Factor Receptor 2-negative Metastatic Breast Research Articles

Abstract P1-16-06: In real world, a high percentage of premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer receive chemotherapy as first-line treatment: A study of the National Cancer Center, China

Abstract Background: In this study, we aimed to observe initial palliative treatment choices and clinical outcomes for premenopausal hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer patients (MBC) in the Chinese population in real life.Methods: The China National Cancer Center database was used to identify 2194 MBC patients diagnosed between 2004 to 2015. Premenopausal patients with HR+ HER2- MBC were included. Clinicopathological features, initial palliative treatment choices and survival information were extracted. First-line progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method and compared using the log-rank test. Prognostic factors associated with OS were analyzed using Cox regression model with 95% confidence interval (95%C.I.).Results: A total of 451 premenopausal patients meeting study criteria were identified. Median age was 44 years. The number of patients receiving chemotherapy alone, endocrine therapy and chemotherapy followed by endocrine therapy as initial palliative treatment strategy were 222(49.2%), 80 (17.7%), and 149 (33.0%), respectively. Patients receiving initial chemotherapy were more likely to be luminal B subtype, had more de novo stage IV disease than recurrent disease and had more liver metastasis, compared with patients receiving initial endocrine therapy. Both PFS and OS were significantly longer for chemotherapy-endocrine therapy group (median PFS 18.9 months and OS 75.0 months), than for endocrine therapy group (median PFS 11.7 months and OS 53.5 months). Chemotherapy alone group presented with worst survival outcomes (median PFS 7.1 months and OS 43.9 months). However, in multivariate analysis, none of the three treatment strategies were independently associated with PFS or OS.Conclusions: In real world, a high percentage of premenopausal patients with HR+ HER2- disease received chemotherapy as initial palliative treatment in China, which was not associated with worsened survival. This unexpected guideline non-adherence reflects the unmet need of establishing treatment guidelines specifically for premenopausal patients in the Chinese population. Further studies with larger sample size across China are needed to explore the relationship between this guideline non-adherence and clinical outcomes. Citation Format: Yiqun Li, Hongnan Mo, Xiuwen Guan, Shaoyan Lin, Zijing Wang, Yimeng Chen, Shanshan Chen, Qiao Li, Ruigang Cai, Jiayu Wang, Yang Luo, Ying Fan, Peng Yuan, Pin Zhang, Qing Li, Fei Ma, Binghe Xu. In real world, a high percentage of premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer receive chemotherapy as first-line treatment: A study of the National Cancer Center, China [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 P1-16-06.

Safety of adjuvant CDK4/6 inhibitors during the COVID-19 pandemic.

Safety of adjuvant CDK4/6 inhibitors during the COVID-19 pandemic.

Subsequent-abemaciclib Treatment After Disease Progression on Palbociclib in Patients With ER-positive HER2-negative Metastatic Breast Cancer.

This study investigated the efficacy of continuing cyclin-dependent kinase (CDK) 4 and 6 inhibitors in patients with estrogen receptor-positive (ER+) human epidermal growth factor receptor 2-negative (HER2- ) metastatic breast cancer (MBC) after disease progression on prior-palbociclib combined with endocrine therapy (ET). This retrospective study based on 25 ER+/HER2- MBC patients reported the efficacy and predictive factors of subsequent-abemaciclib after disease progression on prior-palbociclib. The overall response rate and clinical benefit rate were 16.0% and 44.0%, respectively. The median progression-free survival (PFS) was 5.3 months. In multivariate analysis, the best overall response (BOR) to prior-palbociclib was the only independent predictive factor for PFS (p=0.015). The median time to chemotherapy was 33.9 months. The median PFS in patients treated with next-line chemotherapy after progression on subsequent-abemaciclib was 6.2 months. BOR to prior-palbociclib was the only independent predictive factor for PFS in ER+/HER2- MBC patients undergoing subsequent-abemaciclib after disease progression on prior-palbociclib.

Evaluation of tumour heterogeneity by 18F-fluoroestradiol PET as a predictive measure in breast cancer patients receiving palbociclib combined with endocrine treatment

BackgroundPredictive biomarkers are needed to identify oestrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER + /HER2-) metastatic breast cancer (MBC) patients who would likely benefit from cyclin-dependent kinase 4 and 6 inhibitors combined with endocrine therapy. Therefore, we performed an exploratory study to evaluate the tumour heterogeneity parameters based on 16α-18F-fluoro-17β-oestradiol (18F-FES)-PET imaging as a potential marker to predict progression-free survival (PFS) in MBC patients receiving palbociclib combined with endocrine therapy.MethodsFifty-six ER + MBC patients underwent 18F-FES-PET/CT before the initiation of palbociclib. 18F-FES uptake was quantified and expressed as the standardized uptake value (SUV). Interlesional heterogeneity was qualitatively identified according to the presence or absence of 18F-FES-negative lesions. Intralesional heterogeneity was measured by the SUV-based heterogeneity index (HI = SUVmax/SUVmean). Association with survival was evaluated using the Cox proportional hazards model.ResultsA total of 551 metastatic lesions were found in 56 patients: 507 lesions were identified as 18F-FES-positive, 38 lesions were distributed across 10 patients without 18F-FES uptake, and the remaining 6 were liver lesions. Forty-three patients obtained a clinical benefit, and 13 developed progressive disease (PD) within 24 weeks. Nine out of 10 patients with an 18F-FES-negative site developed PD, and the median PFS was only 2.4 months. Among 46 patients with only 18F-FES-positive lesions, only four patients had PD, and the median PFS was 23.6 months. There were statistically significant differences between the two groups (P < 0.001). For the subgroup of patients with only 18F-FES-positive lesions, low FES-HI patients experienced substantially longer PFS times than those with high FES-HI (26.5 months vs. 16.5 months, P = 0.004).Conclusions18F-FES-PET may provide a promising method for identifying and selecting candidate ER + /HER2- MBC patients who would most likely benefit from palbociclib combined with endocrine treatment and could serve as a predictive marker for treatment response.Trial registration NCT04992156, Date of registration: August 5, 2021 (retrospectively registered).

Real-World Data of Palbociclib in Combination With Endocrine Therapy for the Treatment of Metastatic Breast Cancer in Men.

This report examined the benefits and risks of palbociclib plus endocrine therapy (ET) in men with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). Palbociclib was evaluated using three independent data sources: real-world data from pharmacy and medical claims, a de-identified real-world data source derived from electronic health records (EHRs), and a global safety database. From medical and pharmacy records, 1,139 men with MBC were identified; in the first-line setting, median duration of treatment was longer with palbociclib plus ET (n=37, 8.5months, 95% confidence interval (CI), 4.4-13.0) than ET alone (n=214, 4.3months, 95% CI, 3.0-5.7) and specifically, was longer with palbociclib plus letrozole (n=26, 9.4months, 95% CI, 4.4-14.0) than letrozole alone (n=63, 3.0months, 95% CI, 1.8-4.8). In the EHR-derived database, 59 men received treatment for MBC; real-world response across all lines of therapy in the metastatic setting was reported in 4 of 12 patients (33.3%) in the palbociclib plus ET group vs. 1 of 8 (12.5%) patients in the ET group. Review of the global safety database did not identify any new safety signals in palbociclib-treated men. Real-world data indicated that men with MBC benefit from palbociclib plus ET, with a safety profile consistent with previous observations in women with MBC. Collective data on palbociclib in women and men in this report, including clinical trial data, real-world data, and a well-established risk/benefit profile, led to US approval of an expansion of the palbociclib indication to include men with MBC.

Real-world effectiveness and sensitivity of palbociclib plus endocrine therapy in HR+/HER2- patients with metastatic breast cancer.

Palbociclib has shown satisfactory outcomes when combined with endocrine therapy (ET) in hormone receptor–positive and human epidermal growth factor receptor 2–negative (HR+/HER2–) metastatic breast cancer (MBC). However, data in Asia are currently scarce.This retrospective study aimed to evaluate the real-world effectiveness, sensitivity, and toxicity of palbociclib plus ET in HR+/HER2– MBC in North China. We recruited patients with HR+/HER2– MBC from August 2018 to July 2020 across 7 hospitals in North China. The primary endpoint was to evaluate progression-free survival (PFS) after initial progress on palbociclib therapy. The secondary endpoints included determining predictive biomarkers of palbociclib sensitivity and toxicity of palbociclib.A total of 54 patients were analyzed in this cohort with an estimated median follow-up time of 14.3 months. Patients who received palbociclib as a first-line treatment showed significantly prolonged PFS compared with those who received palbociclib as a second-line or beyond treatment (21.8 months vs 15.9 months vs 6.8 months) (P < .001). Besides, patients with Ki67 <30% (P = .024) and PR ≥20% (P = .041) in metastatic tumors had significantly longer PFS. The Cox proportional-hazards regression analyses proved that different lines (P = .001 in multivariate analysis), Ki67 <30% (P = .035 in multivariate analysis), and PR ≥20% (P = .045 in univariate analysis) in metastatic tumors affected PFS significantly. The most common adverse events were hematologic, with 31.48% of patients having neutropenia.Palbociclib plus ET significantly prolonged PFS for patients with HR+/HER2– MBC who received first-line therapy, with manageable toxicity. The values of Ki67 and PR in metastatic tumors may be potential predictive biomarkers of palbociclib sensitivity.

Efficacy and safety of low-dose everolimus combined with endocrine drugs for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer.

BackgroundTo analyze the efficacy and safety of everolimus 5 mg/day in combination with endocrine drugs in the treatment of hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer using real-world clinical data.MethodsClinical data of hormone receptor (HR)-positive and HER2-negative patients with advanced breast cancer treated with everolimus combined with endocrine drugs in our center between August 2012 and May 2017 were retrospectively analyzed. Curative effect and adverse reactions were evaluated.ResultsA total of 110 patients were enrolled in this study, and 87.3% received salvage chemotherapy. The median number of salvage treatment lines was 5 (range: 1–19). The median follow-up duration was 12 months (range: 1–56.3 months), the overall response rate (ORR) was 6.4%, the clinical benefit rate (CBR) was 31.8%, the median progression-free survival (mPFS) was 4.0 months (95% CI: 2.9–5.1 months), and the median overall survival (OS) was 17 months (95% CI: 12.1–21.9 months). The mPFS for patients who received ≤2 treatment line was 11.8 months (95% CI: 4.3–19.3 months). Univariate and multivariate analyses suggested that absence of liver metastases, secondary endocrine resistance, and number of metastasis sites <3 were the main factors influencing the benefit of everolimus combined with endocrine therapy. The most common adverse events of grade 3 were: stomatitis (5.5%), non-infectious pneumonia (1.8%), and erythra (1.8%). No grade 4 adverse reactions were observed.ConclusionsOur results showed that everolimus (5 mg/day) combined with endocrine therapy was effective and relatively safe for patients with hormone receptor-positive, HER2-negative metastatic breast cancer.

Clinical efficacy of palbociclib-based therapy in women with HR+/HER2- metastatic breast cancer in the real-world setting for Chinese women: a comparison with the IRIS study.

This retrospective study aimed to explore the clinical efficacy of palbociclib with endocrine therapy (ET) in women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer in real-world practice. This retrospective study analyzed the medical records of patients to determine treatment outcomes. Progression-free survival (PFS) curves were generated using log-rank tests with the Kaplan-Meier method. Treatment outcomes in Chinese patients were compared with those in patients from the USA, Argentina, Canada, and Europe in the IRIS study. In total, 69 patients were included in this study. The median PFS was 12.8 months (95% confidence interval: 10.1-15.5). A longer PFS was observed for patients with bone-only metastases, no liver metastases, no previous palliative chemotherapy, no previous palliative ET, and ET sensitivity. The overall response rate was 10.1%, and the clinical benefit rate was 78.3%. Nineteen patients (27.5%) received a reduced dose of palbociclib according to the decision of their physicians. Dose reduction did not affect the clinical efficacy of the combined treatment. Compared with those in the IRIS study, Chinese patients receiving palbociclib-based treatment were younger, and they had fewer bone-only metastases and more visceral and liver metastases. The clinical benefit rate and overall response rate for Chinese patients were lower than those observed for the patients in the IRIS study. ET combined with palbociclib treatment was effective and well-tolerated in HR+/HER2- metastatic breast cancer patients in the real-world setting. Earlier use of palbociclib-ET was associated with more clinical benefits in HR+/HER2- metastatic breast cancer.

Real-World Tumor Response of Palbociclib Plus Letrozole Versus Letrozole for Metastatic Breast Cancer in US Clinical Practice.

BackgroundLimited information exists regarding tumor response to palbociclib plus an aromatase inhibitor (AI) versus AI alone in real-world practice.ObjectiveTo evaluate the real-world tumor response of palbociclib plus letrozole (PAL+LET) versus LET alone as first-line treatment for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer (HR+/HER2‒ MBC) in routine US clinical practice.Patients and MethodsThis retrospective analysis included HR+/HER2‒ MBC patients who initiated PAL+LET or LET as first-line treatment between February 2015 and September 2018 in the Flatiron Health Analytics database. Patients were followed until December 2018. Real-world best tumor response (rwBTR) was determined based on physicians’ assessment of radiologic evidence for change in burden of disease.ResultsOf the 1383 eligible patients who initiated PAL+LET or LET as first-line therapy in the Flatiron database, 968 patients had ≥ 1 tumor response assessment (662 received PAL+LET and 306 received LET). The rwBTR rate (complete response+partial response) in the first-line setting was 59.8% in the PAL+LET group and 39.2% in the LET group (odds ratio 2.31 (95% CI 1.75‒3.04), P < 0.0001). After 1:1 propensity-score matching, the rwBTR rate was 58.6% in the PAL+LET group versus 39.1% in the LET group (odds ratio 2.21 (95% CI 1.50‒3.25), P < 0.0001).ConclusionsThis real-world analysis demonstrated that HR+/HER2‒ MBC patients were more likely to respond to PAL+LET compared to LET. These findings further showed the effectiveness of PAL+LET therapy in the real-world setting and support the combination as a standard of care for MBC.Study RegistrationPfizer; NCT04176354; registered November 25, 2019Supplementary InformationThe online version contains supplementary material available at 10.1007/s11523-021-00826-1.

Establishment of Prognostic Nomograms for Predicting the Survival of HR-Positive, HER2-Negative Metastatic Breast Cancer Patients Treated with Everolimus

BackgroundThere are no clinically available prognostic models for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer treated with everolimus. We aimed to develop a tool to predict the progression-free survival (PFS) and overall survival (OS) of these patients and to identify optimal candidates who would benefit from everolimus-based treatment in this heterogeneous patient population.MethodsThe clinical data of patients with HR+, HER2- metastatic breast cancer receiving everolimus between May 2012 and January 2018 at Sun Yat-sen University Cancer Center were retrospectively retrieved. Based on potential prognostic factors derived from multivariate Cox analysis, we established predictive nomogram models for PFS and OS and evaluated their predictive values by means of the concordance index (C-index). Calibration curves were used to estimate the consistency between the actual observations and the nomogram-predicted probabilities.ResultsA total of 116 patients with HR+, HER2- metastatic breast cancer were enrolled in this study. Three independent prognostic factors, including the line of everolimus in the metastatic setting, everolimus clinical benefit rate and number of liver metastatic lesions, were identified from the multivariate Cox analysis. Prognostic models for individual survival prediction were established and graphically presented as nomograms. The C-index was 0.738 (95% confidence interval [CI]: 0.710–0.767) for the PFS nomogram and 0.752 (95% CI: 0.717–0.788) for the OS nomogram, which showed favourable discrimination. The calibration curves for the probabilities of 6-, 9-, and 12-month PFS and 1-, 2-, and 3-year OS suggested satisfactory consistency between the actual observations and the predicted probabilities.ConclusionWe constructed convenient nomogram models for patients with HR+, HER2- metastatic breast cancer to individually predict their potential benefits from everolimus in the metastatic setting. The models showed good performance in terms of accuracy, discrimination capacity and clinical application value.

Chemotherapy and Targeted Therapy for Patients With Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer That is Either Endocrine-Pretreated or Hormone Receptor-Negative: ASCO Guideline Update.

This guideline updates recommendations of the ASCO guideline on chemotherapy and targeted therapy for patients with human epidermal growth factor receptor 2-negative metastatic breast cancer (MBC) that is either endocrine-pretreated or hormone receptor (HR)-negative. An Expert Panel conducted a targeted systematic literature review guided by a signals approach to identify new, potentially practice-changing data that might translate into revised guideline recommendations. The Expert Panel reviewed abstracts from the literature review and retained 14 articles. Patients with triple-negative, programmed cell death ligand-1-positive MBC may be offered the addition of immune checkpoint inhibitor to chemotherapy as first-line therapy. Patients with triple-negative, programmed cell death ligand-1-negative MBC should be offered single-agent chemotherapy rather than combination chemotherapy as first-line treatment, although combination regimens may be offered for life-threatening disease. Patients with triple-negative MBC who have received at least two prior therapies for MBC should be offered treatment with sacituzumab govitecan. Patients with triple-negative MBC with germline BRCA mutations previously treated with chemotherapy may be offered a poly (ADP-ribose) polymerase inhibitor rather than chemotherapy. Patients with HR-positive human epidermal growth factor receptor 2-negative MBC for whom chemotherapy is being considered should be offered single-agent chemotherapy rather than combination chemotherapy, although combination regimens may be offered for highly symptomatic or life-threatening disease. Patients with HR-positive MBC with disease progression on an endocrine agent may be offered treatment with either endocrine therapy with or without targeted therapy or single-agent chemotherapy. Patients with HR-positive MBC with germline BRCA mutations no longer benefiting from endocrine therapy may be offered a poly (ADP-ribose) polymerase inhibitor rather than chemotherapy. No recommendation regarding when a patient's care should be transitioned to hospice or best supportive care alone is possible.Additional information is available at www.asco.org/breast-cancer-guidelines.

A Real-World Evidence Study of CDK4/6 Inhibitor Treatment Patterns and Outcomes in Metastatic Breast Cancer by Germline BRCA Mutation Status

IntroductionLimited data exist on real-world treatment patterns and the effectiveness of cyclin-dependent kinase (CDK) 4/6 inhibitors in germline BRCA (gBRCA)-mutated breast cancer.MethodsAdults with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (mBC) treated with CDK4/6 inhibitor therapy between 2013 and 2018 were retrospectively selected from the Flatiron Health database. Patients with known gBRCA status were classified as mutated (gBRCAm) or wild type (gBRCAwt). Time-to-first subsequent therapy or death (TFST) and overall survival (OS) were calculated from the earliest line of therapy with a CDK4/6 inhibitor.ResultsOf 2968 patients with HR+/HER2− mBC receiving a CDK4/6 inhibitor, 859 (28.9%) had known gBRCA status, of whom 9.9% were gBRCAm and 90.1% gBRCAwt. Median (95% confidence interval [CI]) TFST was 10 (7–11) months in the gBRCAm group, 10 (9–11) months in the gBRCAwt group, and 11 (10–12) months in the combined gBRCAwt and unknown gBRCA group; median (95% CI) OS was 26 (21–not estimated), 37 (31–51), and 33 (31–35) months, respectively. Cox models indicated the gBRCAm group had shorter TFST (stratified hazard ratio [sHR] 1.24; 95% CI 0.96–1.59) and OS (sHR 1.50; 95% CI 1.06–2.14) than the gBRCAwt group. The gBRCAm group had shorter TFST (sHR 1.38; 95% CI 1.08–1.75) and OS (sHR 1.22; 95% CI 0.88–1.71) than the combined group.ConclusionThe results of this real-world study suggest that treatment outcomes with CDK4/6 inhibitors may be worse in patients with gBRCAm mBC than in their counterparts with gBRCAwt and unknown gBRCA status, suggesting potential differences in tumor biology. This result highlights the unmet need in patients with gBRCAm requiring optimized treatment selection and sequencing. Future exploration in larger samples of patients who have had biomarker testing is warranted.

First-line treatment with a cyclin-dependent kinase 4/6 inhibitor combined with an aromatase inhibitor for hormone receptor-positive, human epidermal growth factor receptor-2 negative metastatic breast cancer: Population-based outcomes for patients treated in Alberta, Canada.

e13020 Background: Cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) in combination with an aromatase inhibitor (AI) has emerged as the standard first line treatment in patients with hormone receptor positive, human epidermal growth factor receptor-2 (HER-2) negative metastatic breast cancer (MBC). In this analysis, we describe population-based outcomes for first-line treatment with a CDK4/6i combined with an AI. Methods: All patients who were prescribed CDK4/6i + AI from January 2016 through June 2019 in a large Canadian province were included. Descriptive statistics were used to summarize patient demographics, tumor and treatment characteristics. Survival distributions were estimated using the Kaplan-Meier method. Multivariate analysis (MVA) using a Cox proportional hazards model was constructed to examine associations between potentially prognostic clinical variables and progression free survival (PFS). Results: A total of 316 patients were included. Median age was 61 years (interquartile range, 53-70 years), 82% were postmenopausal women, 39% had de novo MBC, and 48% had non-visceral disease. Palbociclib was prescribed in 94% of patients and the remaining patients received ribociclib. The CDK4/6i was dose-reduced upfront or during treatment in 47%. While 70% of the patients discontinued treatment due to progression, 30% stopped due to toxicity/patient preference/physician recommendation. With a median follow-up of 28.1 months, the median PFS was 37.9 months (95% CI, 26.7-NR). In the MVA, PR-negative tumour (HR, 2.37; 95% CI, 1.45-3.88; P = 0.001) and dose reduction of the CDK4/6i (HR, 1.51; 95% CI, 1.06-2.16; P = 0.022) predicted worse PFS. Median overall survival (OS) was not reached. The 30-month and 36-month OS rates were 74% and 68%, respectively. Of patients who progressed (n = 131), 89% received second-line treatment (chemotherapy in 46%, single agent hormonal therapy in 35%, hormonal therapy plus a targeted agent in 15%, and other in 4%). Median time to progression on second line chemotherapy was 9.0 (5.8-17.6) months and second line hormonal therapy +/- targeted agent was 4.0 (3.4-8.6) months (P = 0.012). Conclusions: The real-world outcomes of first-line use of CDK4/6i and AI are encouraging. PR negative tumors and dose reduction appear to be negative prognostic markers. CDK4/6i + AI as first-line treatment for HR-positive, HER2-negative MBC in Alberta is justified based on favorable PFS and early OS outcomes.

Characterizing demographics, clinical, and genomic characteristics for U.S. patients with HR+, HER2- metastatic breast cancer following progression on a CDK4 and 6 inhibitor.

1015 Background: Cyclin-dependent kinases 4 and 6 inhibitors (CDK4 &amp; 6i) have advanced the therapeutic landscape for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). However, there is an unmet need for treatment strategies following progression on CDK4 &amp; 6i +/- endocrine therapy (ET). The objective of this analysis is to aid in the development of post-progression treatment by characterizing genomic profiles of tumor biopsies after progression on a CDK4 &amp; 6i +/- ET. Methods: This is a retrospective study comparing two cohorts of US patients (pts) diagnosed with HR+, HER2- MBC since January 2011. One cohort underwent biopsy following progression on a CDK4 &amp; 6i +/- ET (Cohortpost) while the second cohort underwent biopsy with no evidence of CDK4 &amp; 6i treatment (Cohortpre). Tumor tissue was analyzed using the next generation sequencing Tempus xT assay that analyses 595 cancer-related genes. Of 595 molecularly profiled pts, 369 had sufficient medical record data to be eligible for this analysis. Patient characteristics at metastatic diagnosis and CDK4 &amp; 6i initiation were described. For genomic profile comparison, Mann-Whitney U-test was used for continuous variables such as tumor mutation burden (TMB) with significance at P &lt; 0.05; Chi-square or Fishers' exact test was used as appropriate for categorical variables including mutation frequency, with significance at false discovery rate (FDR) &lt; 0.2. Results: Of 369 pts, 177 (48%) were in Cohortpre and 192 (52%) were in Cohortpost. Overall, the mean age at the time of MBC diagnosis was 59 and 55 years, respectively; 47% and 66% of patients had evidence of prior chemotherapy or ET; and 30% and 25% had de novo stage IV MBC. The most common biopsy site was liver, occurring in 38% of pts overall (Cohortpre, 23%; Cohortpost, 52.6%). The xT assay results indicated that pts in Cohortpost had significantly higher TMB compared to patients in Cohortpre (median 2.92 vs 1.67, P &lt; 0.0001). A subset of patients with liver mets across both cohorts (n = 141) showed a similar, but nonsignificant trend (median 2.92 vs 2.08, P = 0.0565). Additionally, pts in Cohortpost had a higher ESR1 alteration frequency compared to Cohortpre (mutations: 32.29% vs 9.60%, FDR &lt; 0.0001; fusions: 7% vs 3%, P = 0.1420). No significant differences were noted in TP53, CCNE1, CCND1, RB1, CDK4, and CDK6 between cohorts. Conclusions: These findings describe clinical characteristics and specific genomic alterations noted after progression on CDK4 &amp; 6i +/- ET. Further analyses will evaluate timing of resistance, mutational and transcriptomic signatures. This may aid in understanding mechanisms of progression associated with CDK4 &amp; 6i +/- ET, ultimately contributing to development of treatment options post progression.

AMEERA-1: Phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with palbociclib (palbo) in postmenopausal women with ER+/ human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC).

1058 Background: AMEERA-1 (NCT03284957) investigates amcenestrant, an oral SERD, as monotherapy and combined with targeted therapies in ER+/HER2– mBC. Here we report data from dose escalation (Part C) and dose expansion (Part D) of amcenestrant + palbo. Methods: Patients (pts) were postmenopausal women with ER+/HER2– mBC and ≥ 6 mos prior advanced endocrine therapy (ET) or adjuvant (adj) ET resistance (relapse on adj ET started ≥ 24 mos ago or &lt; 12 mos after completing adj ET). Prior chemotherapy (≤ 1) for advanced disease was allowed; targeted therapies were not except ≤ 1 CDK4/6i in Part C. Part C assessed dose-limiting toxicities (DLTs) and aimed to establish the recommended phase 2 dose (RP2D) for amcenestrant (200 or 400 mg once daily [QD], in 28-day cycles) in combination with palbo (125 mg QD for 21 days on/ 7 days off). Safety (treatment-emergent adverse events [TEAEs] and lab abnormalities per CTCAE v4.03) and pharmacokinetics (PK) were evaluated. Antitumor activity at the RP2D for amcenestrant + palbo was evaluated in a subset of Part C pts and Part D, according to RECIST v1.1, determined locally by investigators. Results: Feb 8, 2021 data cutoff. In Part C (n = 15; 200 mg: 9; 400 mg: 6), no DLTs occurred and amcenestrant 200 mg QD was selected as the RP2D with palbo, based on PK and safety data. In the pooled safety population at the RP2D (n = 39; Part C: 9; Part D: 30), median (range) age was 59 y (33–86) with ECOG PS 0 (74.4%) or 1 (25.6%) and 2 (1–6) organs involved. Immediate prior therapy was neo/adj (41.0%, all ET resistant) or advanced (59.0%, range 1–4 lines). Median (range) exposure was 32 wks (1–66) with 59.0% pts on ongoing therapy. No amcenestrant dose reductions occurred; 25.6% had ≥ 1 palbo dose reduction. Most common non-hematological TEAEs related to amcenestrant were Grade 1–2 nausea and fatigue (17.9% each), asthenia and hot flush (10.3% each); to palbo were fatigue (30.8%), nausea (25.6%), asthenia and dysgeusia (10.3% each). Two pts discontinued due to AEs. The majority (94.9%) had neutrophil count decrease (53.8% Grade ≥ 3). Preliminary antitumor activity after at least 6 cycles of therapy (unless early treatment discontinuation) is reported in the table below. Conclusions: In pts with ER+/HER2– mBC, safety at the RP2D of amcenestrant + palbo was favorable, with no safety signals of bradycardia or eye disorders. Preliminary antitumor activity was observed (ORR: 31.4% and CBR: 74.3%). Clinical trial information: NCT03284957 .[Table: see text]

CYCLONE 1: A phase 2 study of abemaciclib in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with a novel hormonal agent and taxane-based chemotherapy.

TPS5086 Background: In cancer cells, the cyclin-dependent kinases 4 and 6 (CDK4 &amp; 6)/retinoblastoma protein (Rb) pathway is commonly altered, resulting in uncontrolled cell cycle entry and proliferation. CDK4 &amp; 6 inhibitors represent a major advance in the management of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (ABC or MBC, respectively). Abemaciclib is an oral selective inhibitor of CDK4 &amp; 6 administered on a continuous dosing schedule, approved in combination with endocrine therapy for HR+, HER2- ABC or MBC. In addition, abemaciclib is also approved by the FDA as monotherapy for HR+, HER2- ABC or MBC following endocrine therapy and prior chemotherapy in the metastatic setting. Similar to the estrogen receptor signaling pathway in breast cancer cells, there is evidence that the androgen receptor axis activates CDK4 &amp; 6 to sustain prostate cancer cell proliferation and survival. Preclinical studies in prostate cancer cell lines and xenograft models showed that abemaciclib exhibits single agent activity by inducing cell cycle arrest and tumor growth inhibition. Clinical activity of abemaciclib in combination with abiraterone and prednisone is investigated in a randomized phase 2 study in the first-line mCRPC setting (CYCLONE 2, NCT03706365). Despite recent advances, management of heavily pretreated mCRPC remains a major clinical challenge. Herein, we hypothesize that mCRPC patients whose disease progressed after novel hormonal agents (NHA) and taxane therapies may derive therapeutic benefit from single agent abemaciclib. Methods: CYCLONE 1 is a phase 2, single-arm, multicenter study to assess the safety and efficacy of abemaciclib monotherapy in 40 patients with mCRPC progressing after ≥1 NHA and 2 taxane regimens. Patients will be enrolled at time of prostate specific antigen (PSA) or radiographic progression per PCWG3 criteria and have at least 1 measurable lesion per RECIST 1.1. Metastatic tumor tissue (fresh biopsy or archival material &lt;12 weeks) is required at baseline for biomarker analysis. Patients will receive abemaciclib 200 mg twice daily until unacceptable adverse events or disease progression. The primary objective is investigator-assessed objective response rate (ORR). Key secondary objectives include safety, radiographic progression-free survival, overall survival, PSA response rate, time to PSA progression, time to symptomatic progression, Ki-67 expression, patient-reported outcomes, and pharmacokinetics. Assuming an ORR of 15%, the study has over 73% power to observe a response rate of at least 12.5%. Accrual began in January 2021. Clinical trial information: NCT04408924.

Impact of clinical targeted sequencing on endocrine responsiveness in estrogen receptor-positive, HER2-negative metastatic breast cancer

Clinical targeted sequencing allows for the selection of patients expected to have a better treatment response, and reveals mechanisms of resistance to molecular targeted therapies based on actionable gene mutations. We underwent comprehensive genomic testing with either our original in-house CLHURC system or with OncoPrime. Samples from 24 patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer underwent targeted sequencing between 2016 and 2018. Germline and somatic gene alterations and patients’ prognosis were retrospectively analyzed according to the response to endocrine therapy. All of the patients had one or more germline and/or somatic gene alterations. Four patients with primary or secondary endocrine-resistant breast cancer harbored germline pathogenic variants of BRCA1, BRCA2, or PTEN. Among somatic gene alterations, TP53, PIK3CA, AKT1, ESR1, and MYC were the most frequently mutated genes. TP53 gene mutation was more frequently observed in patients with primary endocrine resistance compared to those with secondary endocrine resistance or endocrine-responsive breast cancer. Recurrent breast cancer patients carrying TP53-mutant tumors had significantly worse overall survival compared to those with TP53-wild type tumors. Our 160-gene cancer panel will be useful to identify clinically actionable gene alterations in breast cancer in clinical practice.

Local Laboratory Testing of Germline BRCA Mutations vs. Myriad: A Single-Institution Experience in Korea.

Genetic diagnosis for human epidermal growth factor receptor 2-negative metastatic breast cancer patients with the germline BRCA (gBRCA) mutation has been emphasized since the development of polyadenosine diphosphate-ribose polymerase inhibitors. Myriad Genetics, Inc.’s (Salt Lake City, UT, USA) companion diagnostics service is almost exclusively used for genetic testing. The aim of this study was to compare the results of germline BRCA mutation tests returned by a local laboratory and those performed by Myriad. Between April 2014 and February 2018, 31 patients with gBRCA 1/2 mutation test results from both Samsung Medical Center (Seoul, Korea) and Myriad were enrolled. “Discordant: Opposite classification” was observed for only one among 27 (3.7%). This discrepancy was due to the detection of a deleterious large genomic rearrangement of BRCA 1 by Myriad. Samsung Medical Center performed multiple ligation-dependent probe amplifications (MLPA) to detect large genomic rearrangements only in high-risk patients. This one case was not suspected as high risk and MLPA was not performed. The concordant rate was 74.1% for all 27 patients. “Discordant: Laboratory’s uncertain classification” was found in 22.2% of the sample (six patients). All discrepancies were generated during interpretation of BRCA 2 gene sequencing. Further studies and standardization of genetic testing for BRCA 1/2 genes are required.

Abstract PD8-08: A phase 1/2 study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), as monotherapy and in combination with other anti-cancer therapies in postmenopausal women with ER-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC): AMEERA-1

Abstract Background SERDs belong to a class of ER-targeted therapies that antagonize and degrade ERs, including in ER-dependent tumors resistant to other endocrine therapies (ET). This study (AMEERA-1; NCT03284957) investigates SAR439859, an oral SERD, as monotherapy and (in ongoing cohorts) in combination with targeted therapies in patients (pts) with ER+/HER2- mBC. Here we report updated safety and antitumor activity with SAR439859 monotherapy, including exploratory analyses by prior therapy and ESR1 status. Methods This open-label, phase 1/2, first-in-human study assessed SAR439859 as monotherapy in Parts A (dose escalation 20-600 mg once daily [QD]) and B (dose expansion with recommended dose at 400 mg QD). Eligible pts were heavily pre-treated, postmenopausal women with ER+/HER2- mBC and measurable disease who received ≥6 months of prior ET in the advanced setting. Prior chemotherapy, mammalian target of rapamycin inhibitors (mTORi) and cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) for advanced disease were allowed. This analysis pooled data from pts receiving SAR439859 ≥150 mg (Part A) and 400 mg (Part B), administered in 28-day cycles. Antitumor activity was assessed by the objective response rate and clinical benefit rate (CBR: complete response [CR], partial response [PR] and stable disease [SD] ≥24 weeks) per RECIST v1.1, determined by investigators. Analyses by prior therapy and baseline ESR1 mutation status were performed. Safety was also evaluated. Results Pts (n = 62; Part A: 13; Part B: 49) had a median age of 63 (range 37-88) years and ECOG PS 0 (59.7%) or 1 (40.3%); 93.5% had visceral metastases. Pts had a median of 2 (range 1-8) prior lines of therapy in the advanced setting (48.4% had ≥3 prior lines): all had prior ET and 72.6% had prior targeted therapy. SAR439859 monotherapy showed antitumor activity in the response-evaluable population (n = 59) and in subset populations with ≤3 prior lines (n = 33) or without prior mTORi, CDK4/6i, or SERD (n = 14) (Table 1). For pts with ESR1 status (n = 58), CBR with SAR439859 was comparable in ESR1 wild-type (36.7%) and mutant mBC (32.1%), with similar results in subpopulations. Treatment-related adverse events (TRAEs) occurred in 62.9% of pts (all grade 1-2); none resulted in SAR439859 discontinuation. Most frequent TRAEs were hot flush (16.1%); constipation and arthralgia (each 9.7%); decreased appetite, vomiting, diarrhea and nausea (each 8.1%); and fatigue (6.5%). Conclusions Among heavily pre-treated pts, SAR439859 demonstrated antitumor activity, similar to historical single-agent fulvestrant activity in less heavily pre-treated pts with advanced/mBC (2L+ setting; no prior targeted agents) (indirect comparison). In both subsets of pts with fewer prior advanced lines of therapy, SAR439859 showed trends of greater clinical activity versus historical fulvestrant activity. SAR439859 had a favorable safety profile with limited TRAEs. No safety signals of cardiac or ocular toxicities were observed. Ongoing parts of the study are investigating SAR439859 in combination with targeted therapies. Based on the monotherapy results, a randomized phase 2 study is investigating SAR439859 compared with physician’s choice in a 2L+ setting (AMEERA-3; NCT04059484). Funding: Sanofi. Antitumor activity overall and in subpopulations by prior lines of therapy (Parts A+B)Overall population (A+B)≤3 Prior advanced linesWithout prior targeted therapy(n = 59)a(n = 33)b(n = 14)cBOR, n (%)–CR000–PR5 (8.5)5 (15.2)3 (21.4)–SD24 (40.7)15 (45.5)8 (57.1)–PD30 (50.8)13 (39.4)3 (21.4)ORR, n (%)5 (8.5)5 (15.2)3 (21.4)CBR, n (%)20 (33.9)14 (42.4)9 (64.3)aPooled cohort (A ≥150 mg QD + B);bSubset of pooled cohort with ≤3 prior lines in the metastatic setting, including ≤1 of either prior chemotherapy or CDK4/6i and no prior mTORi; cSubset of pooled cohort with no prior mTORi, CDK4/6i, or fulvestrant.BOR, best overall response; CBR, clinical benefit rate; CR, complete response; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease. Citation Format: Hannah M Linden, Mario Campone, Aditya Bardia, Gary A Ulaner, Alice Gosselin, Séverine Doroumian, Vasiliki Pelekanou, Marina Celanovic, Sarat Chandarlapaty. A phase 1/2 study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), as monotherapy and in combination with other anti-cancer therapies in postmenopausal women with ER-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC): AMEERA-1 [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD8-08.

Abstract PS10-46: Real-world patient characteristics, utilization patterns, and outcomes of US patients with HR+/HER2- metastatic breast cancer treated with abemaciclib

Abstract Background Abemaciclib is the most recent oral cyclin-dependent kinase 4 and 6 inhibitor (CDK4&amp;6i) to receive FDA approval to treat hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (MBC). We used administrative claims data to describe patient characteristics, real-world utilization patterns, and outcomes in a US patient cohort upon initiating abemaciclib treatment for HR+, HER2- MBC.Methods This retrospective observational study analyzed medical and pharmacy claims from the IBM® MarketScan® Research Databases (Commercial and Medicare Supplemental) between 1-Jan-2007 to 31-Jan-2020. Patients (≥18 years) newly initiating abemaciclib between 1-Sept-2017 and 31-Oct-2019 were included if they had ≥2 breast cancer diagnoses, ≥2 secondary neoplasm diagnoses, evidence of HR+ disease, continuous enrollment ≥6 months before and ≥90 days after abemaciclib initiation (index date), and absence of therapies suggesting HER2 positivity. Patients were grouped by concomitant therapy (+aromatase inhibitor [AI], +fulvestrant [F], 200mg abemaciclib monotherapy [200mgMono], or +other), and stratified by prior CDK4&amp;6i use (yes/no). Line of therapy (LoT) and reason for discontinuation were not able to be determined from this dataset. Baseline demographic, clinical, and treatment characteristics were summarized with descriptive statistics. Kaplan-Meier methods assessed time-to-discontinuation, defined as a gap of 60-days without an abemaciclib fill, following exhaustion of days’ supply from prior fills, or initiation of a different CDK4&amp;6i (ie, palbociclib or ribociclib).Results There were 454 patients included in this analysis (mean [SD] age=57.7 years [10.8]; 98.9% female). Prevalence of new abemaciclib initiators was 29.3% (n=133) in the +AI group, 35.0% (n=159) in the +F group, 10.4% (n=47) in the 200mgMono group, and 25.3% (n=115) in the +other group. Prior CDK4&amp;6i use within each regimen ranged from 37.6% (+AI) to 60.0% (+other). Visceral metastases were present in 50.4% in the +AI group; 49.7% in the +F group; 55.3% in the 200mgMono group; and 47.8% in the +other group. Nearly 75% (n=331) of all abemaciclib initiators began treatment with a 150 mg dose. Chemotherapy use in the 6-month pre-index period was observed for 18.8% in the +AI group; 21.4% in the +F group; 51.1% in the 200mgMono group; and 21.7% in the +other group. Median length of follow-up for all abemaciclib initiators was 321 days (IQR 195-482). Among those without prior CDK4&amp;6i use, the median time-to-discontinuation for the +AI group was not reached (NR) (95% CI, 430 days-NR), the +F group was 531 days (95% CI, 281-NR), the 200mgMono group was 141 days (95% CI, 80-NR), and the +other group was 392 days (95% CI, 300-NR). In the subset with prior CDK4&amp;6i use, the median time-to-discontinuation for the +AI group was 196 days (95% CI, 125-NR), the +F group was 146 days (95% CI, 93-225), the 200mgMono group was 140 days (95% CI, 86-NR), and the +other group was 191 days (95% CI, 113-280).Conclusion These real-world data complement pivotal abemaciclib clinical trial results by examining abemaciclib use among a more heterogeneous patient population in a clinical practice setting. The sizeable number of patients with prior CDK4&amp;6i use, visceral metastases, and prior chemotherapy at abemaciclib initiation suggests many patients had very advanced disease and/or were in later stages of their treatment paradigm. Claims data lack many variables of clinical relevance needed to fully understand disease severity in the study population, such as LoT and degree of endocrine sensitivity; these limitations should be considered when interpreting CDK4&amp;6i administrative claims studies. Citation Format: Kimberly R. Saverno, Julie Beyrer, Emily Nash Smyth, Hamad Abedtash, Angelo DeLuca, Yajun Emily Zhu, Sarah Rybowski. Real-world patient characteristics, utilization patterns, and outcomes of US patients with HR+/HER2- metastatic breast cancer treated with abemaciclib [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-46.