Adjuvant Aromatase Inhibitors Research Articles

Bone mineral density in women with breast cancer receiving adjuvant aromatase inhibitors and anti-resorptive treatment - healthy living after breast cancer

Bone mineral density in women with breast cancer receiving adjuvant aromatase inhibitors and anti-resorptive treatment - healthy living after breast cancer

Abstract PO4-19-12: Trial in progress: An Observational Study to Examine Changes in Metabolic Syndrome Components in Patients With Breast Cancer Receiving (Neo)Adjuvant Aromatase Inhibitors

Abstract Background: (Neo) adjuvant systemic therapy has been shown to adversely impact metabolic health manifested as weight gain, dyslipidemia, and insulin resistance, which ultimately lead to the development of metabolic syndrome (MetS). MetS increases the risk of development for type 2 diabetes mellitus and cardiovascular disease and is associated with an increased risk of breast cancer recurrence, death due to breast cancer, and all-cause mortality. We have previously reported that 76% of metabolically healthy women receiving (neo) adjuvant chemotherapy will develop MetS at a median of 15 weeks. The impact of aromatase inhibitors (AIs) on metabolic health has not been systematically assessed in a longitudinal study. We hypothesize that AIs in the (neo) adjuvant setting will alter metabolic parameters and have embarked on a clinical trial to study this. Methods: This is a prospective observational study that will include: postmenopausal patients with newly diagnosed, early-stage hormone receptor (HR)-positive breast cancer with planned (neo)adjuvant treatment with an AI. Participants will be excluded if they have received or have planned treatment with (neo)adjuvant chemotherapy or are currently receiving antidiabetic medications or cholesterol-lowering agents. All patients will undergo a baseline assessment that includes: BMI, physical exam inclusive of blood pressure, waist circumference, assessment of body fat, lipid profile, insulin, metabolic biomarkers, and completion of the Functional Assessment of Cancer Therapy – Endocrine Symptoms (FACT-ES). Following institution of an AI, reassessment of the aforementioned tests will be repeated after 4 months and 12 months of therapy. The primary endpoint is the change in insulin resistance (as measured by HOMA-IR, homeostatic model assessment for insulin resistance) at 4 months. Secondary endpoints include the change in HOMA-IR at 12 months and the change in individual MetS components, metabolic biomarkers, anthropometric measurements, as well as FACT-ES scores from baseline to 4- and 12-months of AI treatment. The mean paired differences will be calculated for HOMA-IR measurements as well as for the secondary endpoints, and the 1-sided paired t-test will be used to test for statistical significance. One-way analysis of covariance will be used to compare means while adjusting for age, race/ethnicity, and BMI. Using a 1-sided paired t-test for the mean difference in HOMA-IR measurements from baseline to 4 months, we will have 80% power to detect an effect size of 0.405 with 40 patients (α = 0.05). Enrollment began in April 2023 and is ongoing. Contact alevee@coh.org for more information. Given the increased recognition of the importance of metabolic health in breast cancer outcomes, this data will inform future trials that focus on maintaining metabolic health in breast cancer survivors. Citation Format: Alexis LeVee, Nora Ruel, Victoria Seewaldt, Joanne Mortimer. Trial in progress: An Observational Study to Examine Changes in Metabolic Syndrome Components in Patients With Breast Cancer Receiving (Neo)Adjuvant Aromatase Inhibitors [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-19-12.

Abstract PO1-12-10: Zoledronic acid to prevent rebound fractures after stopping adjuvant denosumab: a randomized controlled sub-study of the ABCSG-18 trial

Abstract Introduction ABCSG-18 trial showed that 60mg denosumab subcutaneously every 6 months halves fracture risk in postmenopausal patients with early breast cancer, who are treated with adjuvant aromatase inhibitors. However, it has been reported that stopping denosumab may lead to overactivation of osteoclasts resulting in so called rebound vertebral fractures. As shown previously, zoledronic acid (ZA), when given to patients of the ABCSG-18 trial after stopping denosumab prevents a high bone turnover state that can occur in some patients. Here we report the impact of a single ZA dose on bone mineral density (BMD) and fractures after stopping denosumab. Methods ABCSG-18 trial patients, who had received adjuvant denosumab were re-randomized to receive a single dose of ZA 5mg i.v. or not, 8 months +- 4 weeks after their last denosumab dose. DXA scans, lateral spine X-rays and bone turnover markers (CTX and osteocalcin) were assessed at baseline and at 6, 12 and 18 months thereafter. New clinical fractures were assessed until 18 months after randomization. Results 50 patients were randomized to either ZA (24pts) or control (26pts). All patients of the ZA arm and 25 out of 26 patients of the control arm had received 7 doses of denosumab within the ABCSG 18 trial before re-randomization. Baseline bone health factors were well balanced between the 2 arms: Baseline BMD did not differ between the two arms with regard to femoral neck (ZA: 0.817 g/cm2; SOC: 0.816g/cm2), total hip (ZA: 0.918g/cm2; SOC: 0.921g/cm2) and lumbar spine (ZA: 1.128 g/cm2; SOC 1.142 g/cm2), respectively. Relative changes in BMD differed significantly between both arms for femoral neck after 12 months (ZA: 0.5%; control: -4.98%, p 0.004) and for total hip after 6 months (ZA: -0.73%; control: -4.61%, p< 0.001) and after 12 months (ZA: -0.13%; control: -5.62%; p< 0.001). There was a trend towards a greater decline in BMD at lumbar spine after 6 months in the control arm versus the ZA arm (-3.35% vs 0.67%, p=0.052). After randomization, 3 asymptomatic fractures (lumbar vertebral and thoracic vertebral in one patient and thoracic vertebral in a second patient) occurred in the ZA arm, whereas 2 clinical fractures (one radius fracture and one lumbar vertebral fracture) occurred in the SOC arm. Conclusion A single dose of Zoledronic acid prevents high bone turnover state resulting in loss of BMD in some patients after stopping denosumab. ZA may therefore be offered to breast cancer patients with aromatase inhibitor after stopping denosumab. Citation Format: Georg Pfeiler, Christian F. Singer, Dominik Hlauschek, Manfreda Diether, Ferdinand Haslbauer, Paul Sevelda, Kristin Köck, Karl Tamussino, Arno C. Reichenauer, Florian Fitzal, Dietmar Heck, Richard Greil, Claudia Pasterk, Sonja Heibl, Walter Herz, Marija Balic, Daniel Egle, Lidija Sölkner, Michael Gnant. Zoledronic acid to prevent rebound fractures after stopping adjuvant denosumab: a randomized controlled sub-study of the ABCSG-18 trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-12-10.

Abstract PS17-04: Clinical and Genomic Features of ER-Positive/HER2-negative Metastatic Breast Cancer in AURORA Molecular Screening Initiative (BIG 14-01): Mechanisms of Endocrine Therapy Resistance and Implications for Adjuvant Approaches

Abstract Background: Up to 30% of patients (pts) with ER-positive early breast cancers develop metastatic relapse. The molecular differences between endocrine therapy (ET)-sensitive and ET-resistant relapses, as well as the impact of specific adjuvant ET-based therapies, remain unclear. Methods: The AURORA program (NCT02102165) analyzed multi-omics data of paired primary (prim) and metastatic (meta) tumor tissue, along with plasma samples, from 1,156 patients with metastatic breast cancer (MBC). Targeted genome sequencing (TGS), RNA sequencing, and circulating tumor DNA analysis were performed. ET-resistance at MBC diagnosis was defined following the 5th ESO-ESMO ABC Guidelines. Results: We studied 628 pts with metastatic ER+/HER2- disease. Patient´s median age was 56 years, 133 (21%) were premenopausal, 314 (50%) had ET-resistance at recurrence (9% primary, 41% secondary), 132 (21%) had ET-sensitive recurrence, and the rest were ET-naive recurrences or de novo MBC. Adjuvant treatment was aromatase inhibitor (AI) +/- ovarian function suppression (OFS) in 288 (46%) pts, while 159 (25%) had tamoxifen only (+/- OFS). Gene expression correlation significantly differed (p < 0.005) based on ET-resistance in 92 paired samples. ET-sensitive (n=11) and de-novo tumors (n=41) showed higher correlation than primary (n=7) and secondary ET-resistance (n=32), regardless of adjuvant ET type. Prim and meta showed concordance in 91% of IHC subtypes and 62% of intrinsic subtypes. Intrinsic subtype showed 9% of prim luminal tumors switching to meta non-luminal, with 66% of Luminal A switching to Luminal B. Neither IHC nor intrinsic subtype switching was associated with the type of adjuvant ET or ET resistance. Pts with meta non-luminal intrinsic subtype (18%) had worse PFS on CDK4/6i (HR 4.0, 95% CI 1.9-8.7) and OS (HR 3.6, 95% CI 2.0-5.7) than luminal subtypes. TGS was performed in 534 meta (365 before 1L, 305 pairs). In meta before 1L, the dN/dS algorithm revealed selection in 17 genes, including TP53, PIK3CA, and ESR1. Mutations (mut) in ESR1, ERBB2, ERBB3, and RB1 among others, were specifically identified in meta. The incidence of ESR1mut was 3% in prim, 12.6% before 1L, 23.4% after 1L, and 4.7% in meta from ET-naive tumors (Table). Before 1L, ESR1mut was higher after adjuvant AI vs tamoxifen (21% vs. 4%, p< 0.001). ESR1mut incidence varied with ET-resistance (16% primary, 19% secondary, 9% sensitive, 4% ET-naïve/de novo, p< 0.01). Paired samples showed that ESR1mut were mainly acquired events and associated with higher ER mRNA signaling (hallmark estrogen response) compared to ESR1wt (p < 0.05). The agreement between ESR1mut detected in ctDNA and tissue was high before 1L (90%), and slightly lower after 1L (84%). In a multivariate model with relevant clinical factors, ESR1mut were associated with worse OS (HR 1.76, 95% CI 1.2-2.5, p=0.003), independently of TP53 and PIK3CA mutational status. Conclusion: AURORA study sheds light on metastatic tumor alterations acquired under anti-cancer therapy, in ER+/HER2- MBC. We observed a high prevalence of acquired ESR1mut prior to the initiation of first-line therapy, particularly in tumors exposed to adjuvant AI or with primary or secondary ET_resistance. The association of ESR1muts with poorer OS underscores the importance of implementing effective adjuvant ET strategies to prevent the emergence of these mutations. Frequency of driver gene mutations in primary and metastastic tumors before 1st-line treatment according to adjuvant ET and type of ET resistance Table. Citation Format: Angel Guerrero-Zotano, Matteo Benelli, Alexandre Irrthum, David Cameron, Lorenzo Ferrando, Dario Romagnoli, Marta Paoli, Arnau Llinas, Maya Dadiani, Danai Fimereli, Mafalda Oliveira, Carmela Caballero, Thayane Crestani, Elisa Agostinetto, Diogo Martins-Branco, Florentine Hilbers, Einav Gal-Yam, Marija Balic, Fatima Cardoso, Jorge Reis-Filho, Christos Sotiriou, Giuseppe Curigliano, Barbro Linderholm, Evandro de Azambuja, Susan Knox, Cristina Rotaru, Eva Ciruelos, Nancy E Davidson, Giuseppe Viale, Donatienne Taylor, Jean-Luc Canon, Lourdes Calvo, Joan Albanell, Marco Colleoni, Caroline Duhem, Nadia Harbeck, Catherine Herremans, Sibylle Loibl, Sandrine Marreaud, Elsemieke Scheepers, Alice Raimbault, Theodora Goulioti, Andrea Vingiani, Chiara Biagioni, Sebastian Vosberg, Gabriele Zoppoli, Jose Seoane, David Venet, Philippe Aftimos, Martine Piccart. Clinical and Genomic Features of ER-Positive/HER2-negative Metastatic Breast Cancer in AURORA Molecular Screening Initiative (BIG 14-01): Mechanisms of Endocrine Therapy Resistance and Implications for Adjuvant Approaches [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS17-04.

Abstract PO4-19-09: Comparison of clinical efficacy between letrozole + ribociclib vs. Fulvestrant + letrozole + ribociclib in Hormone receptor positive, HER2 negative metastatic breast cancer – a randomized, phase 2 study (KCSG BR22-20)

Abstract Background The current standard first-line treatment in advanced or metastatic hormone receptor (HR) positive breast cancer is combination of aromatase inhibitor (AI) and cyclin D kinase-4/6 (CDK4/6) inhibitor. Emergence of ESR1 mutation is a key mechanism of resistance during first-line AI + CDK4/6 inhibitor treatment. Selective estrogen receptor downregulator (SERD) such as elacestrant or fulvestrant is suggested as second-line treatment, but the progression-free survival (PFS) outcome of second-line treatment is reported up to 3.78 months in patients who harbour ESR1 mutation. Recently, early switch of AI + CDK4/6 inhibitor to fulvestrant + CDK4/6 inhibitor at the point of rising ESR1 mutation showed prolongation of PFS up to 6 months, suggesting there may be a new strategy to overcome ESR1 mutation by modifying endocrine treatment. SWOG S0226 suggested that upfront fulvestrant + AI is feasible and associated with prolongation of PFS compared to AI alone. After CDK4/6 inhibitor has been introduced to standard treatment, there were no trials evaluating the role of AI + fulvestrant with CDK4/6 inhibitor. In this trial, we investigated triplet combination of AI + fulvestrant + CDK4/6 inhibitor as a treatment to overcome resistant mechanism such as development of ESR1 mutation when compared to current standard treatment of AI + CDK4/6 inhibitor as the first line treatment in HR positive advanced or metastatic breast cancer. Methods This study is a randomized, multicenter, open-label phase II trial comparing AI plus ribociclib versus AI, fulvestrant plus ribociclib in HR-positive advanced or metastatic breast cancer. De novo patients or patients with treatment-free interval (TFI) over 12 months after completion of adjuvant AI can be enrolled. If patients received adjuvant tamoxifen, patients with TFI less than 12 months can be also enrolled for the study. Prior endocrine treatment or cytotoxic chemotherapy at metastatic setting was not allowed. In cases of premenopausal women, gonadotropin releasing hormone agonist (GnRHa) is administered every 4 weeks with treatment. A total of 202 patients will be enrolled for 30 months, and 30 months of follow-up is planned after last-patient enrolment. Patients are randomized to 1:1, stratified based on the presence of visceral metastasis and previous administration of adjuvant AI. Study treatment of the control arm consists of letrozole 2.5mg daily with ribociclib 600mg (Day 1-Day 21 daily by month, 1 week off) until progression. In the experimental arm fulvestrant 500mg intramuscular injection is added (Day 1, Day 15, Day 29 and every 4 weeks thereafter) until progression. For exploratory analysis of ESR1 mutations, circulating tumor DNA (ctDNA) is collected at baseline, and then every 3 months thereafter. Primary endpoint is to evaluate the difference of 24-months PFS rate. Secondary endpoint included PFS, overall survival (OS), emergence and frequency of ESR1 mutation, overall response rate (ORR) and clinical benefit rate (CBR). The analysis is planned after completion of 30 months of follow-up, which provides approximately 90% power to detect superiority 24 months-PFS rate assumed by Kaplan-Meier curve of letrozole + fulvestrant + ribociclib versus letrozole + ribociclib using a log-rank test, assuming a hazard ratio of 0.64 at a two-sided alpha of 0.2. Citation Format: Jieun Lee, Su-Jin Koh, Jung Hye Kwon, Gun Min Kim, Jee Hung Kim, Ho Young Kim, Hee-Jun Kim, Keon-Uk Park, Kyong Hwa Park, Yeon Hee Park, Mi Sun Ahn, Hee Kyung Ahn, Gyeong-Won Lee, Kyoung Eun Lee, Kyung-Hun Lee, Moon Hee Lee, Sung Sook Lee, Jung Lim Lee, Kyung Hae Jung, Joo Young Jung, In Hae Park. Comparison of clinical efficacy between letrozole + ribociclib vs. Fulvestrant + letrozole + ribociclib in Hormone receptor positive, HER2 negative metastatic breast cancer – a randomized, phase 2 study (KCSG BR22-20) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-19-09.

Endothelial dysfunction in breast cancer survivors on aromatase inhibitors: changes over time

BackgroundBreast cancer is estimated to comprise about 290,560 new cases in 2022. Aromatase inhibitors (AIs) are recommended as adjuvant treatment for estrogen-receptor positive (ER+) breast carcinoma in postmenopausal women, which includes approximately two-thirds of all women with breast cancer. AIs inhibit the peripheral conversion of androgens to estrogen by deactivation of the aromatase enzyme, leading to a reduction in serum estrogen level in postmenopausal women with ER+ breast carcinoma. Estrogen is known for its cardiovascular (CV) protective properties through a variety of mechanisms including vasodilation of blood vessels and inhibition of vascular injury resulting in the prevention of atherosclerosis. In clinical trials and prospective cohorts, the long-term use of AIs can increase the risk for hypertension and hyperlipidemia. Studies demonstrate mixed results as to the impact of AIs on actual CV events and overall survival.MethodsA single arm longitudinal study of 14 postmenopausal women with ER+ breast cancer prescribed adjuvant AIs at the University of Minnesota (UMN). Subjects with a history of known tobacco use, hypertension, hyperlipidemia, and diabetes were excluded to eliminate potential confounding factors. Participants underwent routine labs, blood pressure assessments, and vascular testing at baseline (prior to starting AIs) and at six months. Vascular assessment was performed using the EndoPAT 2000 and HDI/PulseWave CR-2000 Cardiovascular Profiling System and pulse contour analysis on two occasions as previously described. Vascular measurements were conducted by one trained vascular technician. Assessments were performed in triplicate, and the mean indices were used for analyses. All subjects were on an AI at the follow-up visit. The protocol was approved by the UMN Institutional Review Board and all participants were provided written informed consent. Baseline and follow-up characteristics were compared using Wilcoxon signed-rank tests. Analyses were performed using R version 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria).ResultsAfter six months of AI treatment, EndoPAT® ratio declined to a median 1.12 (Q1: 0.85, Q3: 1.86; p = 0.045; Figure 1) and median estradiol levels decreased to 2 pg/mL (Q1: 2, Q3: 3; p=0.052). There was no evidence of association between change in EndoPAT® and change in estradiol level (p = 0.91). There were no statistically significant changes in small or large arterial elasticity.ConclusionsWe hypothesize that long-term use of AI can lead to persistent endothelial dysfunction, and further investigation is necessary. In our study, patients were on AI for approximately 5-10 years. As a result, we do not have data on whether these changes, such as EndoPAT® ratio and the elasticity of small and large arterial, are reversible with discontinuation of AI. These findings set the stage for a larger study to more conclusively determine the association between AI exposure and cardiovascular outcomes. Further studies should evaluate for multivariate associations withmodifiable risk factors for CV disease.

Attempted replication of pharmacogenetic association of variants in PPP1R14C and CCDC148 with aromatase inhibitor-induced musculoskeletal symptoms.

Third-generation aromatase inhibitors (AI) are the standard treatment for patients with hormone receptor positive (HR+) breast cancer. While effective, AI can lead to severe adverse events, including AI-induced musculoskeletal syndrome (AIMSS). Genetic predictors of AIMSS have the potential to personalize AI treatment and improve outcomes. We attempted to replicate results from a previous genome-wide association study that found a lower risk of AIMSS in patients carrying PPP1R14C rs912571 and a higher risk in patients carrying CCDC148 rs79048288. AIMSS data were collected prospectively from patients with HR+ breast cancer prior to starting and after 3 and 6 months of adjuvant AI via the Patient-Reported Outcome Measurement Information System and Functional Assessment of Cancer Therapy-Endocrine Symptom. Germline genotypes for PPP1R14C rs912571 and CCDC148 rs79048288 were tested for a similar association with AIMSS as previously reported via $2 tests. Of the 143 patients with AIMSS and genetics data were included in the analysis. There was no association identified between PPP1R14C rs912571 and AIMSS risk ( P > 0.05). Patients carrying CCDC148 rs79048288 variant alleles had lower AIMSS incidence in a secondary analysis ( P = 0.04); however, this was in the opposite direction of the previous finding. The study did not replicate previously reported associations with AIMSS risk for genetic variants in PPP1R14C and CCDC148 and AIMSS risk. Further research is needed to discover and validate genetic predictors of AIMSS that can be used to personalize treatment in patients with HR+ breast cancer.

Fat Body Mass and Vertebral Fracture Progression in Women With Breast Cancer

Women with early breast cancer (EBC) exposed to aromatase inhibitors (AIs) may experience fragility fractures despite treatment with bone-active drugs. Risk factors for fractures in patients receiving AIs and denosumab have not been explored to date. To evaluate whether an association exists between dual x-ray absorptiometry (DXA)-measured fat body mass (FBM) and vertebral fracture (VF) progression in postmenopausal women with EBC undergoing adjuvant therapy with AIs in combination with denosumab and to examine whether VF was associated with common risk factors for bone fracture and parameters of body composition other than FBM. For this prospective, single-center, cohort study, 237 patients with EBC who were undergoing adjuvant treatment with AIs and denosumab (60 mg every 6 months) were enrolled at the Breast Unit of the ASST Spedali Civili of Brescia from September 2014 to June 2018. Data analysis was conducted in June 2022. Body composition parameters, bone mineral density, and morphometric VFs were assessed by DXA at study entry and after 18 months of therapy. VF progression, defined as either new or worsening of preexisting VFs, between the 2 time points. Of the 237 patients enrolled (median [range] age, 61 [28-84] years), 17 (4.4%) reported VF progression. Univariable analysis found an association between VF progression and a history of clinical fractures (odds ratio [OR], 3.22; 95% CI, 1.19-8.74; P = .02), Fracture Risk Assessment Tool (FRAX) score for major fractures (OR, 4.42; 95% CI, 1.23-13.79; P = .04), percentage of FBM (OR, 6.04; 95% CI, 1.69-21.63; P = .006), and android fat (OR, 9.58; 95% CI, 1.17-78.21; P = .04) and an inverse association with appendicular lean mass index-FBM ratio (OR, 0.25, 95% CI, 0.08-0.82; P = .02). Multivariable analysis revealed percentage of FBM (OR, 5.41; 95% CI, 1.49-19.59; P = .01) and FRAX score (OR, 3.95; 95% CI, 1.09-14.39; P = .04) as independent variables associated with VF progression. The findings of this study suggest that baseline FBM is an independent factor for VF progression in patients with EBC treated with adjuvant AIs and denosumab. This observation is new and indicates that diet and exercise may synergize with denosumab in the management of bone health in this patient setting.

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.

Effect of whole-body cryotherapy versus placebo cryotherapy on joint pain induced by aromatase inhibitors in women with early stage breast cancer: a randomised clinical trial

IntroductionHormone therapy (HT) is a major adjuvant treatment for breast cancer. Despite their effectiveness, aromatase inhibitors can cause several side effects, including arthralgia in 35%–50% of patients. These side effects...

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

280P Adjuvant aromatase inhibitors in patients with PIK3CA mutation early breast cancer

280P Adjuvant aromatase inhibitors in patients with PIK3CA mutation early breast cancer

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.

LESS: Single-arm study to de-escalate adjuvant endocrine therapy duration in post-menopausal women with HR+ HER2- early-stage breast cancer at very low risk of metastasis.

TPS615 Background: Adjuvant Endocrine Therapy (ET) is the cornerstone treatment of localized hormone-receptor positive (HR+) breast cancer, with demonstrated benefits on overall survival (30-40% relative decrease in mortality) but also on the risk of local and contralateral relapse (43-50% relative decrease). While the relative benefit of 5 years of ET is identical for small tumors as compared to larger ones, the absolute benefit is much lower, and the risk-benefit ratio becomes questionable given the frequent and impactful side effects of ET which are associated with non-adherence. If recent trials tested longer durations as compared to 5 years for high-risk cancers, older trials have tested shorter durations. Five years appeared at that time as the gold standard because of optimal benefit-risk ratios of tamoxifen among rather high-risk patients. However, shorter treatments of 2-3 years were already associated with substantial benefits and may be enough for very low risk patients. The purpose of this study is to demonstrate that adjuvant ET limited to 2 years of aromatase inhibitor (AI) in postmenopausal women at very low risk of recurrence as determined with a MammaPrint and BluePrint Ultra Low Risk Luminal test result can ensure very high survival without metastatic relapse and allows a reduction of side effects and a better quality of life. Methods: LESS (NCT05297617) is a prospective, national, multicenter, single-arm, interventional, non-threshold crossing phase II study evaluating a therapeutic de-escalation that limits adjuvant ET to 2 years of AI. Approximately 696 post-menopausal patients with an invasive unilateral, HR+, HER2-negative, without indication of adjuvant chemoT and genomically-assessed MammaPrint/BluePrint UltraLow risk Luminal A breast cancer tumors, will be enrolled. LESS will include two sub cohorts: the majority of patients with Grade 2, pT1c-2, pN0/N1mic tumors, and up to 80 patients ≥65 years with Grade 1, pT1, pN0 and Ki67<10% tumors. The primary endpoint is distant metastasis free survival (DMFS) defined as the time from date of registration to date of first event of distant recurrence, death, or second primary non-breast invasive cancer. Secondary endpoints include the assessment of quality of life parameters and psychological aspects related to this de-escalation. The null hypothesis (H0) that, in the study population after 2 years of adjuvant AI, DMFS at 5 years is lower or equal to 94.5% will be tested against the alternative - that it is above 94.5%. For an expected DMFS of 96.7% under the alternative hypothesis, a total of 37 DMFS events are required in order to provide approximately 85% power at a one-sided significance level of 0.05 to reject H0 using a logrank test. The 1st patient was included in October 2022, initiating the 2-year inclusion period and 10 years FU per patient. Clinical trial information: NCT05297617 .

104P Obesity and recurrence in postmenopausal, estrogen-receptor-positive breast cancer patients treated with adjuvant aromatase inhibitors: A Danish population-based cohort study

104P Obesity and recurrence in postmenopausal, estrogen-receptor-positive breast cancer patients treated with adjuvant aromatase inhibitors: A Danish population-based cohort study

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 OT1-04-02: Anastrozole dose escalation for optimal estrogen suppression in postmenopausal early stage breast cancer: A prospective trial

Abstract Introduction: We performed matched case-control studies utilizing cohorts of postmenopausal women with ER+ breast cancer receiving adjuvant aromatase inhibitors (AI) on MA.27 [anastrozole, exemestane] or PreFace [letrozole] to assess the association between estrogen suppression after 6 months of treatment and an early breast cancer (EBC) event within 5 years of AI initiation (Clin Cancer Res 2020;26:2986-98). We found a significant 3.0-fold increase in risk of an EBC event for those taking anastrozole with levels of estrone (E1) ≥1.3 pg/mL and estradiol (E2) ≥0.5 pg/mL, but not for exemestane or letrozole. Given these findings we designed a prospective pharmacodynamic (PD) study to evaluate the impact of anastrozole (1 mg/day: ANA1) on E1 and E2 levels, and among those with inadequate estrogen suppression (IES: E1 ≥1.3 pg/mL and E2 ≥0.5 pg/mL), to evaluate the safety and PD efficacy of high-dose anastrozole (10 mg/day: ANA10), which has been found to be safe in prior clinical trials (Cancer 1998;83:1142-52). Methods: Post-menopausal women with stage I-III, ER ≥1% positive/HER2-negative breast cancer who were candidates for anastrozole were eligible after completion of locoregional therapy and chemotherapy, as clinically indicated. Women who were pre-menopausal at diagnosis were not eligible. All patients received 8-10 weeks of ANA1, after which those with adequate estrogen suppression (AES: E1< 1.3 pg/mL or E2< 0.5 pg/mL) came off study. Those with IES went on to receive ANA10 for 8-10 weeks, followed by letrozole (2.5 mg/day: LET) for 8-10 weeks. All patients were managed at their treating oncologist’s discretion following study discontinuation. E1 and E2 blood levels were measured pre-treatment and after completion of each treatment cycle by a CLIA-approved liquid chromatography with tandem mass spectrometry in the Immunochemical Core Laboratory at Mayo Clinic. With a sample size of 29 patients with IES after ANA1, a one-sided binomial test of proportions with a significance level of 0.05 will have an 87% chance of rejecting the proportion with AES after ANA10 is at most 25% (Ho) when the true proportion is at least 50%. Specifically, the null hypothesis is rejected if the number of women with AES after ANA10 is 12 or more. Data lock was July 6, 2022. Results: Of the 161 women enrolled from April 2020 through May 2022, 3 withdrew consent prior to start of ANA1 and 2 were ineligible; thus, 156 women comprised the study cohort. Median patient age was 64 years (range 44-86), 10% of patients were of Hispanic ethnicity and/or non-white race, and 15% received chemotherapy. Six patients remain on ANA1, and 10 discontinued ANA1 due to refusal (7), adverse event (AE) (2), or COVID-19 (1). Forty-one of the remaining 140 patients (29.3%; 95%CI: 21.9-37.6%) had IES with ANA1. Nine of these 41 patients did not go on to ANA10 due to refusal (6) or AE (3). Of the 32 patients who started ANA10, 8 remain on treatment, 5 discontinued due to refusal (3) or AE (1-grade 2 urinary tract infection; 1-grade 1 palpitations), and 19 had a blood draw 45 days or more after starting ANA10. No grade 3-5 AEs or grade 2 hot flashes or arthralgias were reported. Of these 19 patients, 14 achieved AES with ANA10 (73.7%; 95%CI: 48.8-90.9%). All 19 patients switched to LET of which 3 remain on treatment, 1 is missing E1/E2 data, and 15 had a blood draw 45 days or more after starting LET. Of these 15 patients, 10 maintained AES, 2 acquired AES with LET, and 3 no longer had AES. Anastrozole and letrozole drug levels will be reported at the meeting. Conclusions: Approximately 29% of postmenopausal women with ER+/HER2- BC receiving adjuvant anastrozole 1 mg/daily had IES. A majority of these patients achieved AES with dose escalation to ANA10 without tolerability issues. E1 and E2 levels are logical biomarkers given the mechanism of action of anastrozole, and further study utilizing them to determine the optimal dose of anastrozole for a given patient should be performed. Citation Format: Tufia C. Haddad, Vera Suman, Karthik V. Giridhar, Alvaro Moreno-Aspitia, Donald Northfelt, Brenda Ernst, Kostandinos Sideras, Ciara C. O’Sullivan, Ravinder Singh, Zeruesenay Desta, Jodi Taraba, Barbara Goodnature, Matthew P. Goetz, Liewei Wang, James N. Ingle. Anastrozole dose escalation for optimal estrogen suppression in postmenopausal early stage breast cancer: A prospective trial [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 OT1-04-02.

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.