Standard Endocrine Therapy Research Articles

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) > 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 < 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.

Abstract PD2-04: Molecular plasticity of luminal breast cancer and response to CDK 4/6 inhibition - The biomarker program of the PENELOPE-B trial investigating post-neoadjuvant palbociclib

Abstract Background: Molecular plasticity of breast cancer is crucial for the development of therapy-resistant disease. In this investigation, we studied changes in molecular signatures between pretherapeutic (pre-Tx) and post-therapeutic (post-NACT) tumor samples from patients included in the PENELOPE-B (NCT01864746) trial. The phase III PENELOPE-B study did not show a significant benefit from palbociclib in women with centrally confirmed HR+, HER2- primary breast cancer without a pathological complete response after taxane-containing neoadjuvant chemotherapy (NACT) and at high-risk of relapse (CPS-EG score ≥3 or 2 and ypN+) (Loibl et al. JCO 2021). However, first translational investigations showed that a small number of patients with a luminal-B tumor subtype, based on absolute intrinsic molecular subtyping (AIMS, Paquet & Hallet, JNCI 2014) subtyping after NACT, had a numerical benefit from post-NACT palbociclib. We have therefore extended the analysis and included a cohort of paired pre-Tx and post-NACT samples. Methods: We investigated gene expression in pre-Tx (n=259) tumor tissue samples using the HTG EdgeSeq Oncology Biomarker Panel including 2549 genes (HTG Molecular Diagnostics Inc.); for the same patients the same panel on post-NACT residual tumor samples were available. The paired samples were selected based on a case-cohort approach. Based on 91 genes of this panel, the AIMS subtype was calculated. In addition, we performed exploratory biomarker analyses to identify genes and gene signatures with prognostic and predictive relevance. After completion of NACT, PENELOPE-B patients were randomized to palbociclib versus placebo in addition to standard endocrine therapy. Results: The prevalence of AIMS subtypes, in particular LumA vs LumB, changed in pre-Tx and post-NACT tumors. In the pre-Tx samples, 115 (44%) and 123 (47%) of tumors had LumA and LumB subtypes, respectively, as expected from a high-risk cohort. However, in the post-NACT samples, LumA tumors were predominant (n=183, 71%) over LumB (n=30; 12%). 78 (30%) and 6 (2%) tumors switched their subtype from LumB to LumA and LumA to LumB, respectively. For further analyses, we compared the groups of low proliferating (LumA and NormL) and high proliferating subtypes (LumB, BasalL and HER2E). In bivariable Cox regression analysis, the grouped pre-Tx and post-NACT AIMS subtypes were independent prognostic factors for iDFS: HR=1.85 (1.16-2.98, p=0.011) for pre-Tx LumB/BasalL/HER2E vs LumA/NormL and HR=2.18 (1.24-3.84, p=0.007) for post-NACT. Similar results were found when adjusted for prognostic clinical factors and for DDFS and OS endpoints although the pre-Tx subtype did not reach significance. These and further Cox models investigating interaction effects show that patients with tumors developing from high (pre-Tx) to low proliferation (post-NACT) had a higher iDFS risk compared to stable low proliferating tumors but a lower iDFS risk compared to stable high proliferating tumors. Neither in the pre-Tx LumB/BasalL/HER2E nor in the pre-Tx LumA/NormL subgroup a benefit from palbociclib was observed. Based on the results of the AIMS subtyping, we extended the exploratory analysis to identify genes that might be involved in the prognostic and predictive effects as well as genes driving the subtype switch. The analysis is ongoing and the relevant genes will be presented at the conference. Conclusions: Our findings show that the switch from high-risk molecular subtypes (in particular LumB) to low-risk subtypes (in particular LumA) is common in neoadjuvant therapy of luminal tumors. The adaptation of luminal high-risk tumors to therapy-induced stress is crucial for the clinical outcome and the results suggest that molecular defined tumor subtypes might not be as stable as originally thought. Citation Format: Carsten Denkert, Frederik Marmé, Miguel Martin, Michael Untch, Hervé Bonnefoi, Sung-Bae Kim, Harry Bear, Agnieszka Witkiewicz, Seock-Ah Im, Angela DeMichele, Laura Van’t Veer, Nicole McCarthy, Thorsten Stiewe, Karen A. Gelmon, José A. García-Sáenz, Catherine M. Kelly, Toralf Reimer, Erik Knudsen, Nicholas Turner, Federico Rojo, Peter A. Fasching, Julia Teply-Szymanski, Yuan Liu, Masakazu Toi, Hope S. Rugo, Michael Gnant, Andreas Makris, Bärbel Felder, Karsten Weber, Sibylle Loibl. Molecular plasticity of luminal breast cancer and response to CDK 4/6 inhibition - The biomarker program of the PENELOPE-B trial investigating post-neoadjuvant palbociclib [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 PD2-04.

Abstract P1-17-01: Response of persistent metastatic ER+/Her2- breast cancer treated with fulvestrant plus enzalutamide

Abstract Background: The clinical implications of the androgen receptor (AR), particularly in the context of aromatase inhibitor (AI) refractory metastatic breast cancer (MBC), are unclear. While AR is associated with more indolent primary tumors, in the absence of low estradiol/blocked ER, AR can exert a pro-survival signal. Thus, in a phase II trial of Fulvestrant (Fulv) plus Enzalutamide (Enza) in ER+/Her2- MBC (NCT02953860) we analyzed serial biopsies pre- and post-treatment. Methods: Eligible patients were women with ECOG 0-2, ER+/Her2- MBC. Fulv at 500 mg IM days 1, 15, 29 and every 4 weeks thereafter and Enzaat 160 mg po daily on a continual basis were administered. Biopsies were required at study entry and at ~4 weeks on therapy. The clinical benefit rate at 24 weeks (CBR24) was the primary endpoint for efficacy. We performed mutational analysis using a modified Archer VariantPlex Solid Tumor Assay to detect mutations in ESR1 exon 8 and 67 other gene hotspots. We examined estrogen, progesterone, androgen and glucocorticoid receptor protein by IHC and multiplex for immune cells and PD-L1. Frozen cores were utilized to perform reverse phase protein array (RPPA) based protein pathway activation analysis of over 150 proteins from LCM-enriched tumor in baseline and post-treatment metastatic biopsies. Comparisons of Responders (progression free survival (PFS) equal to or longer than 24 weeks) and Non-Responders were performed using moderated t-tests on log2 transformed data. Results: 32 patients were eligible, median age was 61 years (46-87), and 90.6% had visceral disease with an average of 4 prior non-hormonal therapies and 3 prior hormonal agents (including 37.5% with prior Fulv). PFS >24 weeks was observed in ~22% of patients treated with Fulv plus Enza, including 42% of those who had prior Fulv. When stratified by both AR and ER protein levels, median time to progression was 59 days (95% CI: 55 to Inf) when both targets were high (greater than or equal to 10%), but only 14 days (95% CI: 13 to Inf) when both were less than 10%. Metastases with ESR1 mutations in the ligand binding domain had significantly higher levels of ER and PR protein than those with wild type ESR1 (p<0.05), while AR did not significantly differ. ER significantly decreased following 5 weeks post Fulv plus Enza in a paired t-test (p<0.003). ESR1 mutation positive metastases had significantly more T helper cells, T regulatory cells and macrophages than those with wild type ESR1. In contrast, those with TP53 or PIK3CA mutations had higher CD8+ T cells, but also increased T regulatory cells compared to those WT for these genes. PD-L1 increased with treatment in all patients by paired t test (p<0.03). RPPA analysis indicated that activation of mTOR pathway proteins was associated with non-response to Fulv plus Enza and patients with PIK3CA and or PTEN mutated disease had a shorter progression free survival time following treatment, with the hazard of disease progression for participants with PIK3CA or PTEN mutated disease being 2.27 times (95% CI: 0.94 to 5.46) than without these mutations (p=0.068). Conclusions: PFS >24 weeks was observed in 22% of patients treated with Fulv plus Enza, including 42% who had prior Fulv treatment, suggesting contribution of the anti-androgen. Response was significantly better when metastases were >10% for ER and AR. Poor response to Fulv plus Enza was significantly associated with mTOR pathway activation and patients with PIK3CA and or PTEN mutated metastases had a significantly shorter PFS. Mutation status also affected hormone receptor expression and immune infiltrates. The increase in PD-L1 protein following treatment with Fulv plus Enza warrants further pre-clinical investigation into whether the addition of anti-androgen can enhance efficacy of checkpoint inhibitor therapy in ER+ metastatic disease resistant to standard endocrine therapy approaches. Citation Format: Jennifer Richer, Nicole Spoelstra, Alyse Winchester, Julia Wulfkuhlue, Rosa Gallagher, Sharon Sams, Gregory Vidal, Peter Kabos, Jennifer Diamond, Elena Shagisultanova, Anosheh Afghahi, Jose Mayordomo, Tessa McSpadded, Gloria Crawford, Virginia Borges, Dexiang Gao, Emanuel Petricoin, Anthony Elias. Response of persistent metastatic ER+/Her2- breast cancer treated with fulvestrant plus enzalutamide [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 P1-17-01.

Role of abemaciclib in primary breast cancer: a narrative review of MonarchE

Role of abemaciclib in primary breast cancer: a narrative review of MonarchE

Integrating CDK4/6 inhibitors in the treatment of patients with early breast cancer

CDK4/6 inhibitors have an established role in the treatment of hormone receptor positive HER2-negative advanced breast cancer. All studies conducted in metastatic breast cancer showed a benefit in delaying progression when added to standard endocrine therapy, regardless of therapy line, pretreatment, menopausal status, site of metastasis, CDK4/6 inhibitor used and associated endocrine therapy. A benefit in overall survival has also been demonstrated. In early breast cancer, only the MonarchE study has shown an improved invasive disease-free survival with abemaciclib taken for 2 years, whereas the Penelope-B did not meet the primary endpoint and the PALLAS study was terminated early for futility. Studies conducted in the neoadjuvant setting might help to explain the discordant results.

Phytoprogestins: Unexplored Food Compounds with Potential Preventive and Therapeutic Effects in Female Diseases.

In recent years, there has been an increasing interest in natural therapies to prevent or treat female diseases. In particular, many studies have focused on searching natural compounds with less side effects than standard hormonal therapies. While phytoestrogen-based therapies have been extensively studied, treatments with phytoprogestins reported in the literature are very rare. In this review, we focused on compounds of natural origin, which have progestin effects and that could be good candidates for preventing and treating female diseases. We identified the following phytoprogestins: kaempferol, apigenin, luteolin, and naringenin. In vitro studies showed promising results such as the antitumoral effects of kaempferol, apigenin and luteolin, and the anti-fibrotic effects of naringenin. Although limited data are available, it seems that phytoprogestins could be a promising tool for preventing and treating hormone-dependent diseases.

Accelerating progress to innovation for patients: Trial design and risk stratification

In early breast cancer, we integrate risk stratification and trial design, together with subtype, to focus on clinical questions in specific patient populations. In the past, trials enrolled an “all-comers,” broadly-defined population. More recently, trials enroll low-to intermediate-risk populations for whom testing strategies to de-escalate therapy are appropriate, or intermediate-to high-risk populations for whom testing additional and novel therapeutic strategies are needed. For example, in patients who have triple-negative breast cancer, the presence of residual disease after neoadjuvant therapy has become an approach to risk stratification for defining a trial population testing approaches to adjuvant therapy. In patients with hormone receptor positive, HER2-negative breast cancer, trials testing the addition of adjuvant CDK4/6 inhibitors to standard endocrine therapy have enrolled intermediate-to high-risk populations using various definitions and with heterogeneous results. Results of the recent generation of clinical trials testing systemic therapy for early breast cancer provide an opportunity to learn and improve future trial designs and accelerate progress to innovation for patients.

P.097 Adrenal Insufficiency among Children treated with Hormonal Therapy for Infantile Spasms

Background: Hormonal therapy is a standard treatment for infantile spasms. The high doses given and long treatment duration expose patients to the risk of adrenal insufficiency (AI). This study aims to quantify the incidence of AI among children with infantile spasms treated with corticosteroids and/or adrenocorticotropic hormone (ACTH). Methods: A retrospective chart review of patients treated for infantile spasms was performed between January 2009 to March 2020 in one pediatric specialized hospital. Variables collected included patient and treatment characteristics, risk factors of AI and adrenal function testing. Analysis included descriptive statistics. Results: Thirty-one patients met the inclusion criteria and received a total of 33 separated courses of treatment. Adrenal function following each course of treatment was evaluated in all patients. AI occurred in 25/33 (76% [95CI 58-89]) children. There was no predictive factor of AI. No drug regimen was deemed safe. The two patients (6%) with an acute adrenal crisis were the youngest of the cohort. Conclusions: Adrenal suppression is frequent and can lead to adrenal crisis after standard hormonal therapy for infantile spasms. A routine laboratory assessment of adrenal function should be done for all patients. Hydrocortisone replacement therapy should be given until testing results are obtained, particularly for younger infants.

71 Adrenal Insufficiency among Children treated with Hormonal Therapy for Infantile Spasms

Abstract Primary Subject area Endocrinology and Metabolism Background Hormonal therapy is a standard treatment for children with infantile spasms. However, the high doses given and long treatment duration exposes patients to the potential risk of adrenal insufficiency (AI). There is, presently, limited data on occurrence of AI after hormonal therapy in this population. Objectives This study aims to quantify the incidence of AI among children with infantile spasms treated with high-dose corticosteroids and/or adrenocorticotropic hormone (ACTH). Design/Methods A retrospective chart review of patients less than 2 years old treated for infantile spasms was performed between January 2009 to March 2020 in one pediatric specialized hospital. Variables collected included sex, age, etiology, age at treatment initiation, type of hormonal treatment, dose and duration of treatment, concomitant medication and illness, other corticosteroid uses, hydrocortisone replacement therapy use, adrenal function testing, and signs of AI. Analysis included descriptive statistics, such as incidence and bivariate analysis. Results Thirty-one patients met the inclusion criteria and received a total of 33 separated courses of hormonal treatment. Adrenal function following each course of treatment was evaluated in all patients, either by tests or by the presence of adrenal crisis. Oral hydrocortisone replacement therapy was received by 32/33 (97%) children. AI occurred in 25/33 (76% [95% CI 58-89]) children. There was no predictive factor for adrenal insufficiency after hormonal treatment, and no drug regimen (duration or total received dose) was safe. Two patients (6%) presented to the emergency room with an acute adrenal crisis the day following the weaning off of hormonal treatment. They were the youngest children of the cohort, with an age of 1,6 and 2,7 months at the initiation of treatment. All other patients were aged 4 months and older. Conclusion This study suggests that adrenal suppression is frequent after standard hormonal therapy regimen for infantile spasms. This can lead to serious complications, such as adrenal crisis, if not supplemented. A routine laboratory assessment of adrenal function should be done after hormonal therapy for all patients. We suggest that hydrocortisone replacement therapy should be given at the end of hormonal therapy and until testing results for adrenal function are obtained, particularly for younger patients.

Top 3 abstracts concerning hormone-receptor-positive early breast cancer

SummaryThe three top abstracts at the 2020 virtual San Antonio Breast Cancer Symposium regarding hormone-receptor-positive early breast cancer, from our point of view, were the long-awaited results from PenelopeBand RxPONDER as well as the data from the ADAPT trial of the West German Study Group. PenelopeBfailed to show any benefit by adjuvant palbociclib when added to standard endocrine therapy in patients without pathologic complete response after neoadjuvant chemotherapy. RxPONDER demonstrated that postmenopausal patients with early hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2−) breast cancer, 1–3 positive lymph nodes and an Oncotype DX Recurrence Score of less than 26 can safely be treated with endocrine therapy alone. In contrast, in premenopausal women with positive nodes, adjuvant chemotherapy plays still a role even in case of low genomic risk. Whether the benefit by chemotherapy is mainly an indirect endocrine effect and if ovarian function suppression would be similarly effective, is still a matter of debate. The HR+/HER2− part of the ADAPT umbrella trial investigated the role of a Ki-67 response to a short endocrine therapy before surgery in addition to Oncotype DX—performed on the pretreatment biopsy—to identify low-risk patients who can safely forgo adjuvant chemotherapy irrespective of menopausal status.

P–312 Clinical applications of platelet-rich plasma in poor endometrium patients with adenomyosis

Abstract Study question Does the intrauterus application of platelet-rich plasma (PRP) allow improving the thickness of endometrium in patients with adenomyosis: comparative characteristics of the PRP-techniques? Summary answer The endometrial thickness in poor-endometrium-patients is increased after subendometrial PRP- injection comparing with the endometrium size after PRP- irrigation of the uterine cavity (P < 0.05). What is known already The endometrium plays an important role in achieving optimal outcomes of assisted reproductive technologies. PRP is a novel method that is used in reproductive medicine to improve the IVF outcome. The mechanisms of PRP have not been completely elucidated, but laboratory studies have shown that the high concentration of growth factors in PRP can potentially speed up the healing process. Recently, the intrauterine PRP-infusion and the subendometrial PRP-injection during the hysteroscopy have been described as a way to promote endometrial growth and receptivity. Study design, size, duration Totally 64 patients with adenomyosis and poor endometrium (≤ 6 mm) were divided into three experimental groups depending on PRP administration: intrauterine PRP-infusion, subendometrial PRP-injection and standard hormonal therapy of adenomyosis without PRP application. The period of study – December 2019 – November 2020. The study’s protocol was approved by the Center’s IRB. Participants/materials, setting, methods Intrauterine PRP-infusion was performed for 23 patients with age 34.2±3.6 y.o. (Group 1). Subendometrial PRP-injection was applied for 16 patients with the middle age 32,6±2,4 y.o. (Group 2). Additional hormonal therapy was carried out for patients from Groups 1, 2. The third control Group 3 consisted of 25 adenomyosis women with the middle age 35.7±4.1 y.o. Only the hormonal therapy was performed for patients of the control group. Main results and the role of chance The procedure of intrauterine PRP-infusion was done using the intrauterine catheter on the 8th and 12th days of the f hormone replacement therapy. Subendometrial PRP-injection was performed during the hysteroscopy on the 8th–10th day of the previous menstrual cycle. The control of the endometrium size was done by ultrasound examination. T-test was used for data analysis. P < 0.05 was considered statistically significant. After subendometrial PRP-injection, the average endometrium thickness was significantly higher comparing with the control (8.7±1.1mm vs. 5.8±0.8mm) (Student t-test t = 2.13, P = 0.04). PRP-infusion also showed significantly strong positive result comparing with the control group (8.3±0.9mm vs. 5.8±0.8mm) (Student t-test t = 2.08, P = 0.043). There is the tendency that subendometrial PRP-has a greater impact on endometrium size comparing with the PRP-infusion. Further investigations should be done. Limitations, reasons for caution Patients with Asherman’s syndrome were excluded from experiment. Wider implications of the findings: It is not clear how the intrauterine administration of PRP may act to affect endometrial thickness. Results from studies on the role of endometrial thickness on implantation and live births are contradictory. There is the urge for well-designed randomized studies to improve our knowledge on PRP in reproductive medicine. Trial registration number -

Prognosis of patients with prostate cancer and bone metastasis from the Japanese Prostatic Cancer Registry of Standard Hormonal and Chemotherapy Using Bone Scan Index cohort study.

ObjectiveTo determine prognostic factors including the Bone Scan Index in prostate cancer patients receiving standard hormonal therapy and chemotherapy.MethodsThis multicenter Prostatic Cancer Registry of Standard Hormonal and Chemotherapy Using Bone Scan Index study involved 30 hospitals and enrolled 247 patients (age 71 ± 8 years) with metastatic hormone‐sensitive prostate cancer (n = 148) under hormone therapy and metastatic castration‐resistant prostate cancer (n = 99) under chemotherapy. The Bone Scan Index (%) was determined by whole‐body bone scintigraphy using 99mTc‐methylenediphosphonate. Patients were classified into tertiles and binary groups, and predictors of all‐cause death including Bone Scan Index, prostate‐specific antigen, and bone metabolic markers were determined using survival and proportional hazard analyses.ResultsDuring a mean follow‐up period of 716 ± 404 days, 81 (33%) of the patients died, and 3‐year mortality rates were 20% and 52% in the metastatic hormone‐sensitive prostate cancer and metastatic castration‐resistant prostate cancer groups, respectively. Survival analysis showed that a Bone Scan Index >3.5% was a significant determinant of death in the metastatic hormone‐sensitive prostate cancer group, whereas prostate‐specific antigen >55 ng/mL before chemotherapy was a determinant of prognosis in the metastatic castration‐resistant prostate cancer group. A Bone Scan Index >3.5% was also associated with a high incidence of prostate‐specific antigen progression in the metastatic hormone‐sensitive prostate cancer group. Patients with metastatic hormone‐sensitive prostate cancer and a better Bone Scan Index response (>45%) to treatment had lower mortality rates than those without such response.ConclusionThe Bone Scan Index and hot spot number are significant determinants of 3‐year mortality, and combining the Bone Scan Index with prostate‐specific antigen should contribute to the management of prostate cancer patients with bone metastasis.

Randomized trial of high-dose pyridoxine in combination with standard hormonal therapy in West syndrome

ObjectiveTo determine whether high-dose, oral pyridoxine in combination with standard adrenocorticotropic hormone (ACTH) therapy has superior effectiveness than ACTH therapy alone in increasing cessation of epileptic spasms for children with West syndrome. MethodsThis study was an open-label, randomized controlled trial with masked endpoint assessments. Eligible children with West syndrome, age ranged 3-18 months, were randomized into the intervention (n = 43) and the standard arm (n = 37) of therapy. The intervention group received oral pyridoxine at 100-300 mg/kg/day in addition to standard therapy of intramuscular ACTH at 150 IU/m2/day. Primary effectiveness outcome was a complete cessation of spasms at two weeks and sustained till six weeks. ResultsComparison of effectiveness measures between intervention and standard groups were : complete cessation of epileptic spasms (48.8% vs 58.3%; group difference -9.6%; 95% confidence interval [CI] -30% to 12.3%; p = 0.4), median EEG scores (Q1-Q3) by Jeavons Score at six weeks [3 (1-5) vs 3 (1-5); p = 0.6], median motor scores (Q1-Q3) by DASII (Development Assessment Scales for Indian Infants) at 12 weeks [35 (29-49) vs 42 (34.3-63.8), p = 0.04], and median mental scores (Q1-Q3) by DASII at 12 weeks [35 (29.5-46) vs 41.5 (31.3-60), p = 0.02]. Adverse events were comparable in both arms. ConclusionsThere was no evidence to suggest the superiority of high-dose pyridoxine in combination with ACTH versus ACTH alone for the treatment of West syndrome, considering the limitations of the study design.

Efficacy of enobosarm, a selective androgen receptor (AR) targeting agent, correlates with the degree of AR positivity in advanced AR+/estrogen receptor (ER)+ breast cancer in an international phase 2 clinical study.

1020 Background: The AR is expressed in up to 90% of ER+ breast cancer where it acts as a tumor suppressor. Historically, therapy with synthetic androgens had efficacy, but virilizing side effects and toxicity limited their use. Enobosarm is a selective AR activating agent that does not cause masculinization and has positive attributes such as promotion of bone and improvement of physical function. In a phase 2 study, correlation between the degree of AR staining and antitumor activity in AR+/ER+ patients with metastatic breast cancer (MBC) was examined. Methods: A phase 2, open label, parallel design randomized study was conducted in 136 patients to evaluate the efficacy and safety of enobosarm in heavily pretreated women with AR+/ER+ MBC. Patients were randomized to 9 mg (n=72) or 18 mg (n=64) of oral daily enobosarm. AR expression (%AR nuclei staining) in breast cancer samples was determined centrally by immunohistochemistry. The correlation between %AR staining and clinical outcomes was examined with a focus on the 9mg dose, selected for the phase 3 study and the optimal %AR staining established. Results: Tumor objective outcomes correlated with percent AR staining (Table). Further, using a 40% AR staining cutoff in patients with measurable disease, the clinical benefit rate (CBR) for ≥40% AR is 80% and <40% is 18% (p<0.0001). Best objective tumor response (BOR) in patients with ≥40% AR is 48% and <40% is 0% (p<0.0001). At ≥40% AR, median radiographic progression free survival (rPFS) is 5.47 and mean is 7.15 months vs <40% AR where the median rPFS is 2.72 and mean is 2.7 months. Similar %AR staining correlation was observed in the 18mg cohort. Enobosarm treatment was well tolerated with significant positive effects on quality of life measurements. Conclusions: Enobosarm is a novel oral selective AR activating agent in which a higher % AR staining correlates with a greater antitumor activity. By targeting and activating AR, enobosarm may represent a new hormone treatment approach for AR+/ER+ MBC. The phase 3, ARTEST trial will commence in early 2021 and randomize patients with AR+/ER+/HER2- heavily treated MBC that have progressed on a non-steroidal aromatase inhibitor, fulvestrant and CDK 4/6 inhibitor to receive enobosarm or standard endocrine therapy. Clinical trial information: NCT02463032 .[Table: see text]

Abemaciclib, a CDK4 and 6 inhibitor with unique pharmacological properties for breast cancer therapy.

e12506 Background: Breast cancer is the second most common cancer worldwide. Pharmacologically targeting cyclin-dependent kinases 4 and 6 (CDK4 & 6) has proven to be a successful therapeutic approach in patients with estrogen receptor positive (ER+) breast cancer. Differences in both efficacy and toxicity among the available CDK4 & 6 inhibitors has generated interest in a biological explanation. Abemaciclib is an adenosine triphosphate-competitive, reversible, selective inhibitor of CDK4 & 6 that has shown antitumor activity as a single agent and in combination with standard endocrine therapy (ET), in hormone receptor positive (HR+) metastatic breast cancer patients including those with ET resistance, and in combination with ET in high-risk early breast cancer patients. This study examines attributes of abemaciclib and other CDK4 & 6 inhibitors. Methods: The potency of abemaciclib for CDK4 was evaluated using biochemicals and breast cancer cell-based assays. Additionally, different combinations with an anti-estrogen therapy (e.g., tamoxifen, fulvestrant) were analyzed in an in vitro palbociclib (CDK4 & 6 inhibitor)-resistant breast cancer cell model, as well as in a set of CDK4 & 6 sensitive breast cancer cell models. Using cell-free assays, high content imaging and flow cytometry approaches, a subset of markers were monitored to characterize the phenotype of sensitive cell lines in a continuous dose schedule. Results: In in vitro, cell-free assays, abemaciclib shows selectivity for CDK4 over CDK6, and in cell-based assays, abemaciclib preferentially inhibits the proliferation of cells dependent on the presence of CDK4, not CDK6. Abemaciclib inhibits cell proliferation in a wide range of breast cancer cell lines, showing activity regardless of human epidermal growth factor receptor 2 (HER2) and PI3KCA gene mutation status. Furthermore, in a cell line resistant to palbociclib, abemaciclib in combination with fulvestrant (ET) restores CDK4 & 6 sensitivity, leading to cell senescence and cell death. Finally, in human bone marrow progenitor cells, abemaciclib shows a lesser impact on myeloid maturation than other CDK4 & 6 inhibitors, palbociclib and ribociclib, allowing for continuous dosing. Conclusions: In pre-clinical experiments, abemaciclib is a potent cell growth inhibitor, inhibiting preferentially the CDK4/CyclinD1 complex, leading to cell senescence and cell death. These pre-clinical results support the differentiated safety and efficacy profile of abemaciclib observed in clinical trials.

EMonarcHER: A phase 3 study of abemaciclib plus standard adjuvant endocrine therapy in patients with HR+, HER2+, node-positive, high-risk early breast cancer.

TPS596 Background: Hormone receptor positive (HR+), human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) with high-risk characteristics has a high risk of disease recurrence. Novel therapeutic options for this population are urgently needed. Abemaciclib is an oral, selective, and potent CDK4 & 6 inhibitor administered on a continuous schedule which is approved for HR+, HER2- advanced BC (ABC) as monotherapy and in combination with endocrine therapy (ET). Abemaciclib combined with ET demonstrated a statistically significant improvement in invasive disease-free survival (IDFS) in participants (pt) with HR+, HER2-, node-positive, high risk early breast cancer (EBC) and also clinical activity in HR+, HER2+ ABC. The eMonarcHER trial investigates whether abemaciclib plus ET will improve IDFS in pts with HR+, HER2+, node-positive, high risk EBC. Methods: eMonarcHER is a phase 3 global, randomized, double-blinded, placebo (PB)-controlled trial in participants with HR+, HER2+, node-positive, high risk EBC who have completed adjuvant HER2-targeted therapy (tx). Eligible participants are randomized 1:1 to receive either abemaciclib 150 mg twice daily or PB, plus standard ET. Study intervention period will be ≤26 cycles (approximately 2 years) followed by ≤8 years of ET as medically indicated. Participants must have undergone definitive surgery of the primary breast tumor and have high-risk disease. High-risk disease is defined as (i) detection of residual axillary nodal disease at the time of definitive surgery in participants with prior neoadjuvant (neoadj) tx; or (ii) in patients not receiving neoadj tx, must have either ≥4 pathologically positive axillary lymph nodes (pALNs), or 1-3 pathological pALNs and either: histologic Grade 2-3 and/or primary invasive tumor size ≥5 cm. Participants must have received either adjuvant pertuzumab plus trastuzumab with chemotherapy or adjuvant T-DM1. Stratification factors include treatment with neoadj tx, menopausal status, and region. The study is powered at approximately 80% to detect the superiority of abemaciclib plus ET over PB plus ET in terms of IDFS (as defined by the STEEP system) at a 1-sided α =.025 using a log-rank test. Assuming a hazard ratio of 0.73, this requires approximately 324 events at final IDFS analysis. Key secondary objectives include overall survival, distant relapse free survival, safety, pharmacokinetics, and patient-reported outcomes. The study is planned to start in March 2021. Approximately 525 centers in 23 countries plan to enroll ̃2450 participants. Clinical trial information: NCT04752332.

Prognostic impact of recurrence score, endocrine response and clinical-pathological factors in high-risk luminal breast cancer: Results from the WSG-ADAPT HR+/HER2- chemotherapy trial.

504 Background: In HR+/HER2- N0-1 early BC, postmenopausal patients (pts) with RS™ > 25 and a substantial proportion of premenopausal pts seem to benefit from addition of adjuvant chemotherapy (CT) to endocrine therapy (ET). However, the magnitude of absolute benefit from this treatment intensification seems to depend on clinical-pathological and biological prognostic factors. For the first time, we present outcome from the CT part of the prospective phase III WSG-ADAPT HR+/HER- trial combining both static (RS in baseline core biopsy (CB) and dynamic (Ki67 response) biomarkers to optimize adjuvant therapy in luminal EBC. Methods: Pts with clinically high-risk HR+/HER2- EBC (cT2-4 OR clinically N+ OR G3 OR Ki67>15%) were initially treated by 3 (+/-1) weeks of standard ET (postmenopausal: mostly AI; premenopausal: TAM) before surgery or sequential CB. Pts with cN2-3 or G3/Ki67>40% were randomized directly to the CT trial. pN0-1 pts with RS0-11 OR RS12-25/ET-response (central Ki67postendocrine<10%) received ET alone; the remaining high-risk cohort was randomized to the CT trial: (neo)adjuvant dose-dense CT (4xPaclitaxelà4xEC q2w vs. 8xNab-Paclitaxel q1wà4xEC q2w) followed by ET. Primary endpoint is efficacy comparison of CT schedules for survival; secondary endpoints reported here involve impacts of key prognostic factors on survival. Kaplan-Meier and Cox proportional hazard models were used to estimate survival curves and hazard ratios. For this analysis, subgroups free of selection bias by RS/ET-response were defined. Results: 5625 pts were screened and 4621 (ITT) entered the trial. After 4.9y median follow-up, higher baseline and post-endocrine Ki-67 levels were associated with poorer iDFS (both p < 0.001). In the CT cohort (n = 2331), higher RS, nodal status, and tumor size were generally associated with poorer iDFS. However, iDFS differed between N1 and N0 status only among younger pts (<50 years). In pts with >4 positive LN (n = 390), lower RS was associated with improved iDFS (RS0-11 vs RS > 25: plog-rank= 0.016, 5y-iDFS 90% vs. 64%). In pts with RS > 25 (n = 965), low Ki67postendocrine, N0 status, and c/pT1 status were associated with improved iDFS. In particular, ET-responders had higher 5y-iDFS (84%) than ET-non-responders (77%; plog-rank= 0.040). Younger patients (<50 years old) with N0-1 RS 12-25/ ET-non-responders treated by CT had non-significantly poorer 5-year iDFS (89%) compared to those with ET-response treated by ET only (92%) (plog-rank= 0.249). Conclusion: First results from the prospective high risk cohort from a large prospective phase III ADAPT trial provide evidence for good prognosis in some pts with >4 positive LN and e.g. low RS. Moreover combination of lower post-endocrine Ki-67 and limited tumor burden may be a promising criterion for CT de-escalation strategies even in patients with high RS. Clinical trial information: NCT01779206.

Efficacy and safety analysis of Chinese patients in monarchE: Abemaciclib combined with adjuvant endocrine therapy for high risk HR+, HER2- early breast cancer.

522 Background: In monarchE, abemaciclib (oral CDK4&6 inhibitor) plus endocrine therapy (ET) as adjuvant treatment for HR+, HER2- high risk early breast cancer (EBC), demonstrated a statistically significant improvement in invasive disease-free survival (IDFS) compared to ET alone. Here we present the efficacy and safety analysis of Chinese patients from monarchE. Methods: The overall study design was reported previously. Eligible patients were randomized to receive abemaciclib (150 mg BID for 2 years) combined with standard adjuvant ET or ET alone. The primary endpoint was IDFS per STEEP criteria. Secondary endpoints included distant relapse-free survival (DRFS), overall survival, and safety. Exploratory subgroup analyses were conducted among Chinese patients enrolled from Mainland China, Hong Kong, and Taiwan in the intent-to-treat (ITT) population. Results: A total of 501 Chinese patients were randomized to receive abemaciclib plus ET (259 patients) or ET alone (242 patients). At the time of data cutoff (July 8, 2020), 356 (71.1%) patients were still in the 2-year treatment period. A total of 26 IDFS events were observed (11 and 15 events in abemaciclib plus ET and ET arm, respectively). Comparing to ET alone, abemaciclib combined with ET reduced the risk of developing invasive disease or death by 34.3% (HR: 0.657, 95% CI: 0.301, 1.435) for Chinese patients, together with a clinically meaningful improvement in the 2-year IDFS rate (95.6% vs 92.1%). The addition of abemaciclib to ET also resulted in an improvement in DRFS (HR: 0.601, 95% CI: 0.245, 1.477) for Chinese patients, with the 2-year DRFS rate at 96.7% (ET alone: 93.4%). In the abemaciclib arm, the most frequent treatment-emergent adverse events (TEAEs) and grade ≥3 TEAEs: diarrhea (90.3% and 5.0%), leukopenia (76.8% and 21.2%), and neutropenia (76.4% and 23.9%), respectively. Conclusions: Abemaciclib combined with adjuvant ET demonstrated clinically meaningful IDFS and DRFS benefits among Chinese patients with HR+, HER2-, high risk EBC, which was consistent with the ITT population as reported previously. The safety profile of abemaciclib in Chinese EBC patients was consistent with global population and also with that observed in Chinese metastatic breast cancer patients. Clinical trial information: NCT03155997.

Subgroup of post-neoadjuvant luminal-B tumors assessed by HTG in PENELOPE-B investigating palbociclib in high risk HER2-/HR+ breast cancer with residual disease.

519 Background: About one third of patients with hormone-receptor-positive (HR+), HER2‐ primary breast cancer with residual invasive disease after neoadjuvant chemotherapy will relapse despite adjuvant endocrine therapy. Therapeutic inhibition of cyclin-dependent kinase 4 and 6 (CDK 4/6) by palbociclib combined with endocrine therapy demonstrated highly relevant efficacy in metastatic breast cancer. The phase III PENELOPE-B (NCT01864746) study did not show a significant benefit from palbociclib in women with centrally confirmed HR+, HER2- primary breast cancer without a pathological complete response after taxane‐containing neoadjuvant chemotherapy and at high-risk of relapse (CPS‐EG score ≥3 or 2 and ypN+) for the primary endpoint (Loibl et al. JCO 2021). Methods: After completion of neoadjuvant chemotherapy and locoregional therapy, PENELOPE-B patients were randomized (1:1) to receive 13 cycles (1 year) of palbociclib 125mg daily or placebo on days 1-21 in a 28d cycle in addition to standard endocrine therapy. Analysis of the primary endpoint of invasive disease-free survival (iDFS) was planned after 290 events. Secondary objective included iDFS in luminal-B group by treatment. Gene expression in post-neoadjuvant surgical residual tumor tissue samples was profiled using the HTG EdgeSeq Oncology Biomarker Panel targeting 2559 genes (HTG Molecular Diagnostics Inc.). Based on 91 genes of this panel the AIMS subtype (Paquet & Hallett, JNCI 2014) was calculated. Results: Gene expressions were measured in tumors from 906 of 1250 (72%) PENELOPE-B patients; 663 had LumA subtype, 64 LumB, 135 NormL, 16 BasalL, and 28 HER2E. Compared to LumA the LumB patients were older, had higher post-neoadjuvant Ki-67, higher risk status (CPS-EG), and higher grade; no significant correlation was found for the region of participating sites, cT, ypT, and ypN. Patients with LumB tumors had an estimated 3-year iDFS of 71.9% with palbociclib vs 44.8% with placebo HR = 0.50 (0.24-1.05); outcome was similar in patients with LumA tumors (3-year iDFS 83.9% vs 79.5%, HR = 0.93 (0.68-1.28), interaction p = 0.132); this was confirmed in multivariable analyses. Ki-67 by IHC and proliferation biomarkers from the HTG panel also showed no significant interaction with treatment. Conclusions: PENELOPE-B did not show a benefit from the addition of 1 year palbociclib to endocrine therapy compared to placebo in the total enrolled high-risk primary breast cancer population. However, the small group of luminal-B tumors (n = 64) derived benefit from palbociclib, although without a statistically significant interaction. Further investigation is required in a larger cohort to validate a palbociclib benefit that might be confined to this group.

Presentation and management of diverse cutaneous reactions after cyclin-dependent kinase 4/6 inhibitor use

To the Editor: Small-molecule, cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6is), including palbociclib, abemaciclib, and ribociclib, first obtained regulatory approval for hormone receptor+ breast cancer patients who have progressed or relapsed on standard endocrine therapy. CDK4/6is have been shown to increase progression-free survival when used in combination with endocrine therapy following disease progression on endocrine therapy alone.1-3