL (LASEmaR 1500™-EUFOTON)in this non-randomized pilot study. The effects of the laser have been evaluated at baseline, 10 wk and 24 wk using a visual analogue scale (VAS), the Vaginal Health Index (VHI), the Vulvar Health Index (VuHI), the Female Sexual Function Index (FSFI), the EORTC QLQ-BR23, the Vaginal Maturation Index (VMI) and vaginal pH. At 10-week follow-up vs. baseline there were no statistically significant differences in FSFI, lubrication and EORTC QLQ-BR23. In all the subjective (dyspareunia, VHI, VuHI, FSFI, QLQ) and objective parameters (VMI and pH) there was a statistically significant improvement at the 6-month follow-up. Satisfaction was very high (4.7 out of 5), with 95.7% of patients being satisfied, more than or very satisfied. Preliminary results of SSVL treatment of VVA and dyspareunia in BCSs after AI treatment suggest clinical improvement, without relevant side effects and with a high degree of satisfaction.

Vinorelbine-related tetraplegia due to severe peripheral neuropathy.

Vinorelbine, a semi-synthetic vinca alkaloid with anticancer activity by binding to tubulin, has shown to be successful in the treatment of cancer types including advanced non-small cell lung cancer, uterine cancer, and metastatic breast cancer. Myelosuppression, hematological effects, nausea, vomiting, exhaustion, and neuropathy are some of the most typical side effects of vinorelbine. We discuss the unusual presentation of vinorelbine-induced tetraplegia in a breast cancer patient. A 66-year-old patient with breast cancer, who was followed up with adjuvant aromatase inhibitor therapy after mastectomy, presented with lung and bone metastases. She progressed in the follow-ups after receiving platinum and taxane chemotherapy, vinorelbine treatment was then started. The patient complained of weakness, weariness, and trouble walking after receiving a total dose of 180 mg. Tetraplegia was found after a neurological assessment. It was thought that vinorelbine was responsible for the recent acute weakness. The patient's vinorelbine treatment was stopped. During follow-up, upper extremity paresis regressed, while lower extremities muscle strength remained unchanged. Vinorelbine, frequently used in oncology practice, causes some side effects. Although very rare in the literature, in this case severe peripheral neuropathy has been reported in the follow-up of post-vinorelbine quadriparesis.

Abstract OT1-04-01: AMEERA-6: Phase 3 Study of Adjuvant Amcenestrant Versus Tamoxifen for Patients With Hormone Receptor-Positive Early Breast Cancer, Who Have Discontinued Adjuvant Aromatase Inhibitor Therapy Due to Treatment-related Toxicity

Abstract Background: About 30% of patients (pts) with hormone receptor (HR)-positive early breast cancer (EBC) on adjuvant aromatase inhibitor (AI) therapy discontinue due to toxicity with 22% of pts discontinuing during the first year (Henry et al. JCO 2012). For these patients who struggle with adjuvant AIs, there are limited alternatives including switch to a different AI which may have similar side effects, tamoxifen, or observation. This paucity of effective and tolerable options may contribute to poor adherence and/or early discontinuation of adjuvant endocrine therapy, which is associated with worse outcomes. Amcenestrant (SAR439859) is an optimized oral selective estrogen receptor degrader (SERD) with potent dual activity which antagonizes and degrades the estrogen receptor (ER), resulting in inhibition of the ER signaling pathway. In the phase 1/2 AMEERA-1 first-in-human trial (SABCS 2020 PD8-08), amcenestrant showed strong antitumor activity and favorable safety profile in the treatment of HR+ metastatic breast cancer. The phase 2 window-of-opportunity study AMEERA-4 evaluating two doses of amcenestrant demonstrated robust Ki67 reductions, strong engagement of the ER target, and continued to show a favorable safety profile in an early breast cancer population. Based on pharmacodynamic activity, safety, and emerging results from other ongoing amcenestrant trials, the 200 mg daily dose of amcenestrant was selected for the AMEERA-6 study. Trial Design: This is a prospective, randomized, international, double-blind, double-dummy, phase 3 superiority study of amcenestrant versus tamoxifen. Eligible pts are men and women with any menopausal status with HR+ stage IIB/III breast cancer, irrespective of human epidermal growth factor receptor 2 (HER2) status. If neoadjuvant systemic therapy was administered, pts must have residual nodal disease after definitive breast surgery (ypN1-3). Pts will be centrally assessed to have ER-positive and/or progesterone receptor-positive (≥10% positive stained cells) status by immunohistochemistry assay. Pts must have received at least 6 months of adjuvant AIs (≥3 months in the adjuvant setting if they received prior neoadjuvant AI) and discontinued within 30 months of initiation due to AI-related toxicity. Pts may have been treated with more than one AI. All adjuvant therapies including chemotherapy, anti-HER2 treatment, cyclin-dependent kinase (CDK) 4/6 inhibitor, and/or poly (ADP-ribose) polymerase (PARP) inhibitors must be completed or stopped prior to randomization. 3738 pts will be randomized 1:1 to receive either amcenestrant 200 mg daily or tamoxifen 20 mg daily for 5 years and will be followed for 10 years from randomization. Men and pre/peri-menopausal women will also receive a GnRH analog. Extended adjuvant endocrine therapy upon completion of study treatment is allowed per investigator discretion. Stratification factors include duration of prior AI therapy, HER2 status and prior chemotherapy, prior CDK4/6 inhibitors, geographic region, and menopausal status. The primary endpoint is invasive breast cancer-free survival (IBCFS) based on STEEP criteria version 2.0 defined as occurrence of first recurrence of the disease: ipsilateral or regional invasive, distant recurrence, contralateral invasive breast cancer and death. Key secondary endpoint is invasive disease-free survival (IDFS) and other secondary endpoints include overall survival, safety, patient reported outcomes, and pharmacokinetics of amcenestrant. Adherence to treatment and biomarkers are exploratory endpoints. AMEERA-6 recruited the first patient in March 2022 and is being conducted in partnership with AFT, BIG, EORTC, and Sanofi. Clinical trial information: NCT05128773 Citation Format: Otto Metzger, Christina Herold, Coralie Poncet, Heidi De Swert, Jose Casas-Martin, Ann Partridge, Samia Guita, Lisa Carey, Eva Schumacher, Theodora Goulioti, Thomas Meyskens, Joseph Gannon, Khadija Benlhassan, Giovanna Rossi, Eleni Xenophontos, Amal Arahmani, Amylou C. Dueck, Gautier Paux, Etienne Brain, David A. Cameron. AMEERA-6: Phase 3 Study of Adjuvant Amcenestrant Versus Tamoxifen for Patients With Hormone Receptor-Positive Early Breast Cancer, Who Have Discontinued Adjuvant Aromatase Inhibitor Therapy Due to Treatment-related Toxicity [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-04-01.

Abstract CC1-2-1: Duration of endocrine therapy

Abstract Patients with hormone-receptor positive, early-stage breast cancer are at considerable risk for late recurrence. Previous randomized clinical trials have shown that extending adjuvant tamoxifen to ten vs. five years improves disease-free survival (and overall survival in one trial). Adding five years of an aromatase inhibitor (AI) after five years of tamoxifen has also been shown to significantly improve disease-free survival in postmenopausal patients. Benefit from extending adjuvant AI therapy beyond five years in patients who have received five years of an AI or tamoxifenàAI has also been recently demonstrated in several clinical trials but the absolute benefit appears small and the ideal duration of the extended therapy is still a topic of debate. Over the past decade, efforts have focused on identifying predictors of risk of late recurrence and predictors of benefit from extended endocrine therapy. Clinicopathologic factors and circulating tumor cells can predict risk of late recurrence but not benefit from extended ET. Several commercially available genomic classifiers can further stratify risk of late recurrence, and some have also been found to predict benefit from extended ET. Their clinical utility for tailoring the use of extended endocrine therapy continues to evolve. Citation Format: Eleftherios (Terry) Mamounas, Kathryn Ruddy. Duration of endocrine therapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr CC1-2-1.

The clinical effectiveness of denosumab (Prolia®) in patients with hormone-sensitive cancer receiving endocrine therapy, compared to bisphosphonates, selective estrogen receptor modulators (SERM), and placebo: a systematic review and network meta-analysis.

This study assessed the effectiveness and safety of denosumab (Prolia®) compared to bisphosphonates (alendronate, ibandronate, risedronate, zoledronate), selective estrogen receptor modulators (SERMs) (bazedoxifene, raloxifene) and placebo for the treatment of osteoporosis in hormone-sensitive cancer patients receiving endocrine therapy (men with prostate cancer [MPC] on hormone ablation therapy [HAT], and women with breast cancer [WBC] on adjuvant aromatase inhibitor therapy [AAIT]). Systematic literature searches were conducted in three biomedical databases to identify randomized controlled trials (RCTs). Frequentist network meta-analyses and/or pairwise meta-analyses were performed on predetermined outcomes (i.e., vertebral/nonvertebral fractures, bone mineral density [BMD], mortality, treatment-related adverse events [AEs], serious AEs [SAEs], withdrawal due to treatment-related AEs). A total of 14 RCTs (15 publications) were included. Denosumab was found to prevent vertebral fractures in cancer patients receiving endocrine therapy, relative to placebo. Similarly, denosumab, zoledronate, and alendronate improved BMD at the femoral neck (FN) and lumbar spine (LS) in MPC on HAT, relative to placebo. Denosumab, ibandronate and risedronate improved BMD at the LS and total hip (TH) in WBC on AAIT, relative to placebo. Denosumab and risedronate improved trochanteric (TRO) BMD in WBC on AAIT, relative to placebo. Similarly, denosumab improved FN BMD in WBC on AAIT. In MPC on HAT, denosumab (relative to placebo) was effective at preventing vertebral fractures and improving BMD at the FN and LS. Moreover, in WBC on AAIT, denosumab (relative to placebo) improved BMD at the FN, LS, TH, and TRO, as well as prevent vertebral fracture.

Increased Clinical Pain Locations and Pain Sensitivity in Women After Breast Cancer Surgery: Influence of Aromatase Inhibitor Therapy.

Aromatase inhibitors (AIs), which potently inhibit estrogen biosynthesis, are a standard treatment for hormone sensitive early-stage breast cancer. AIs have been associated with substantial joint pain and muscle stiffness (aromatase inhibitor-associated musculoskeletal syndrome). However, the link between AIs and number of clinical pain locations and pain sensitivity are less well understood. The aim of this study was to compare longitudinal changes in clinical pain and quantitative pain sensitivity between women who did or did not receive AI therapy. Women with early-stage breast cancer were prospectively enrolled and assessed for clinical pain in surgical and nonsurgical body areas using the Brief Pain Inventory and Breast Cancer Pain Questionnaire, and for pain sensitivity using quantitative sensory testing preoperatively and at 1 year postoperatively. Pain outcomes between participants who did and did not begin adjuvant AI therapy were compared using Wilcoxon Signed-Ranks and generalized estimating equation linear regression analyses. Clinical pain and pain sensitivity were comparable between AI (n=49) and no-AI (n=106) groups preoperatively. After adjusting for body mass index, AI therapy was associated with a greater increase in the number of painful nonsurgical body sites (significant time by treatment interaction, P =0.024). Pain location was most frequent in knees (28%), lower back (26%), and ankles/feet (17%). Quantitative sensory testing revealed a significant decrease in pain sensitivity (increased pressure pain threshold) in the no-AI group over time, but not in the AI group. AI therapy was associated with increased diffuse joint-related pain and greater post-treatment pain sensitivity, potentially implicating central sensitization as a contributing pain mechanism of aromatase inhibitor-associated musculoskeletal syndrome worthy of future investigation.

Sleep disturbances and restless legs syndrome in postmenopausal women with early breast cancer given adjuvant aromatase inhibitor therapy

IntroductionWhether adjuvant therapy with aromatase inhibitors (AIs) causes sleep disturbances or not in postmenopausal women with early breast cancer (EBC) is still a controversial issue. MethodsBetween March 2014 and November 2017, validated questionnaires for assessing insomnia, anxiety, depression, quality of life (QoL) and restless legs syndrome (RLS) were administered to 160 EBC patients at baseline and after 3, 6, 12, and 24 months of AI therapy. ResultsAI therapy significantly decreased the patients’ QoL, but did not influence insomnia, anxiety or depression. However, it significantly increased the frequency and severity of RLS. Patients with RLS at baseline (19%) or who developed RLS during AI therapy (26.3%) reported statistically lower quality of sleep, higher anxiety and depression, and worse QoL compared to patients who never reported RLS (54.7%). ConclusionAlthough AI therapy does not affect sleep quality, it may increase RLS frequency. The presence of RLS could identify a group of EBC patients who may benefit from psychological support.

Adjuvant aromatase inhibitor therapy and early markers for cardiovascular disease in breast cancer survivors.

Aromatase inhibitors (AIs) are an important component of the adjuvant treatment of hormone receptor positive breast cancer (BC) but concerns regarding their cardiovascular safety remain. In this cross-sectional study nested in a breast cancer cohort, we investigated the association between AI exposure and early markers for cardiovascular disease in BC survivors. The study population consisted of 569 women, who were 5-7years (n = 277) or 10-12years (n = 292) after BC diagnosis. All participants underwent carotid ultrasound, skin autofluorescence measurement and laboratory evaluation. To quantify AI exposure, we obtained the AI ratio by dividing the duration of AI use by the total duration of endocrine therapy (ET). Patients were classified according to their AI ratio into low (no ET or AI ratio < 0.40), intermediate (0.40 ≤ AI ratio ≤ 0.60) or high AI exposure (AI ratio > 0.60). The association between AI ratio and carotid intima media thickness (cIMT), advanced glycation end products (AGEs) and the presence of dyslipidemia was assessed using linear and logistic regression. Median age at study visit was 55.5years (range 45.2-63.8). Forty percent (n = 231) of the study population had used AIs, of whom the majority sequentially with tamoxifen; median duration of AI use was 3.0years. Mean cIMT and mean AGEs did not differ across AI exposure groups in univariable and multivariable analysis. The occurrence of dyslipidemia did not vary across AI exposure groups. Intermediate AI exposure was associated with more frequent occurrence of the combined endpoint (elevated cIMT, elevated AGEs and/or dyslipidemia). This association, however, was not present in the group with highest AI exposure. AI exposure was not associated with cIMT, AGEs or the presence of dyslipidemia. These results do not prompt a change in current clinical practice, although further research is warranted to validate our findings over time and in different BC populations. Trial registration number (clinicaltrials.gov): NCT02485626, June 30, 2015.

Efficacy and Safety of Monthly Minodronate Therapy in Postmenopausal Breast Cancer Patients Receiving Aromatase Inhibitors.

Post-menopausal breast cancer (BC) patients who receive adjuvant aromatase inhibitor (AI) therapy may be at increased risk of bone loss, osteoporosis, and bone fracture. We aimed to evaluate the efficacy and safety of oral bisphosphonate minodronate in preventing bone loss complications. Patients receiving AI and 80% of those with suboptimal bone mineral density (BMD) were prescribed monthly oral minodronate 50 mg every 4 weeks for 72 weeks. BMD, bone metabolism markers, incidence of bone fractures, medication compliance, and other adverse events (AE) were examined every 24 weeks following administration. Fifty postmenopausal BC patients with a median age of 64.0 years were enrolled. The mean value of lumbar spine BMD was higher than that of the value before the minodronate administration at each observation point. Before and after the treatment, the median serum values of Tartrate-resistant Acid Phosphatase 5b (TRACP-5b) (mU/dl) and serum type I collagen cross-linked N-telopeptide (NTX) (nmolBCE/l) were decreased from 535.7 and 18.5 to 230.1 and 11.9, respectively. No adverse grade 2 or higher event was observed throughout this study. The combined administration of minodronate and AIs was safe and effective in preventing bone loss complications in postmenopausal BC patients.

Socioeconomic disparities in supportive therapy use and tolerance of aromatase inhibitors in patients with early-stage, hormone-positive breast cancer.

523 Background: Socioeconomic disparities impact breast cancer survival with significantly higher mortality among women of lower socioeconomic status. Little is known about how disparities affect patients with early-stage hormone receptor positive (HR+) breast cancer (BC) and patients’ tolerance and adherence to standard of care adjuvant aromatase inhibitor (AI) therapy. AI-related adverse effects are common and can cause therapy intolerance and early discontinuation. Supportive therapies have been shown to improve symptom tolerability when utilized by patients. This study assessed socioeconomic disparities in utilization of supportive therapies and adherence to initial AI therapy. Methods: We performed a retrospective chart review of all female patients at our academic institution with early-stage, HR+, BC who were initiated on adjuvant AI between 2011-2020. We collected information on side effects, duration of first AI and use of supportive therapies. We linked median family income with zip codes based on national census data and sorted them based on the Pew Research Center categorization. Primary endpoints were the rate of discontinuation of AI at 1-year and utilization of supportive therapies in relation to income, insurance coverage and primary language. The Fisher's exact test, Pearson's Chi-squared test, and Wald test methods were used to compare rates of discontinuation of front-line AI therapy and use of supportive therapies for each group. Results: We identified 1006 patients of whom 95% (n = 954) had AI related side effects yet only 31% (n = 311) received supportive therapies in the first year of AI treatment. The majority (59%) of patients were in the middle-income range ($52,200-$156,000), followed by upper (24%) and lower (17%) income. Upper-income was associated with higher use of supportive therapies (OR 1.46, p = 0.031) but was not associated with lower 1-year discontinuation rate. Medicare was the most common insurance coverage (45%), followed by Commercial (32%) and Medicaid (23%). English was the primary language for 86% of patients. Neither insurance coverage nor primary language was associated with either endpoint. In evaluating race, Black patients had the least use of supportive therapies (p &lt; 0.001), yet this group had the lowest 1-year discontinuation rate (p = 0.005). Conclusions: Our results demonstrate that income and race were associated with use of crucial supportive therapies that are proven to help patients mitigate AI toxicities. The etiology of these disparities is likely multifactorial and requires further study to ensure equitable care and access for all patients.

Adjuvant study of amcenestrant (SAR439859) versus tamoxifen for patients with hormone receptor-positive (HR+) early breast cancer (EBC), who have discontinued adjuvant aromatase inhibitor therapy due to treatment-related toxicity (AMEERA-6).

TPS607 Background: There are currently limited treatment options for patients with HR+ EBC who have discontinued adjuvant treatment with aromatase inhibitors (AIs) due to treatment-related toxicity. Amcenestrant is an optimized oral selective estrogen receptor degrader (SERD) with potent dual activity which antagonizes and degrades the ER resulting in inhibition of the ER signalling pathway. Preliminary clinical evidence from the phase 1/2 AMEERA-1 trial has demonstrated meaningful antitumour activity and a favourable safety profile of amcenestrant in the treatment of HR+ advanced breast cancer (Linden HM, Campone M, Bardia A, et al: Abstract PD8-08: A phase 1/2 study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), as monotherapy and in combination with other anti-cancer therapies in postmenopausal women with ER-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC): AMEERA-1. SABCS 2020 PD8-08). Methods: AMEERA-6 is a prospective, randomized, international, double-blind, double-dummy, phase 3 study. 3738 patients will be randomized 1:1 to receive either amcenestrant 200 mg daily or tamoxifen 20 mg daily. Eligible patients are pre-or postmenopausal women or men with HR+ EBC (stage IIB-III) who have received at least 6 months of adjuvant AIs (at least 3 months in the adjuvant setting if they have received prior neoadjuvant AI therapy) and discontinued them within 30 months of initiation due to treatment-related toxicity. Participants will be centrally assessed to have ER+ and/or PgR+ (≥10% positive stained cells) status by immunohistochemistry assay. Prior use of adjuvant CDK4/6 inhibitors are allowed. Patients are eligible irrespective of HER2 status; for patients with HER2-positive disease adjuvant anti-HER2 treatment and chemotherapy must be completed prior to randomization. Stratification factors include: duration of AI therapy, HER2 status, prior chemotherapy, prior CDK4/6 inhibitors, geographic region, and menopausal status. Planned treatment duration is 5 years. Patients will be followed-up for 10 years from randomization. The primary endpoint is invasive breast cancer-free survival (IBCFS). Invasive disease-free survival is a key secondary endpoint, while other secondary endpoints include distant relapse-free survival (RFS), locoregional RFS, overall survival, breast-cancer specific survival, safety, patient reported outcomes and pharmacokinetics. Adherence to treatment is an exploratory endpoint. AMEERA-6 opened for recruitment in January 2022. Clinical trial information: NCT05128773.

90TiP Adjuvant study of amcenestrant (SAR439859) versus tamoxifen for patients with hormone receptor-positive (HR+) early breast cancer (EBC), who have discontinued adjuvant aromatase inhibitor therapy due to treatment-related toxicity (AMEERA-6)

About 30% of patients (pts) with HR+ EBC on treatment with aromatase inhibitors (AIs), discontinue AIs due to toxicity (Henry et al. JCO 2012). For this population, there are currently limited therapy options, including switch to another AI or tamoxifen. Amcenestrant is an optimized oral selective estrogen receptor degrader (SERD) with potent dual activity which antagonizes and degrades the estrogen receptor (ER), resulting in inhibition of the ER signaling pathway. In the phase 1/2 AMEERA-1 trial (SABCS 2020 PD8-08), amcenestrant showed strong antitumor activity and favorable safety profile in the treatment of HR+ metastatic breast cancer.

Abstract P5-18-11: Impact of supportive therapies on tolerance of aromatase inhibitors in patients with early-stage, hormone-positive breast cancer

Abstract Background: Aromatase inhibitors (AI) are standard of care in the treatment of early-stage hormone positive (HR+) breast cancer (BC). Commonly, these medications cause significant side effects which limit tolerability and often require a change in therapy. Supportive therapies are an essential part of treatment plans to improve adherence and quality of life. Studies in the last decade have demonstrated the critical role of supportive management in mitigating side effects from AI, such as the reduction in AI related joint pain with acupuncture or use of low dose oxybutynin for hot flashes. The aim of this study was to evaluate the real world use of supportive therapies for AI toxicities over the last decade and to determine if they were associated with patient adherence to initial AI treatment. Methods: We performed a retrospective chart review of all female patients at our academic institution with early-stage, HR+ BC who were initiated on adjuvant AI therapy between 2011-2020. From the electronic medical record, we collected information on patient demographics, AI side effects (hot flashes, vaginal dryness, joint pains, osteopenia/osteoporosis), use of supportive therapies, and duration of first AI therapy. Primary endpoint was the rate of discontinuation of AI at 1 year among those who used supportive therapies compared with those who did not. The Wilcoxon rank sum test, Fisher's exact test, Kruskal-Wallis rank sum test, and Pearson's Chi-squared test methods were used to compare rates of discontinuation of front-line AI therapy for each group. Results: We identified 990 patients (pts) with early-stage, HR+ BC who were started on adjuvant AI between 2011-2020. Of these patients, 97% (n= 963) had AI related side effects yet only 51% (n=504) received supportive therapies. The overall discontinuation rate within 1 year was 14.8% (147 of 990 pts). Patients who received at least 1 supportive therapy were more likely to remain on AI and had a lower 1 year discontinuation rate of 10% (51 of 504 pts) compared to 20% (96 of 486 pts) for those who did not receive any supportive therapy (p&amp;lt;0.001). The most commonly used supportive therapies were bone strengthening agents, with 35.6% (n=352) of patients receiving either denosumab or zoledronic acid, followed by acupuncture used in 11.2% (n=111) of patients. The use of acupuncture increased in 2018, compared to years prior (35 pts from 2011-2017, and 76 pts from 2018-2020). Similarly, oxybutynin use increased in 2019, compared to years prior (9 pts from 2011-2018, and 28 pts from 2019-2020). Upon further analysis, younger age was significantly associated with a higher 1 year discontinuation rate (median age 62 years in &amp;lt;1 year AI treatment group, and 64 years in &amp;gt;1 year AI treatment group, p=0.003). Race also appeared to have an impact on AI tolerance. Although only 31% (39 of 126 pts; p &amp;lt; 0.001) of Black patients received supportive therapy, this group had the lowest 1 year discontinuation rate at 8.7% (11 of 126 pts). Conversely, 56% (277 of 491 pts) of White patients received at least one supportive therapy, yet had the highest 1 year discontinuation rate at 17% (83 of 491 pts). Conclusions: Supportive therapies are essential to help patients mitigate side effects of AI. Patients who received at least one supportive therapy had increased rates of AI adherence beyond 1 year compared to those who did not receive any supportive treatment. The most commonly used therapies were bone strengthening agents and acupuncture. Use of acupuncture and low dose oxybutynin have increased in the past 3 years and 2 years, respectively, following publication of their efficacy. It is critical to further evaluate the impact that race and age have in relation to duration of treatment and use of supportive management. Further studies on how to improve patient tolerability and adherence to AI therapy are needed. Citation Format: Melanie W Kier, Zhiqiang Li, Brittney S Zimmerman, Rima Patel, Yunchen Yang, Mark Y Fink, Jason D Wells, Xiang Zhou, Scott Newman, Rong Chen, Eric Schadt, William Oh, Amy Tiersten. Impact of supportive therapies on tolerance of aromatase inhibitors in patients with early-stage, hormone-positive 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 P5-18-11.

Abstract OT2-11-06: SERENA-4: A Phase III 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

Abstract 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. In most countries, current standard-of-care first-line treatments include an aromatase inhibitor or fulvestrant, a selective ER degrader, combined with cyclin-dependent kinase 4/6 inhibitors. Concurrent use of luteinizing hormone-releasing hormone agonists is recommended for men and premenopausal women with ABC. Nevertheless, almost all ABCs eventually become resistant to endocrine therapy and the disease is incurable in these cases. New therapies are needed to combat endocrine therapy resistance, maintain patient health-related quality-of-life, and delay the need for chemotherapy. AZD9833 (camizestrant) is a highly potent, next-generation selective ER degrader and pure ER antagonist that has demonstrated anticancer properties across a range of preclinical models, including those with ER-activating mutations (Scott et al, AACR 2020). A Phase I dose-escalation and expansion study (SERENA-1) has demonstrated that AZD9833 is well tolerated and has a promising antitumor activity when administered alone or in combination with the cyclin-dependent kinase 4/6 inhibitor palbociclib (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 systemic treatment in the advanced disease setting. Methods: SERENA-4 will enroll 1342 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 aromatase inhibitor or tamoxifen therapy for at least 24 months without relapse. Patients will be randomized 1:1 to receive oral treatment with either (a) AZD9833 75 mg once daily, palbociclib 125 mg once daily for 21 days followed by 7 days off treatment and a placebo for anastrozole 1 mg once daily or (b) anastrozole 1 mg once daily, palbociclib (same as active arm) and a placebo for AZD9833 75 mg once daily. Men and premenopausal women will also receive a luteinizing hormone-releasing hormone agonist. The primary endpoint is progression-free survival (PFS; up to 5 years). Secondary endpoints include overall survival (up to 8 years), second PFS, time to chemotherapy, objective response rate, and changes in health-related quality-of-life measures. Enrollment began in January 2021. As of 02 July 2021, the number of open sites is 57 across 15 countries. Acknowledgments: We thank Julia Mawer, PhD, of Oxford PharmaGenesis, Oxford, UK, for providing medical writing support funded by AstraZeneca Funding: The SERENA-4 trial is funded and overseen by AstraZeneca. © 2021 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2021 ASCO Annual Meeting. All rights reserved. Citation Format: Fabrice André, Seock-Ah Im, Patrick Neven, Richard D Baird, Johannes Ettl, Matthew P Goetz, Erika Hamilton, Hiroji Iwata, Zefei Jiang, Anil Abraham Joy, Vincent Haddad, Andrew Walding, Manuel Selvi Miralles, Cynthia Huang Bartlett, Antonio Llombart-Cussac. SERENA-4: A Phase III 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 [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 OT2-11-06.

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.

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

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

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.