Hormone Receptor-positive Advanced Breast Research Articles

Endocrine therapy for early breast cancer in the era of oral selective estrogen receptor degraders: challenges and future perspectives.

Growth and survival of hormone receptor positive breast cancer cells are dependent on circulating hormones (e.g., estrogen and progesterone). Endocrine therapy improved outcomes in both early and advanced hormone receptor positive breast cancer. These treatments include drugs with different mechanisms of action, namely selective estrogen receptor modulators (SERM), aromatase inhibitors, and selective estrogen receptor degraders (SERDs). SERDs represent estrogen receptor antagonists, favoring its degradation and thus interfering with proliferation genes transcription and activation. Fulvestrant is the first approved SERD, administered intramuscularly for treating advanced breast cancer. Oral SERDs have been tested to overcome the limitation of the intramuscular administration, and to increase SERD bioavailability. Recently, an oral SERD, Elacestrant, has been approved by the Food and Drug Administration (FDA) for patients carrying an ESR1 mutation. In fact, oral SERDs seem to be effective in tumors harboring ESR1 mutations, a well known mechanism of resistance to endocrine therapy (especially aromatase inhibitors). More recently, oral SERDs have been tested in patients with early hormone receptor positive breast cancer, although their impact on survival and in this curative setting compared to standard endocrine therapy still needs to be elucidated. The best timing and duration of SERD administration and specific biomarkers in (neo)adjuvant setting remain largely unknown.

Abstract PO5-04-11: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) beyond progression in hormone receptor positive advanced breast cancer: a systematic review and meta-analysis

Abstract Introduction The use of CDK 4/6i (palbociclib/ribociclib/abemaciclib) with endocrine therapy (ET) is a widely adopted first line standard treatment for hormone receptor positive advanced breast cancer (HR+ABC). Data supporting incorporation of CDK 4/6i ± ET beyond progression are less clear. Recent studies have evaluated either the continuation of or switching to a different CDK 4/6i, with a change in ET after progression on 1st line CDK4/6i with varying results. A pooled analysis of this strategy could be useful for clinical decision making. Methods We reviewed reports of both observational and clinical studies that evaluated continuing the same CDK4/6i or switching to a different agent after progression on first line CDK4/6i with ET. The search included the grey literature without exclusions for publication year or language. The mean overall response rate (ORR), clinical benefit rate (CBR) and progression free survival (PFS) weighted by study sample size were calculated. Meta-regression comprising linear regression weighted by sample size (mixed effects) was performed to explore the association between disease and treatment-related factors and benefit from continuing a CDK4/6i. Quantitative significance was assessed using the Burnand criteria. Analyses were performed using SPSS version 28 (IBM Corp, Armonk NY). Results Thirteen studies (N=1006 patients) were included; 7 were prospective trials and 2 cohorts of the same retrospective study included separately). Study patients had a median age of 57.8 years and 66% had visceral metastases. Among patients whose type of first-line CDK 4/6i exposure was reported (84.5%), 81.21% received Palbociclib 3.28% received Ribociclib and 0.89% received Abemaciclib. Six patients received both Palbociclib and Ribociclib. The median duration of first line CDK 4/6i therapy was 13.8 months. In the second line,the mean ORR was 12.8%, CBR 38.8%, and median PFS was 4.6 months. The ORRs for Palbociclib, Ribociclib and Abemaciclib, irrespective of type of prior CDK 4/6i, were 7.3%, 14.7% and 18.6%, respectively. The CBR for Palbociclib, Ribociclib and Abemaciclib were 33.1%, 42.2% and 46.8%, respectively. The median PFS based the CDK 4/6i used in second line was 4.2 (Palbociclib), 5.5 (Ribociclib) and 9.2 (Abemaciclib) months. Meta-regression analysis of PFS is included in the table. Conclusion Continuing a CDK 4/6i± ET beyond progression yields modest benefits. Switching CDK4/6i offers slightly better ORR and PFS. Continuing Palbociclib beyond progression does not seem beneficial. Longer duration of CDK4i exposure in the first line appears to be associated with shorter PFS in the second line. Small number of studies with limited number of patients likely affect results. Meta-regression analysis of PFS of CDK 4/6i with or without ET in subsequent line of therapy. Citation Format: Neha Pathak, Sudhir Kumar, Diego Malon Gimenez, Massimo Di Iorio, Consolacion Molto Valiente, Danielle Cuthbert, Meredith Li, Atul Batra, Michelle Nadler, Eitan Amir, Abhenil Mittal. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) beyond progression in hormone receptor positive advanced breast cancer: a systematic review and meta-analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-04-11.

Abstract PO2-05-06: Palbociclib in advanced hormone receptor positive breast cancer: A real world study in South America

Abstract BACKGROUND: First-line combined endocrine therapy is the standard of care for hormone receptor-positive (HR+) human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC). Palbociclib, in combination with aromatase inhibitors or fulvestrant, is a treatment option for HR+/HER2-negative ABC patients. We aimed to analyze the real-world experience of palbociclib in this setting in South America. METHODS: Real-world study collecting sociodemographic and clinical data from women with ABC treated with palbociclib in centers from Chile (n = 40), Perú (n = 61), and Ecuador (n = 10). Treatment efficacy and safety were analyzed. RESULTS: The median age was 54 years (range: 28 – 83), and 81.1% of women had received previous treatment: adjuvant therapy (20.0%), ABC treatment (31.1%), or both (48.9%). The median duration of palbociclib treatment was 14 months (range: 1 – 57), with differences among countries (longer in Perú; p = 0.009). The dose was reduced in 28.2% of women and only 6.5% returned to the previous one. Most women (97.3%) received combined endocrine therapy, letrozole (48.1%) or fulvestrant (44.4%), with differences between countries (p < 0.001). Palbociclib was usually the first-line therapy in Ecuador (60.0%) and Perú (80.3%), and the third line in Chile (37.5%). Considering all women, it was the first- or second-line therapy for 52.3% and 20.7% of them, respectively. The overall response rate was 34.2% and progressive disease was significantly lower in patients receiving first-line palbociclib (25.9 vs. 66.0%, p < 0.001). The disease-free survival was longer than 12 months in 67.2% of patients treated with first-line palbociclib. Regarding safety, 38.7% of women had any relevant adverse event (AE) during the treatment, most frequently neutropenia (39.5%), diarrhea (9.3%), and elevated transaminase levels (4.7%). The number of patients who developed any relevant AE was lower among the first-line treated patients (19.0% vs. 60.4%, p< 0.001). CONCLUSION: The study reflects differences among countries in routine palbociclib use. But considering all data, palbociclib has confirmed its efficacy and safety, supporting its use in HR+/HER2-negative patients, especially as a first-line therapy. Citation Format: Cesar SÁNCHEZ, Suraj Samtani, Henry Gómez, Silvia Falcon-Lizaraso, René Muñoz, Tannia Soria. Palbociclib in advanced hormone receptor positive breast cancer: A real world study in South America [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-05-06.

ESR1 F404 Mutations and Acquired Resistance to Fulvestrant in ESR1-Mutant Breast Cancer.

Novel F404 ESR1 mutations may be acquired to cause overt resistance to fulvestrant when combined with preexisting activating ESR1 mutations. Novel combinations of mutations in the ER ligand binding domain may cause drug-specific resistance, emphasizing the potential of similar drug-specific mutations to impact the efficacy of oral ER degraders in development. This article is featured in Selected Articles from This Issue, p. 201.

Real world evidence of systemic therapy in hormone receptor positive advanced breast cancer (HR+ ABC) in Australia: ARORA Registry.

e13054 Background: The last decade has seen a rapid increase in systemic treatment options for patients with HR+ ABC. The incorporation of CDK4/6 inhibitors in first line (1L) is now standard practice leading to improved survival. However, there is a paucity of data on uptake of standard therapies and associated toxicities in the real-world setting. Methods: ARORA is a secondary data use study of Australian patients with HR+ ABC capturing prospective data on patient characteristics, systemic therapy sequencing and treatment outcomes in routine clinical practice. Patients aged > 18 diagnosed after 1 Jan 2020 are eligible. Results: Data from 294 patients at 16 sites was analysed with a median follow up of 15 months. Mean age was 63 years; 23% > 75 years. 64% were ECOG 0, 5.4% had a familial syndrome, 61% had relapsed metastatic disease and 19.4% had bone only metastases at diagnosis. Of patients who relapsed, 14.6% and 52.8% received neoadjuvant and adjuvant chemotherapy respectively, and 77.5% received adjuvant endocrine therapy (ET). 41% relapsed on or within 12 months of stopping adjuvant ET. 5 patients (1.7%) did not receive any systemic therapy for ABC. Of those on 1L therapy, 223 (77%) received CDK4/6i + ET, 38 (13.1%) received ET alone and 26 (9%) received chemotherapy. Choice of 1L CDK4/6i was palbociclib (50.7%), ribociclib (34.5%) and abemaciclib (9.9%). Patients who received 1L ET alone were older (mean age 75 vs 62 years; 68.4 vs 16.6% > 75 years) with poorer performance status (34.2 vs 6.3% ECOG ≥2) and more comorbidities (76.3 vs 36.8% Charlson index > 2) compared to those who received 1L CDK4/6i + ET. Conversely, those on 1L chemotherapy were younger (mean age 54, 96.2% < 75years), with better performance status (69.2% ECOG 0-1) and fewer comorbidities (88.5% Charlson index < 2). Patients receiving 1L chemotherapy were more likely to have visceral metastases compared to those on CDK4/6i + ET (69.2 vs 43.1%, p = 0.01). The most common reported toxicities in patients receiving CDK4/6i were diarrhea (59% abemaciclib vs 3.9% ribociclib vs 2.7% palbociclib), neutropenia (38.1% palbociclib vs 32.5% ribociclib vs 22.7% abemaciclib) and nausea/vomiting (27.3% abemaciclib vs 22.1% ribociclib vs 12.4% palbociclib). Abnormal LFTs occurred in 9.1% of patients on abemaciclib (vs 3.9% ribociclib and < 1% palbociclib). 2 patients (1.8%) on palbociclib had pneumonitis whilst 1 (1.3%) on ribociclib had QTc prolongation. Survival data is immature. Conclusions: Despite CDK4/6i + ET being gold standard treatment in 1L HR+ ABC, only 3/4 of patients received this combination, with a substantial minority receiving ET alone or chemotherapy. Age, ECOG status, comorbidity burden and presence of visceral disease appear to be major determinants of treatment choice. Toxicity profile of the CDK4/6i agents were mostly in line with clinical trial results, although longer follow up is needed to confirm this.

Capivasertib in Hormone Receptor–Positive Advanced Breast Cancer

BackgroundAKT pathway activation is implicated in endocrine-therapy resistance. Data on the efficacy and safety of the AKT inhibitor capivasertib, as an addition to fulvestrant therapy, in patients with hormone receptor–positive advanced breast cancer are limited.MethodsIn a phase 3, randomized, double-blind trial, we enrolled eligible pre-, peri-, and postmenopausal women and men with hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer who had had a relapse or disease progression during or after treatment with an aromatase inhibitor, with or without previous cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor therapy. Patients were randomly assigned in a 1:1 ratio to receive capivasertib plus fulvestrant or placebo plus fulvestrant. The dual primary end point was investigator-assessed progression-free survival assessed both in the overall population and among patients with AKT pathway–altered (PIK3CA, AKT1, or PTEN) tumors. Safety was assessed.ResultsOverall, 708 patients underwent randomization; 289 patients (40.8%) had AKT pathway alterations, and 489 (69.1%) had received a CDK4/6 inhibitor previously for advanced breast cancer. In the overall population, the median progression-free survival was 7.2 months in the capivasertib–fulvestrant group, as compared with 3.6 months in the placebo–fulvestrant group (hazard ratio for progression or death, 0.60; 95% confidence interval [CI], 0.51 to 0.71; P<0.001). In the AKT pathway–altered population, the median progression-free survival was 7.3 months in the capivasertib–fulvestrant group, as compared with 3.1 months in the placebo–fulvestrant group (hazard ratio, 0.50; 95% CI, 0.38 to 0.65; P<0.001). The most frequent adverse events of grade 3 or higher in patients receiving capivasertib–fulvestrant were rash (in 12.1% of patients, vs. in 0.3% of those receiving placebo–fulvestrant) and diarrhea (in 9.3% vs. 0.3%). Adverse events leading to discontinuation were reported in 13.0% of the patients receiving capivasertib and in 2.3% of those receiving placebo.ConclusionsCapivasertib–fulvestrant therapy resulted in significantly longer progression-free survival than treatment with fulvestrant alone among patients with hormone receptor–positive advanced breast cancer whose disease had progressed during or after previous aromatase inhibitor therapy with or without a CDK4/6 inhibitor. (Funded by AstraZeneca and the National Cancer Institute; CAPItello-291 ClinicalTrials.gov number, NCT04305496.)

204P Phase Ib study of gedatolisib plus palbociclib and endocrine therapy in women with hormone receptor positive advanced breast cancer: Updated results in treatment naïve patients

204P Phase Ib study of gedatolisib plus palbociclib and endocrine therapy in women with hormone receptor positive advanced breast cancer: Updated results in treatment naïve patients

Abstract PD13-05: PD13-05 Updated results of a Phase 1b study of gedatolisib plus palbociclib and endocrine therapy in women with hormone receptor positive advanced breast cancer: Subgroup analysis by PIK3CA mutation status

Abstract Background: Addition of PI3K/mTOR inhibitor after progression on CDK4/6 inhibitor (CDK4/6i) and endocrine therapy (ET) can potentially restore sensitivity to CDK4/6i and prevent adaptive activation of the PI3K/mTOR pathway. To evaluate this hypothesis, we conducted a Phase Ib study of gedatolisib (G), a dual inhibitor of PI3K/mTOR, palbociclib (P) a CDK4/6i, and ET (with letrozole [LET] or fulvestrant [FUL]) in women with hormone receptor positive (HR+)/HER2- advanced breast cancer (ABC). Manageable toxicity and preliminary antitumor activity were observed in 35 patients(pts) enrolled in the dose escalation portion of the study (Forero-Torres, ASCO 2018) and 103 pts enrolled in the expansion portion of the study (Layman, SABCS 2021). Here, we report updated efficacy and safety data and sub-group analysis by PIK3CA mutation status in the four expansion study arms with a March 3, 2022, data cut-off. Methods: Pts with HR+/HER2- ABC were treated in four expansion arms: A) G+P+LET as first-line treatment, B) G+P+FUL as 2nd line treatment in pts without prior CDK4/6i; C &amp; D) G+P+FUL as 2nd or 3rd line therapy in pts with prior CDK4/6i. P, LET, and FUL were administered at standard doses. G 180 mg was intravenously administered weekly in Arms A, B, and C and three weeks on/one week off in Arm D. The primary endpoint was investigator assessed objective response rate (ORR). Secondary endpoints included safety, duration of response and progression free survival (PFS). Results: Of the 103 pts treated with G+P+ ET in the expansion arms (A-D), 100% had measurable disease at baseline, 71% (73/103) lacked PIK3CA mutations (wild type; WT), 27% (28/103) had PIK3CA-mutations (MT), 70% (72/103) had evidence of bone metastases, and 59% (61/103) had liver metastases. The most frequent grade 3 and 4 treatment related AEs (TRAE) with G+P+ET included neutropenia (63%), stomatitis (27%), rash (20%), fatigue (11%) and hyperglycemia (7%). Treatment discontinuation due to TRAEs was 6.5% in Arm A, 15.4% in Arm B, 9.4% in Arm C and 3.7% in Arm D. Efficacy data for each arm is presented in Table 1. Promising ORR and PFS were seen in all arms regardless of PIK3CA mutation status. In Arm D, ORR was 63% overall, 73% in PIK3CA-MT pts, and 60% in PIK3CA-WT pts. Median PFS in Arm D was 12.9 months with a median follow up of 29 months. 60% and 48% of pts in the PIK3CA-MT and PIK3CA-WT Arm D sub-groups, respectively, were progression free at 12 months. Conclusions: These preliminary data demonstrate promising activity of G+P+ET combination in pts who were CDK4/6i-naïve and in those whose disease progressed on or after CDK4/6i therapy regardless of PIK3CA mutation status. Encouraging results in CDK4/6i treatment naïve patients warrant further evaluation of gedatolisib in combination with CDK4/6i treatment in the front-line setting. Arm D results provide a strong basis for the initiated Phase 3 study (VIKTORIA-1) in pts whose disease progressed on or after CDK4/6i therapy. Table 1. Efficacy Data by Expansion Arms Citation Format: Robert Wesolowski, Hope Rugo, Erica Stringer-Reasor, Hyo S. Han, Jennifer M. Specht, E. Claire Dees, Peter Kabos, Ulka Vaishampayan, Seth A. Wander, Janice Lu, Keerthi Gogineni, Alexander I. Spira, Anne F. Schott, Maysa Abu-Khalaf, Pratima Nayak, Brian F. Sullivan, Igor Gorbatchevsky, AND Rachel M. Layman. PD13-05 Updated results of a Phase 1b study of gedatolisib plus palbociclib and endocrine therapy in women with hormone receptor positive advanced breast cancer: Subgroup analysis by PIK3CA mutation status [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD13-05.

Long-Term Results with Everolimus in Advanced Hormone Receptor Positive Breast Cancer in a Multicenter National Real-World Observational Study

Everolimus is the first oral targeted therapy widely used in advanced HR+/HER2- breast cancer. We sought to evaluate the impact of everolimus-based therapy on overall survival in the ESME-MBC database, a national metastatic breast cancer cohort that collects retrospective data using clinical trial-like methodology including quality assessments. We compared 1693 patients having received everolimus to 5928 patients not exposed to everolimus in the same period. Overall survival was evaluated according to treatment line, and a propensity score with the inverse probability of treatment weighting method was built to adjust for differences between groups. Crude and landmark overall survival analyses were all compatible with a benefit from everolimus-based therapy. Adjusted hazard ratios for overall survival were 0.34 (95% CI: 0.16-0.72, p = 0.0054), 0.34 (95% CI: 0.22-0.52, p < 0.0001), and 0.23 (95% CI: 0.14-0.36, p < 0.0001) for patients treated with everolimus in line 1, 2, and 3 and beyond, respectively. No clinically relevant benefit on progression-free survival was observed. Causes for everolimus discontinuation were progressive disease (56.2%), adverse events (27.7%), and other miscellaneous reasons. Despite the limitations inherent to such retrospective studies, these results suggest that adding everolimus-based therapy to the therapeutic sequences in patients with advanced HR+/HER2- breast cancer may favorably affect overall survival.

Utility-based Bayesian personalized treatment selection for advanced breast cancer.

A Bayesian method is proposed for personalized treatment selection in settings where data are available from a randomized clinical trial with two or more outcomes. The motivating application is a randomized trial that compared letrozole plus bevacizimab to letrozole alone as first-line therapy for hormone receptor positive advanced breast cancer. The combination treatment arm had larger median progression-free survival time, but also a higher rate of severe toxicities. This suggests that the risk-benefit trade-off between these two outcomes should play a central role in selecting each patient's treatment, particularly since older patients are less likely to tolerate severe toxicities. To quantify the desirability of each possible outcome combination for an individual patient, we elicited from breast cancer oncologists a utility function that varied with age. The utility was used as an explicit criterion for quantifying risk-benefit trade-offs when making personalized treatment selections. A Bayesian nonparametric multivariate regression model with a dependent Dirichlet process prior was fit to the trial data. Under the fitted model, a new patient's treatment can be selected based on the posterior predictive utility distribution. For the breast cancer trial dataset, the optimal treatment depends on the patient's age, with the combination preferable for patients 70 years or younger and the single agent preferable for patients older than 70.

251P Real-world clinical outcomes of palbociclib plus endocrine therapy (ET) in hormone receptor–positive advanced breast cancer: Results from the POLARIS trial

Palbociclib (PAL), a CDK4/6 inhibitor, is approved for the treatment of hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) advanced breast cancer (ABC). This analysis describes real-world characteristics, treatment (tx) patterns, and clinical outcomes of pts with ABC on PAL + ET. POLARIS is a prospective, observational, multicentre real-world study of pts with HR+/HER2‒ ABC treated with PAL + ET. Real-world response rate (rwRR) is the proportion of pts with a physician-assessed best response (BR) of complete response (CR) or partial response (PR). Real-world clinical benefit rate (rwCBR) is the proportion of pts with physician-assessed BR of CR or PR at any time or stable disease for at least 24 weeks from the regimen start date. Real-world progression-free survival (rwPFS) is the time (months [mo]) from PAL + ET start to the physician-documented progression or death due to any cause, whichever occurs first. Overall survival (OS) is the time (mo) from PAL + ET start to date of death due to any cause. As of Mar 30, 2022, 1242 pts were treated with PAL + ET. Pt demographics and baseline characteristics are shown in the Table. PAL + ET was initiated as first-line (1L) ABC tx in 902 pts and as second-line or later (≥2L) in 340 pts. After a median follow-up 37.9 mo, median rwPFS (95% CI) was 32.2 mo (29.4–35.1) and 24.2 mo (19.9–30.1) in the 1L and ≥2L settings, respectively. The rwRR/rwCBR were 33.0%/67.7% in the 1L and 21.5%/57.5% in the ≥2L setting. After a median follow-up of 35.7 mo, median OS (95% CI) was 50.8 mo (42.3–65.4) and 40.0 mo (32.2–43.1) in the 1L and ≥2L settings, respectively.Table: 251PN=1242Age, yMedian (range)64 (22–97)RaceWhite1,019 (82.0)Black138 (11.1)Other22 (1.8)Asian20 (1.6)American Indian/Alaska Native8 (0.6)Native Hawaiian/other Pacific Islander5 (0.4)EthnicityNot Hispanic/Latino1,101 (88.6)Hispanic/Latino104 (8.4)Disposition of diagnosis*Recurrent from earlier stage, stages 0–III843 (67.9)De novo, newly diagnosed stage IV*340 (27.4)Sites of metastases, numberMedian (range)2.0 (1, 10)Bone involvement*†Bone + other metastases476 (40.4)Bone-only404 (34.3)Visceral disease*‡No756 (60.9)Yes486 (39.1)Data are n (%) unless otherwise stated *At baseline (bl) †In pts with metastasis at bl (N=1177) ‡Metastases of brain, liver, or lung/pleura Open table in a new tab Data are n (%) unless otherwise stated *At baseline (bl) †In pts with metastasis at bl (N=1177) ‡Metastases of brain, liver, or lung/pleura Results from this large prospective, real-world study are consistent with clinical trial results and support the use of PAL + ET for the treatment of HR+/HER2– ABC.

ESR1 F404 mutations and acquired resistance to fulvestrant in the plasmaMATCH study.

1009 Background: The selective estrogen receptor modulator (SERD) fulvestrant is commonly used to treat patients with hormone receptor positive advanced breast cancer, although potential mechanisms of acquired resistance are poorly understood. plasmaMATCH cohort A (NCT03182634) investigated the activity of fulvestrant in patients with activating ESR1 mutations in circulating tumor DNA (ctDNA). Here we present analysis of baseline and end-of-treatment (EOT) ctDNA to identify potential resistance mutations to fulvestrant. Methods: Paired baseline and EOT plasma samples from patients enrolled into plasmaMATCH underwent ctDNA sequencing (Guardant360, Guardant Health) to identify acquired mutations. For F404 analysis, MCF-7 cells were transiently transfected with estrogen receptor expression constructs containing either wildtype ESR1 (WT), single ESR1 mutations (D538G, E380Q, F404L), or compound mutations (D538G_F404L, E380Q_F404L), alongside an estrogen response element (ERE)-luciferase reporter construct. Transfected cells were treated with or without fulvestrant and ERE-luciferase activity compared. Results: Of 84 patients enrolled in cohort A, 69 had paired baseline and EOT sequencing. Patients with baseline ESR1 Y537S had shorter progression free survival (PFS), and Y537C longer PFS, than those wild-type for each respective mutation (p = 0.03 and p = 0.04). Patients frequently acquired mutations at EOT (n = 35, 51%), including potentially targetable mutations in 25% (including 3 PTEN, 3 BRCA1/2, 2 PIK3CA, 2 HER2, 1 BRAF). Three (4%) patients acquired ESR1 p.F404 mutations (F404L, F404I, F404V), with 7 mutations in total. Of 26 patients with PFS of ≥16 weeks, 3 patients (12%) acquired ESR1 F404. In 800 patients screened for entry to plasmaMATCH, one harbored a F404 mutation (0.13%), with a prior history of fulvestrant. F404 mutations resided in cis with E380Q in 6/7 assessable mutations. In vitro structural modelling revealed that ESR1 p.F404 resides within the ESR1 ligand binding domain, and contributes to estrogen and fulvestrant binding through a pi-stacking bond between the aromatic ring of phenylalanine and estrogen/fulvestrant, with all F404 mutations disrupting this bond. Transient transfection demonstrated that single mutations D538G, E380Q, F404L and wild-type ESR1 were sensitive to fulvestrant (p &lt; 0.0001, p = 0.0006, p = 0.04 and p = 0.0001), whereas compound mutations D538G_F404L and E380Q_F404L were resistant. Further investigation of relative sensitivity of the F404 mutant ESR1 to other anti-estrogens will be presented. Conclusions: We have identified a novel resistance mechanism to fulvestrant, with F404 mutations acquired in patients with pre-existing activating ESR1 mutations. F404 confers fulvestrant resistance through the loss of a pi-stacking bond and likely reduced fulvestrant binding affinity, identifying a new potential target to overcome endocrine therapy resistance.

Treatment sequence for hormone receptor-positive HER2-negative advanced breast cancer: Results of a retrospective analysis of Russian patients diagnosed with aBC in 2014-2021.

e13032 Background: CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) have dramatically changed therapeutic landscape of hormone receptor-positive HER2-negative advanced breast cancer (HR+ HER2- aBC). There are three iCDK4/6 in Russia, which are available and included into the clinical guidelines as a preferred first line treatment option beginning since 2018. The aim of this study was to assess evolution of treatment approaches to HR+ HER2- aBC and identify demographic and disease characteristics in correlation with available groups of therapy (chemotherapy, endocrine therapy ±mTOR inhibitors/ CDK4/6i). Methods: Аdult patients diagnosed with de novo or recurrent HR+ HER2- aBC in 2014-2021 identified in outpatient departments of Moscow state oncology hospitals were included into our non-interventional, descriptive, retrospective cohort study. Primary objective of this real-world study was to describe the rate of CDK4/6i usage in the first line setting. As a secondary objective, we describe patient and disease characteristics in iCDK4/6 group, as well as in the endocrine monotherapy and chemotherapy groups. Results: From the cohort of 1000 patients (full-set analysis population) 874 cases were selected, who received treatment since 2018. 45.9% (95% CI 42.6, 49.2) patients were treated with CDK4/6i in combination with endocrine therapy in the first-line setting. From them in the subgroups of patients with or without visceral metastases 50.5% (95% CI 45.5, 55.5) and 42.1% (95% CI 37.7, 46.5) were treated with CDK4/6i in the first line setting, respectively. Among 874 cases 78.0% (95% CI 75.3, 80.7) patients received endocrine therapy ± targeted therapy; in the subgroups of patients with or without visceral metastases 69.5% (95% CI 64.9, 74.1) and 84.9% (95% CI 81.7, 88.1) were treated with endocrine therapy ± targeted therapy in the first line setting, respectively. Conclusions: Endocrine therapy is a predominant therapeutic option in the first line setting for HR+ HER2- aBC. Clinical trial information: NCT04852081. [Table: see text]

Natural History and Characteristics of ERBB2-mutated Hormone Receptor-positive Metastatic Breast Cancer: A Multi-institutional Retrospective Case-control Study from AACR Project GENIE.

We wanted to determine the prognosis and the phenotypic characteristics of hormone receptor-positive advanced breast cancer tumors harboring an ERBB2 mutation in the absence of a HER2 amplification. We retrospectively collected information from the American Association of Cancer Research-Genomics Evidence Neoplasia Information Exchange registry database from patients with hormone receptor-positive, HER2-negative, ERBB2-mutated advanced breast cancer. Phenotypic and co-mutational features, as well as response to treatment and outcome were compared with matched control cases ERBB2 wild type. A total of 45 ERBB2-mutant cases were identified for 90 matched controls. The presence of an ERBB2 mutation was not associated with worse outcome determined by overall survival (OS) from first metastatic relapse. No significant differences were observed in phenotypic characteristics apart from higher lobular infiltrating subtype in the ERBB2-mutated group. ERBB2 mutation did not seem to have an impact in response to treatment or time-to-progression (TTP) to endocrine therapy compared with ERBB2 wild type. In the co-mutational analyses, CDH1 mutation was more frequent in the ERBB2-mutated group (FDR < 1). Although not significant, fewer co-occurring ESR1 mutations and more KRAS mutations were identified in the ERBB2-mutated group. ERBB2-activating mutation was not associated with a worse OS from time of first metastatic relapse, or differences in TTP on treatment as compared with a series of matched controls. Although not significant, differences in coexisting mutations (CDH1, ESR1, and KRAS) were noted between the ERBB2-mutated and the control group.

Abstract GS1-06: A randomized control phase III trial of entinostat, a once weekly, class I selective histone deacetylase inhibitor, in combination with exemestane in patients with hormone receptor positive advanced breast cancer

Abstract Background Entinostat is a novel, potent, once weekly, orally bioavailable, class I selective histone deacetylase (HDAC) inhibitor. In a previous Phase II study, the combination of entinostat with exemestane showed significant improvement of overall survival in patients with advanced hormone receptor (HR) positive breast cancer. To verify and further confirm the benefit of HDAC inhibitor in combination with exemestane we designed a randomized, controlled trial to assess the efficacy and safety in a larger population of Chinese patients with advanced, HR positive breast cancer. Methods We carried out the randomized, double-blind, placebo-controlled, Phase III trial at 35 sites in China. Eligible patients were women (aged ≥18 years) with HR positive, human epidermal growth factor receptor-2 (HER2) negative breast cancer, whose disease had relapsed or progressed after at least one endocrine therapy (either in advanced or metastatic or adjuvant setting), and who had at least one measurable lesion, adequate organ function, ECOG performance status of 0-1, and adequate haematological and biochemical parameters. Patients were randomly assigned (2:1) via an interactive web-response system to orally take 5 mg entinostat or placebo. Both groups received oral administration of 25 mg exemestane daily. Randomization was stratified according to previous usage of CDK4/6 (yes vs no), fulvestrant (yes vs no), chemotherapy (yes vs no), and the presence of visceral metastases (yes vs no). Patients, investigators, study site staff, and the sponsor were masked to treatment assignment. The primary endpoint was Independent Radiographic Committee (IRC)-assessed progression free survival (PFS). Efficacy and safety analyses were done in all patients who received at least one dose of any study treatment. The study has reached the required number of events for final analysis of the primary endpoint. The trial is no longer enrolling patients, but follow-up for investigation of overall survival is ongoing. This study was registered with ClinicalTrials.gov with the number of NCT03538171. Results From April 16th, 2019 to May 13th, 2020, 354 patients were enrolled and randomly assigned as 235 to the entinostat group and 119 to the placebo group. IRC-assessed median PFS was 6.32 months (95% CI 5.30-9.11) in the entinostat group and 3.72 months (95% CI 1.91-5.49) in the placebo group (HR 0.74 [95% CI 0.57-0.96]; p&amp;lt;0.001). The most common Grade 3 or 4 adverse events in the entinostat group vs placebo group were neutropenia (103 [43.8%] vs 119 [0.8%] ), thrombocytopenia (20 [8.5%] vs 1 [0.8%]), and leucopenia (15 [6.4%] vs 0). Serious adverse events occurred in 28 out of 235 patients (11.9%) in the entinostat group and 11 out of 119 patients (9.2%) in the placebo group. Conclusions Entinostat and exemestane combination treatment significantly improved PFS compared with exemestane alone in patients with advanced, HR positive, HER2 negative breast cancer that progressed after previous endocrine therapy. Entinostat and exemestane combination was generally tolerated and can offer meaningful clinical benefit in these patients with unmet medical need. This phase III trial was sponsored by Taizhou EOC Pharma Co., Ltd. Citation Format: Binghe Xu, Qingyuan Zhang, Xichun Hu, Qing Li, Tao Sun, Wei Li, Quchang Ouyang, Jingfen Wang, Zhongsheng Tong, Min Yan, Huiping Li, Xiaohua Zeng, Changping Shan, Xian Wang, Xi Yan, Jian Zhang, Yue Zhang, Jiani Wang, Liang Zhang, Ying Lin, Jifeng Feng, Qianjun Chen, Jian Huang, Yongkui Lu, Hongsheng Li, Jinsheng Wu, Jing Cheng, Yanrong Hao, Cuizhi Geng, Min Lu, Yanping Li, Xi Chen, Lihua Song, Xueying Wu, Changlu Hu, Xinhong Wu, Xiaojia Wang, Yueyin Pan, Yuehong Cui, Guohua Yu, Sanyuan Sun. A randomized control phase III trial of entinostat, a once weekly, class I selective histone deacetylase inhibitor, in combination with exemestane in patients with hormone receptor positive advanced 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 GS1-06.

Abstract P1-18-19: Long term results with everolimus in advanced hormone receptor positive breast cancer in a multicenter national real world observational study (ESME)

Abstract Background The everolimus (EVE)-exemestane combination has been included in the International guidelines for metastatic HR+/HER2- breast cancer (mBC) since the results of the Bolero-2 trial. Marketing authorization has been granted in France in July 2012. A first report of the UNICANCER Epidemiological Strategy and Medical Economics (ESME) Research program described the real world use of everolimus therapy (ESMO 2017, #266). We report here updated data with long-term overall survival (OS) analyses, focusing on patients treated from 2012 onwards. Methods All patients (pts) who initiated treatment for a newly diagnosed mBC between 2008 and 2017 in all 18 French Comprehensive Cancer Centers have been included in the real life ESME database, which collects retrospective data using a clinical trial-like methodology. The primary endpoint of the present report was overall survival in pts who received everolimus. In order to adjust for differences between groups (EVE treated vs non EVE treated patients), we analyzed the impact of everolimus on OS and PFS by using a propensity score and inverse probability of treatment weighting (IPTW) sensitivity analyses, built with relevant cancer-related clinical variables in relation to survival and allocation of treatment. Those analyses were performed by line 1, 2 or 3 of treatment for mBC. Results The ESME program included 23,698 pts of whom 1897 with HR+/HER2- mBC received at least 1 dose of EVE and were diagnosed after 2012. Median age was 63 y (22-103). EVE pts were slightly younger than non-EVE pts (25.9% and 23.7% under 52 y, respectively, p=0.0574). EVE treated pts had more frequent non visceral metastases (52.3% vs 47.9%) and bone only metastases (38.5% vs 31.3%) at metastatic diagnosis, and less symptoms at mBC diagnosis (42.4% vs 47.5%) than non-EVE pts (all p values &amp;lt;.001). 94.3% of EVE pts had received an EVE-exemestane combination. EVE was administered either in the 1st, 2nd or 3rd line+ setting, in 3.3%, 14.7% and 25.3% of all cases respectively. At each line, treatments in the non-EVE treated pts included various endocrine therapy or chemotherapy regimen. Median follow-up was 47.9 m (0-98.7), and 61.4 m (2.1-98.7) for the overall- and EVE treated populations, respectively. Crude and landmark (6 and 12 months) OS analyses all suggested a longer OS with EVE based therapy. IPTW analyses by lines of treatment, comparing EVE-treated and non-EVE-treated patients, suggested a longer progression free survival with EVE when administered in the 3rd line setting (HR=0.82 CI95% [0.745-0.903], p&amp;lt;.0001). IPTW analyses consistently showed a significantly longer OS with EVE based treatment when administered in lines 1, 2 and 3 with respective HR values of 0.34, 0.34 and 0.23 (Table). Causes for EVE discontinuation were mainly disease progression (54%) and toxicity (26.6%). An exploratory analysis showed that 998 EVE treated patients (52.6%) also received a CDK4/6 inhibitor based treatment, mostly after EVE therapy (n=826, 82.8%). Median duration of CDK4/6 inhibitor therapy for those patients was 4.6 months (IQR 2.9-8.7). Conclusions These results are limited by the retrospective nature of the study and the lack of performance status, comorbidity or nutritional data. However, the long-term follow up of the ESME database suggests a favorable association between everolimus therapy and overall survival in HR+, HER2- mBC, persistent after IPTW adjusted analyses. HR (CI95%)p value12 months OS EVE vs not (unadjusted Kaplan Meier)Line 10.34 (0.16-072).005497% vs 93%Line 20.34 (0.22-0.52)&amp;lt;.000194% vs 85%Line 30.23 (0.14-0.36)&amp;lt;.000195% vs 79% Citation Format: Hélène Francois-Martin, Audrey Lardy-Cleaud, Barbara Pistilli, Christelle Levy, Véronique Diéras, Jean-Sébastien Frenel, Séverine Guiu, Marie-Ange Mouret-Reynier, Audrey Mailliez, Jean-Christophe Eymard, Thierry Petit, Mony Ung, Isabelle Desmoulins, Paule Augereau, Thomas Bachelot, Lionel Uwer, Marc Debled, Jean-Marc Ferrero, Corinne Veyret, Antony Goncalves, Michael Chevrot, Paul H Cottu. Long term results with everolimus in advanced hormone receptor positive breast cancer in a multicenter national real world observational study (ESME) [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 P1-18-19.

Abstract P5-16-11: Ipatasertib (ipat) in combination with palbociclib (palbo) and fulvestrant (fulv) in patients (pts) with hormone receptor-positive (HR+) HER2-negative advanced breast cancer (aBC)

Abstract Background: Ipat is a potent oral AKT inhibitor that has been studied in multiple clinical trials, primarily in breast and prostate cancers. Combining fulv and AKT inhibition demonstrated efficacy in pts with HR+ aBC regardless of PI3K/AKT pathway alterations [Jones, Lancet Oncol 2020]. IPATunity150 (NCT04060862) was designed as a phase III trial with an open-label phase Ib portion adding ipat to palbo plus fulv in biomarker-unselected HR+ HER2-negative aBC. The biological rationale was to prevent or delay resistance to CDK4/6 inhibition plus endocrine therapy (ET). AKT1 alterations and PTEN loss have been implicated in resistance to CDK4/6 inhibitors [Wander, Cancer Discov 2020; Costa, Cancer Discov 2020]. We report results from the open-label phase Ib portion. Patients and Methods: The primary objective was to assess safety and pharmacokinetics (PK) of ipat in combination with palbo and fulv; several efficacy parameters were also analyzed. Pts with measurable disease who had not previously received a CDK4/6 inhibitor and had experienced relapse during adjuvant ET were treated with ipat at a dose of 300 mg/d, d1-21 q28d, plus standard-of-care doses of palbo (125 mg/d, d1-21 q28d) plus fulv (500 mg q28d with a loading dose in cycle 1). The selected ipat dose was lower than the 400 mg typically used in other studies because of the anticipated drug-drug interaction (DDI) when combining ipat (a sensitive CYP3A4 substrate and mild-to-moderate CYP3A inhibitor) with palbo (a weak time-dependent CYP3A4 inhibitor and CYP3A substrate). Results: Of the 20 pts treated, 20% were Asian, 65% had primary endocrine resistance (relapse ≤2 years after starting adjuvant ET), 80% had received prior (neo)adjuvant chemotherapy, and 60% had liver and/or lung metastases. At the data cutoff (19 Mar 2021; median follow-up 6.1 months), median treatment duration was 5.1, 5.9, and 5.3 months for ipat, palbo, and fulv, respectively. Treatment was ongoing in 13 pts. Grade 3/4 adverse events (AEs) occurred in 80% of pts (no grade 5). The most common AEs were diarrhea (80% any grade, 10% grade 3, no grade 4) and neutropenia (75% any grade, 45% grade 3, 20% grade 4). Other notable grade ≥3 AEs were grade 3 liver function test elevations in 10%. There were no cases of febrile neutropenia and only 1 case of pneumonitis (grade 1). AEs led to at least one dose reduction of ipat in 6 pts (30%; diarrhea n=3 [with vomiting in 1 pt], neutropenia n=3 [with fatigue in 1 pt]) and of palbo in 9 pts (45%; all for neutropenia). One pt (5%) discontinued ipat and palbo permanently due to ongoing neutropenia after protocol-defined dose reductions. As expected, a DDI led to increased ipat exposure (AUC0-24,ss ~60% and Cmax ~40%) when ipat and palbo were combined. Based on population PK analysis, palbo AUC0-24,ss was ~30% higher than reported from the PALOMA 1 and 2 trials, which was expected and consistent with previously reported physiologically based PK modeling of palbo exposure when administered with moderate CYP3A inhibitors [Yu, J Clin Pharmacol 2017]. All 20 pts had at least one post-baseline tumor assessment. Best overall response rate was 45% (95% CI: 23-68%), including confirmed responses in 7 pts (35%; 5% complete response, 30% partial response) at the clinical cutoff date. Median duration of response was 9.6 months (95% CI: 7.1-not estimable). An additional 10 pts (50%) had stable disease. Progression-free survival results were immature (events in 7 pts). There was no obvious association between efficacy and mutations in PIK3CA/AKT1 as tested in ctDNA. Conclusion: The triplet combination of ipat, fulv, and palbo had an acceptable safety profile generally consistent with that of the individual study drugs; ipat exposure was increased through a predicted DDI. Updated results will be presented. Citation Format: Mafalda Oliveira, Aditya Bardia, Sung-Bae Kim, Naoki Niikura, Cristina Hernando, Gustavo Werutsky, Yoland Antill, Pedro Liedke, Catherine Oakman, Eriko Tokunaga, Seth Wander, Vanessa Krause, Toshinari Yamashita, Frauke Schimmoller, Jacob Rotmensch, Heidi Savage, Rucha Sane, Nicholas Turner. Ipatasertib (ipat) in combination with palbociclib (palbo) and fulvestrant (fulv) in patients (pts) with hormone receptor-positive (HR+) HER2-negative advanced breast cancer (aBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-16-11.

Abstract OT1-18-01: A randomized controlled phase III study of bevacizumab and paclitaxel in combination with atezolizumab as a treatment for patients with locally advanced or metastatic hormone receptor-positive HER2 negative breast cancer: JCOG1919E/AMBITION study

Abstract Background: Hormone receptor (HR)-positive HER2-negative breast cancers have a lower tumor mutation burden than other types of cancer and triple-negative breast cancer, resulting in relatively low immunogenicity. It is also known that estrogen suppressively regulates immunity through regulatory T cells in the tumor microenvironment. Therefore, the development of immunotherapy in HR-positive and HER2-negative breast cancer is a challenging issues. Anti-VEGF therapy has been shown to improve antigen presentation, local migration of cytotoxic T lymphocytes, and suppressive tumor microenvironment in preclinical and clinical studies of various cancers. Anti-VEGF therapy can be hypothesized to modulate immunotherapy. Methods: JCOG1919E (AMBITION) is a randomized, multicenter, open-label, phase III trial to evaluate efficacy and safety of bevacizumab and paclitaxel in combination with atezolizumab (BEV+PTX+ATZ) comparing to bevacizumab and paclitaxel (BEV+PTX) in patients with HR-positive HER2 negative locally advanced or metastatic breast cancer. The key eligibility criteria are as follows: 1) ECOG PS 0-2, 2) ER and/or PgR positive and HER2-negative breast cancer, 3) endocrine resistance or life-threatening disease, 4) measurable disease, 5) centrally confirmed programmed death-ligand 1 (PD-L1) status on tumor-infiltrating immune cells, 6) no prior chemotherapy for locally advanced or metastatic breast cancer, 7) adequate organ function. Patients will be randomized (staratified by recurrence/de novo, liver metastasis, or PD-L1 status) in a 1:1 ratio, to BEV+PTX arm or BEV+PTX+ATZ arm. Patients in arm A receive PTX (90 mg/m2/day, days 1, 8 and 15, iv) and BEV (10 mg/kg/day, days 1 and 15, iv) on a 28-day cycle. Patients in arm B receive PTX and BEV plus ATZ (840 mg/body/day, days 1 and 15, iv). Treatment in both arms is continued until disease progression or unacceptable toxicity. The primary endpoint is progression-free survival (PFS) assessed by investigators. The secondary endpoints include overall survival, PFS assessed by blinded independent central review, response rate, adverse events, PFS (PD-L1 positive), and OS (PD-L1 positive). We assumed a median PFS of 16 months in BEV+PTX+ATZ arm and 11 months in BEV+PTX arm. The planned sample size was calculated as a total of 280 patients (140 patients per arm) with a one-sided alpha of 2.5%, power of 80%, an accrual period of 2.5 years, and a follow-up period of 2 years. Translational research also will be conducted accompanying with this trial. Patient accrual was started in January 29, 2021 and 37 patients were enrolled by June 18, 2021. Safety of patients in this study is being monitored by IDMC. For further information on this trial, visit ClinicalTrials.gov (NCT04732598). Citation Format: Fumikata Hara, Makiko Ono, Shigehisa Kitano, Shigehira Saji, Akihiko Shimomura, Takashi Yamanaka, Takayuki Kadoya, Mitsuya Ito, Hiroko Bando, Hiroyuki Yasojima, Keita Sasaki, Tomoko Kataoka, Tadahiko Shien, Kan Yonemori, Hiroji Iwata. A randomized controlled phase III study of bevacizumab and paclitaxel in combination with atezolizumab as a treatment for patients with locally advanced or metastatic hormone receptor-positive HER2 negative breast cancer: JCOG1919E/AMBITION study [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 OT1-18-01.

Abstract OT2-19-06: Phase 2 study of abemaciclib in combination with endocrine therapy with or without paclitaxel induction in patients with hormone receptor-positive, HER2-negative advanced breast cancer and aggressive disease criteria: ABIGAIL

Abstract Background: Endocrine therapy (ET) is the preferred therapy option for patients (pts) with hormone receptor-positive (HR[+]) advanced breast cancer (ABC), except for pts with visceral crisis who often receive chemotherapy to achieve rapid symptom control. Cyclin-dependent kinases 4/6 inhibitors have improved the effectiveness of ET across all subgroups of pts with ABC by targeting potential mechanisms of resistance. An exploratory analysis revealed that the addition of abemaciclib to ET conferred the largest benefit in pts with poor prognostic characteristics (liver metastases, high grade tumors, or progesterone receptor-negative status) [Di Leo, NPJ Breast Cancer 2018; 4: 41]. ABIGAIL aims to provide consistent evidence that abemaciclib plus ET is superior or non-inferior to paclitaxel in terms of early overall response as first-line regimen in HR[+], HER2-negative ABC pts with poor prognosis. Trial Design: This is a multicenter, randomized, open-label, phase 2 trial. Eligible participants are men and women of any menopausal status aged ≥18 years with HR[+], HER2-negative ABC who had no prior systemic therapy in the advanced setting and at least one of the following aggressive disease criteria: (i) Visceral disease; (ii) High histological grade and/or progesterone receptor-negative status; (iii) Lactate dehydrogenase &amp;gt;1.5 × the upper limit of normal; (iv) Relapse while on or within 36 months of completing adjuvant ET. Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease as per RECIST 1.1, and adequate organ function are also required. A total of 160 pts will be randomly assigned (1:1) to receive abemaciclib (300 mg/day orally during each 28-day cycle) plus ET as per investigator’s criteria (either letrozole [2.5 mg/day orally] or fulvestrant [500 mg intramuscularly on days 1, 15 of cycle 1, and on day 1 thereafter], or paclitaxel (90 mg/m² intravenously on days 1, 8, 15). Men and pre-/peri-menopausal women will receive a gonadotropin-releasing hormone agonist if randomized to abemaciclib plus ET. At investigator’s discretion, pts in the paclitaxel arm could receive abemaciclib plus ET at any point after the first 12 weeks or extend chemotherapy for a total of 6 cycles. Randomization will be stratified according to the presence of visceral disease and endocrine therapy. The primary endpoint is 12-week overall response rate (ORR) as per RECIST 1.1. Key secondary endpoints include ORR, clinical benefit rate, 12-week progression-free survival, progression-free survival, time to response, duration of response, overall survival, time to first subsequent therapy, time to second subsequent therapy, and time to first chemotherapy for pts in abemaciclib plus ET arm, patient-reported outcomes, and safety as per NCI-CTCAE 5.0. The sample size assumes the comparison of two proportions in an asymptotical normal test. We expect that 12-week ORR will be higher in the abemaciclib plus ET arm than paclitaxel arm (30% vs. 15%), with the assumption of a 5% non-inferiority margin. Based on a 10% dropout rate, a sample size of 160 pts is necessary to attain 80% power at nominal level of two-sided alpha of 0.05. We will test the superiority of abemaciclib plus ET as compared with paclitaxel if the non-inferiority is achieved. Both analyses, will be conducted with the Newcombe hybrid score method for confidence intervals. This trial was opened to accrual in May 2021. Citation Format: Antonio Llombart-Cussac, Joseph Gligorov, Serena Di Cosimo, Cinta Albacar, Patricia Cortez, Eduardo Martinez-De Dueñas, Ana López, Vicente Carañana, Jacques Medioni, Luigi Cavanna, Marina Elena Cazzaniga, Sofia Braga, Passos Coelho, Miguel Sampayo-Cordero, Andrea Malfettone, José Manuel Pérez-García, Javier Cortes. Phase 2 study of abemaciclib in combination with endocrine therapy with or without paclitaxel induction in patients with hormone receptor-positive, HER2-negative advanced breast cancer and aggressive disease criteria: ABIGAIL [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-19-06.

Abstract P2-01-18: Orthogonal assessment of PIK3CA and ESR1 mutation detection in longitudinal cfDNA samples from endocrine-resistant HR+/HER2- advanced breast cancer patients using dPCR and NGS-based SafeSEQ technology

Abstract Background: Indentification of actionable or therapy resistance-associated mutations may guide sequential treatments in Hormone Receptor-positive and HER2-negative (HR+/HER2-) Advanced Breast Cancer (ABC) patients with resistance to prior endocrine therapies. Molecular profiling from cell-free DNA (cfDNA) is progressively permeating the clinical setting as an alternative or adjunct to tissue biopsies. Digital PCR (dPCR) assays permit the detection of genomic alterations with high sensitivity but are associated with cumbersome workflows and limited genomic coverage. NGS-based cfDNA assays are being increasingly adopted, as they can offer broader coverage while maintaining competitive sensitivity. Methods:Mutation testing was performed on plasma samples obtained from patients with HR+/HER2- ABC who had recurred or progressed after receiving an aromatase inhibitor. Samples were collected at the start of new treatment, during therapy, and at progression. dPCR tests were carried out using QuantStudio3D Digital PCR at the Molecular Oncology Laboratory at Clínico San Carlos Hospital. dPCR targets included PIK3CA E542K, E545K, and H1047R, and ESR1 Y537S and D538G. Samples[CdS1] were also tested with the SafeSEQ Breast Cancer Panel to assess clinically relevant genomic regions across PIK3CA, ESR1, AKT1, TP53, KRAS, and ERBB2. SafeSEQ testing was performed in Sysmex Inostics’ CLIA-certified, CAP-accredited laboratory. Results: Mutational data obtained from both dPCR and SafeSEQ testing were available for concordance analysis in 107 samples from 50 patients for PIK3CA, and 86 samples from 41 patients for ESR1. Combined results showed PIK3CA mutations in 47 samples (43.9%), with H1047R (14%), E545K (11.2%), and E542K (9.3%) being the most frequent mutations detected. ESR1 mutations were present in 35 samples (32.7%), where D538G (19.6%) and Y537S (9.3%) were most commonly observed. Among samples with no mutations detected by dPCR, the expanded coverage of SafeSEQ enabled the detection of clinically relevant mutations in PIK3CA and ESR1 in 10 (9.3%) and 3 (2.8%) samples, respectively. The concordance rates for dPCR and SafeSEQ were 93.1% and 88.9% for PIK3CA and ESR1, with positive percent agreements (PPA) of 93.8% and 84.6%, and negative percent agreements (NPA) of 92.8% and 90.9% for PIK3CA and ESR1, respectively. A strong correlation was observed between MAF levels (Spearman's ρ = 0.87 [95% CI 0.79-0.93], p&amp;lt;0.001) as well as number of mutant molecules per mL of plasma (ρ = 0.79 [95% CI 0.66-0.88], p&amp;lt;0.001). When samples with MAFs&amp;lt;0.1% were evaluated, lower concordance rate was detected (38.5%; N=13; 46.2% detected by SafeSEQ and 92.3% by dPCR). Finally, no significant difference between assays was found when comparing concordance rates among samples at different timepoints. Regarding longitudinal ctDNA data, 18 and 16 patients showed mutations in PIK3CA and/or ESR1 in plasma at least in one timepoint. Monitoring results were concordant in 50%/56.3% of patients for PIK3CA/ESR1 (during therapy and/or at progression time, 5.6%/18.8% of patients showed decrease or clearance of ctDNA and 38.9%/25% showed increase of ctDNA).Conclusion:In this cohort of AI-progressing HR+/HER2- ABC patients, dPCR and SafeSEQ methods showed high overall agreement for the detection of mutations in PIK3CA and ESR1, key genes for clinical decision-making and enrollment in clinical trials. The expanded coverage of SafeSEQ makes it a powerful tool to inform patient management considering the growing pool of clinically relevant genomic alterations in this type of patients. Efforts are ongoing to expand the analysis to a larger cohort and incorporate long-term outcomes and multivariate adjustment. Supported by AstraZeneca. Citation Format: Jesus Fuentes Antras, Vanesa García-Barberán, Fernando Moreno, Hillary Sloane, Igor López-Cade, Alicia De Luna, Alejandro Pascual, Carmen Ramirez-Ruda, Victor Lorca, Paloma Flores, Pedro Perez-Segura, Alberto Ocaña, Jennifer Preston, Hannah Quinn, Frederick Jones, Jose Angel Garcia-Saenz. Orthogonal assessment of PIK3CA and ESR1 mutation detection in longitudinal cfDNA samples from endocrine-resistant HR+/HER2- advanced breast cancer patients using dPCR and NGS-based SafeSEQ technology [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 P2-01-18.