HER2-negative Advanced Breast Cancer Research Articles

Clinical characteristics, treatment patterns, and outcomes in adult patients with germline BRCA1/2-mutated, HER2-negative advanced breast cancer: a retrospective medical record review in the United States

Clinical characteristics, treatment patterns, and outcomes in adult patients with germline BRCA1/2-mutated, HER2-negative advanced breast cancer: a retrospective medical record review in the United States

Abstract PO1-04-12: Palbociclib versus ribociclib in first-line treatment of patients with hormone-receptor positive HER2 negative advanced breast cancer – real world outcome data from the German registry platform OPAL

Abstract Introduction CDK4/6 inhibitors (CDKi) plus endocrine therapy (ET) are standard of care in first-line (1L) treatment of hormone receptor-positive (HR+) HER2-negative (HER2-) advanced breast cancer (ABC). In the pivotal trials the three CDK4/6i (palbociclib, ribociclib and abemaciclib) + ET showed similar progression-free survival (PFS) benefit over ET alone. However, other than ribociclib, palbociclib failed to demonstrate overall survival (OS) benefit. As patient (pts) characteristics differed between the trials, especially in the number of pts with treatment-free interval (TFI) of < 12 months after end of adjuvant ET, head-to-head comparisons of the CDKi are of clinical interest. Here we analyze the outcome of pts treated with palbociclib + ET or ribociclib + ET with real-world data from OPAL. Methods OPAL (NCT03417115) is a prospective observational, open, longitudinal multicenter cohort study (clinical registry) in Germany. Pts with ABC and early breast cancer can be recruited at start of their first systemic treatment. There are no treatment restrictions. Sites from all medical sectors can participate in OPAL (medical and gynecologic oncologists from outpatient centers and hospitals). Details on all (sequential) treatments, patient and tumor characteristics, biomarker testing, clinical and patient-reported outcomes are collected. Follow-Up is until death or up to 5 years. Between 01/2018 and 07/2021 1049 pts with HR+ HER2- ABC were recruited by 143 sites. Database cut was on 31/08/2022. 384 pts received palbociclib + ET and 231 pts received ribociclib + ET as 1L treatment. All endocrine combination partners including switch of ET during first line therapy was allowed, whereas switch of CDK4/6i (n=25) were excluded. PFS in registries can differ from PFS in clinical trials, since the RECIST criteria are usually not applied in routine care. PFS in registries represents the time to clinically relevant progression in routine care. PFS and OS were estimated using the Kaplan-Meier method. To adjust for confounding, inverse probability of treatment weighting (IPTW) by propensity score analysis was used to compare PFS and OS between 1L palbociclib+ET and ribociclib+ET. IPTW was performed for the following variables: age, menopausal status, ECOG, any comorbidity, Charlson comorbidity index, metastatic stage, type of metastasis, number of metastatic sites, estrogen-/progesterone status, IHC status, previous chemo-/endocrine therapy, kind of endocrine combination partner, disease-free interval, and treatment-free interval. Results From 2018 to 2021, the proportion of CDK4/6i increased from 68% to 86% in 1L of HR+HER2- ABC. Overall, palbociclib was used in 44% and ribociclib in 26% of all first-line treatments in OPAL. Median age of pts receiving palbociclib/ribociclib was 66/68 years and for 77/81% of pts at least one comorbidity was documented. 37/35% of pts already had metastasis at diagnosis (M1) and 25/26% of pts had a TFI < 12 months. After IPTW, the two treatment groups were comparable for all tested characteristics. 42/46% of patients had a progression (palbociclib/ribociclib group). IPTW-adjusted median PFS was 25.1 months (95% Confidence interval (CI) 20.1 – 30.1) for the palbociclib and 27.0 months (95%-CI 21.1 – 31.6) for the ribociclib group. Hazard ratio was 0.91 (0.71 – 1.17) for palbociclib versus ribociclib. 26/29% of patients had an OS event (palbociclib/ribociclib group). IPTW-adjusted median OS was 36.7 months (95%-CI 33.0 – NA) for the palbociclib and 36.6 months (95%-CI 33.1 – NA) for the ribociclib group. Hazard ratio was 0.95 (0.69 - 1.30) for palbociclib versus ribociclib. Conclusions This analysis of real word data in the OPAL registry platform showed similar PFS and OS for palbociclib + ET compared to ribociclib + ET, when adjusted for a wide range of potential confounding variables. Further analyses will investigate whether one drug showed favorable results in certain subgroups of pts. Citation Format: Marc Thill, Mark-Oliver Zahn, Anja Welt, Arnd Nusch, Matthias Zaiss, Kathrin Engelken, Gabriele Kaltenecker, Kai Ringwald, Katja Gratzke, Lisa Kruggel, Martina Jänicke, Holger Schulz, Christoph Losem, Volker Hagen, Roland Fricker, Elmar Stickeler, Nadia Harbeck, Achim Wöckel, Thomas Decker. Palbociclib versus ribociclib in first-line treatment of patients with hormone-receptor positive HER2 negative advanced breast cancer – real world outcome data from the German registry platform OPAL [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-04-12.

Abstract PO1-16-06: LuciA-15 - A real-world prospective study of PARP inhibitors for the treatment of Latin American patients with HER-2 negative metastatic breast cancer with mutation of BRCA1/2 genes or in the Homologous Recombination Repair genes

Abstract Background PARP inhibitors (PARPi) improves progression free survival among patients with HER2 negative (HER2-ve) advanced breast cancer (ABC) and a BRCA1 or BRCA2 mutation compared to physician choice of chemotherapy (CT). The AIM of this prospective study was to evaluate the clinical benefit of PARPi treatment in terms of response, outcomes and survival by breast cancer type and treatment in a Latin-American population. Methods We analyzed data of patients with HER2-ve ABC with germline and/or somatic mutation of BRCA 1 or BRCA 2 or in the Homologous Recombination Repair genes, treated with olaparib or talazoparib in daily clinical practice by oncologist from Argentina and México. From September 2019 and April 2023, we collected baseline characteristics, previous systemic treatments, type and pattern of use, treatment beyond PARPi progression, and patient predisposition. Objective responses, best response rate, real-world progression-free survival (rwPFS) and real-world overall survival (rwOS) were analyzed with R software and RStudio version 14.0. Results After a median follow-up of 18.07 months (CI95% 10.53 - 30.07), 51 patients were treated with PARPi. Mean age at start treatment was 47,08 years. 62.7% had ER+ve/HER2-ve and 35.3% had triple negative breast cancer (TNBC). 62.7% and 37.3% of patients received talalaparib and olaparib, respectively. BRCA 1 and 2 germline mutations were the most common alterations found in 96% of patients. 37.5% of patients received platinum-based CT (PbCT) in the (neo)adjuvant/metastatic setting. 57.5% had visceral metastasis and the median number of metastatic sites were 2 (range 1-4). Median number of lines at the time to start PARPi was 2 (range 0-8), 23.5% and 31.4% received PARPi in the 1st line and 2nd line, respectively. The rwORR was 47.0%, and the median rwPFS1 was 7.77 months (CI95% 5.67-14.7). There was a tendence of better rwPFS1 in patients without previous CT versus previous CT in the advance setting, 14.30 months (CI95% 6.47-NR) versus 6.37 months (CI95% 5.03-8.73), respectively (p 0.084). The median rwOS was 26.97 months (CI95% 13.50-NR) and higher in the subgroup of patients naïve for CT versus previous exposure to CT in the advance setting, the median rwOS was 32.1 months (CI95% 27.0-NR) versus 13.0 (IC95%10.1-NR), respectively (p 0.022). 23.5% of patients progressed on PARPi during the first 6 months of treatment, 32.4% with visceral compromise, 27.8% with visceral crisis, and 26.5% with ≥2 metastatic sites. CT was the treatment of choice in most patients (55.3%). The medium rwPFS2 (next treatment after PARPi failure) was 4.00 months (CI95% 3.43 – 7.13). Treatment was discontinued for adverse events in 4.0 % of patients. Conclusion This is the first Latin-American evidence that replicate the data already published in randomized clinical trials and other scanty real-world evidence studies in this field, positive results in rwORR and rwPFS, encouraging data in rwOS. Notably, high proportion of patients with visceral progression even with visceral crisis and need for CT. Interestingly, similar rwOS results among subgroups (TNBC versus ER+ve/HER2-ve, talazoparib versus Olaparib, etc). <graphic> Citation Format: Fernando E. Petracci, Cynthia Villarreal-Garza, Facundo Argañaraz, Gonzalo Gómez Abuin, José Peñaloza, Marcos A. Flores, Luciano Piazzoni, Cecilia Riggi, Lucía Fabiano, Lucía González, Belén Cieplinski, Sergio Rivero, Ernesto Korbenfeld, Pablo Mandó. LuciA-15 - A real-world prospective study of PARP inhibitors for the treatment of Latin American patients with HER-2 negative metastatic breast cancer with mutation of BRCA1/2 genes or in the Homologous Recombination Repair genes [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-16-06.

Abstract PO5-05-01: ASSESING THE CLINICAL AND SURVIVAL RESULTS OF PATIENTS WITH HR-POSITIVE, HER2 NEGATIVE ADVANCED BREAST CANCER TREATED WITH CDK 4/6 INHIBITORS IN A SPANISH COHORT

Abstract BACKGROUND First line treatment of HR-positive, HER2 negative advanced breast cancer is based on endocrine therapy plus CDK 4/6 inhibitors (CDK 4/6i). Recently, there has been published in ASCO 2023 results from SONIA trial, which explores the use of CDK 4/6i in second-line treatment after monotherapy with endocrine therapy. This trial have shown using a CDK4/6i in the first-line setting did not significantly prolong the time from random assignment to progression on second-line therapy (PFS2) or overall survival (OS) when compared with deferred use until the second-line setting. METHODS We conducted a descriptive, observational and retrospective analyses of patients treated in our centre with CDK4/6i, comparing demographic, clinical and survival results. We also analysed different outcomes between first versus second line CDK4/6i. RESULTS A cohort of 153 patients were included, treated between January 2018 and June 2023, with a median age of 50 years. At diagnosis, 49% were stage I-II and 31% stage IV. 59% had visceral metastases at the start of CDK4/6i treatment. Palbociclib was the most commonly CDK4/6i used (55%), followed by Ribociclib (32%) and Abemaciclib (12.5%). The most widely endocrine therapy used was letrozole (60%), followed by fulvestrant (38%). 58% received CDK4/6i in first-line setting while 9% received them in second-line. The overall median progression-free survival (mPFS) was 18 months. In a subgroup analysis, the mPFS was 19 months with Palbociclib, 26 months with Ribociclib, and 31 months with Abemaciclib. Baseline characteristics were similar between subgroups of CDK4/6i. Better survival data were obtained with letrozole than with fulvestrant (not reached versus 29 months OS respectively). After CDK4/6i disease progression the most common subsequent treatment was chemotherapy (capecitabine, 23%). The median OS with palbociclib and abemaciclib was 37 months, while not reached with ribociclib. We analysed PFS2 using CDK4/6i in the first-line setting compared with deferred use until the second-line. The use of CDK4/6i in second-line showed a PFS2 of 45 months, while first-line PFS2 was 26 months. CONCLUSIONS Our study results are consistent with previous studies assesing the efficacy of cyclin inhibitors in first and second-line setting. Palbociclib seems to have a lower PFS rate. Patients treated with letrozole had a stadistically significant benefit in survival outcomes. Our data continue the trend observed in the SONIA trial in terms of PFS2. Using endocrine therapy as first-line monotherapy may be a valid treatment option. However, larger sample sizes are required to draw definitive conclusions. The identification of potential predictors of treatment response may help in the selection of the most effective treatment for patients with HR-positive HER2 negative advanced breast cancer. Citation Format: Alicia Cano-Jimenez, Rocio Urbano-Cubero, Ruben Garcia-Muñoz, Ana Maria Jaen-Morago, Maria Lomas-Garrido, Pedro Sánchez-Rovira. ASSESING THE CLINICAL AND SURVIVAL RESULTS OF PATIENTS WITH HR-POSITIVE, HER2 NEGATIVE ADVANCED BREAST CANCER TREATED WITH CDK 4/6 INHIBITORS IN A SPANISH COHORT [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 PO5-05-01.

Abstract PO2-05-01: Famitinib, a multi-targeted receptor tyrosine kinase inhibitor, combined with dalpicilib and fulvestrant in advanced HR-positive and HER2-negative breast cancer

Abstract Background: CDK4/6 inhibitors combined with endocrinotherapy (ET) represent an essential part of the treatment for HR-positive and HER2-negative breast cancer (BC). However, the role of angiogenesis inhibitors, such as bevacizumab, in these patients (pts) is controversial. While it has been demonstrated to improve progression-free survival (PFS), it has failed to show a significant overall survival (OS) benefit in HER2-negative BC. Several preclinical studies have explored the combination of anti-angiogenesis multi-targeted receptor tyrosine kinase inhibitors (TKIs) and CDK4/6 inhibitors in other cancers, suggesting a synergistic effect. Our phase Ib/II trial (NCT05176080, ChiCTR2100053950) aims to evaluate the safety and efficacy of a novel anti-angiogenesis TKI famitinib (F) added to dalpiciclib (D) and ET in advanced HR-positive and HER2-negative BC. Here we report the results of Phase Ib. Methods: A 3+3 de-escalation design was used in this dose-exploring phase (phase Ib). Pts with HR-positive and HER2-negative BC, who had no more than two prior chemotherapies in the advanced setting, were enrolled and administered F (orally, at doses of 15 mg/d, 10 mg/d, or 15 mg qod), D (orally, at doses of 150, 125 or 100 mg/d, 21 days on and 7 days off) and fulvestrant (intramuscularly, at a fixed dose of 500 mg every four weeks) until progression, unaccepted toxicities, or withdrawal. The initial dose level (Level 1) was set as F 15 mg daily and D 150 mg/d. The primary endpoints were recommended phase 2 dose (RP2D) and safety. Results: From December 2021 to June 2022, 18 pts were enrolled, and 3, 6, 3, and 6 pts were assigned to Level 1 (F 15 mg + D 150 mg), Level 2 (F 10 mg + D 125 mg), Level 3 (F 15 mg qod + D 125 mg), and Level 4 (F 10 mg + D 100 mg), respectively. 14 (77.8%) pts had visceral metastasis, and 7 (38.9%) had prior systemic therapies in the advanced setting. 13 (72.2%) pts had received ET, and 11 (61.1%) were resistant to ET before enrolled. A total of 6 dose-limiting toxicities (DLTs) were observed, including 3 Grade 4 thrombopenia (2 in Level 1, 1 in Level 2) and 3 Grade 4 neutropenia (2 in Level 3, 1 in Level 4), 4 of which were serious adverse events (AEs). The most common (≥20%) treatment-related AEs of Grade 3 or above were neutropenia (100.0%), leukopenia (88.9%), thrombocytopenia (33.3%), anemia (27.8%), lymphopenia and hypertension (both 22.2%). No death was reported. Overall 10 pts (55.6%) achieved confirmed partial responses and 16 (88.9%) achieved clinical benefits. Confirmed objective response rates (ORRs), clinical benefit rates (CBRs), and DLTs in different dose levels were shown in Table 1. Considering the efficacy and safety profiles, Level 4 was selected as RP2D. Conclusion: The anti-angiogenesis multi-targeted receptor TKI famitinib combined with CDK4/6i and fulvestrant has shown antitumor effects in advanced HR-positive and HER2-negative BC, and no new safety signals were observed. Citation Format: Min Yan, Mengwei Zhang, Limin Niu, Huimin Lv, Zhenzhen Liu, Huiai Zeng, Shengnan Zhao, Huihui Sun, Jing Wang, Yajing Feng, Huajun Li. Famitinib, a multi-targeted receptor tyrosine kinase inhibitor, combined with dalpicilib and fulvestrant in advanced HR-positive and HER2-negative breast cancer [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 PO2-05-01.

Abstract PO4-04-12: A Phase 1b/2 study of palazestrant (OP-1250) in combination with ribociclib or alpelisib in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative, advanced and/or metastatic breast cancer

Abstract Background: Endocrine therapy (ET) when administered with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors has improved outcomes in patients (pts) with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (BC) or metastatic breast cancer (MBC) and is the current standard of care for first-line treatment. Addition of the PIK3 inhibitor alpelisib to ET significantly improved progression-free survival in pts with PIK3CA-mutated, ER-positive, HER2-negative MBC, and alpelisib + fulvestrant is the standard of care for second or later-line treatment. Most pts will acquire resistance to ET, with mutations in ESR1 constituting the most common mechanism of resistance. Palazestrant (OP-1250) is a small molecule oral complete ER antagonist (CERAN) and selective ER degrader (SERD) that binds the ligand binding domain of ER and completely blocks ER-driven transcriptional activity in both wild-type (ESR1-wt) and mutant (ESR1-mut) forms of ER. In preclinical studies, palazestrant in combination with ribociclib demonstrated activity in both ESR1-wt and ESR1-mut xenograft models and showed efficacy in brain metastasis xenograft models. In a Phase 1/2 monotherapy study in pts with ER-positive, HER2-negative MBC, palazestrant was well tolerated with demonstrated antitumor efficacy and favorable pharmacokinetics (PK) supporting once a day (qd) dosing at the recommended Phase 2 dose (RP2D) of 120 mg. The aim of this study is to evaluate the safety, PK, and antitumor activity of palazestrant + ribociclib or alpelisib in pts with ER-positive, HER2-negative advanced BC or MBC. Methods: Eligible pts have evaluable ER-positive, HER2-negative advanced BC or MBC; ≤2 prior ETs (prior CDK4/6 inhibitors allowed); and ≤1 prior line of chemotherapy. In the alpelisib arm, pts must have a PIK3CA mutation in the tumor or ctDNA. Patients are administered oral palazestrant at escalating doses of 30, 60, and 120 mg qd in combination with the approved dose of oral ribociclib (600 mg qd; days 1–21 of 28-day cycle) or approved dose of oral alpelisib (300 mg qd) in a 3+3 design to identify the RP2D. The dose-expansion part will assess additional safety and PK parameters and the antitumor activity of palazestrant in combination with ribociclib or alpelisib (NCT05508906). Results: As of June 15, 2023, 10 pts have received 30 mg and 60 mg doses of palazestrant in combination with ribociclib (n=6) or alpelisib (n=4). No dose-limiting toxicities have been observed. After administration in the first two combination dose levels of 30 and 60 mg, palazestrant exposure was consistent with monotherapy administration; exposure data show no drug–drug interactions (DDI) when compared to published exposure parameters. Most reported treatment-emergent adverse events (TEAEs) were grade 1 or 2 and consistent with the known safety profiles of all 3 drugs. In the ribociclib arm, the TEAEs occurring in ≥2 pts included grade 1 nausea (n=4), grade 1 constipation (n=2), and neutropenia (grade 2, n=1; grade 3, n=3). For the 3 pts in the 30 mg palazestrant + alpelisib cohort, the only TEAE occurring in ≥2 pts was grade 1 diarrhea. One pt had grade 1 hyperglycemia. Conclusions: In this ongoing study, palazestrant in combination with ribociclib or alpelisib was well tolerated, and enrollment to the palazestrant 120 mg dose with ribociclib or alpelisib is ongoing. No new safety signals were observed for the 3 drugs, and no clinically significant DDIs were observed between palazestrant and ribociclib or alpelisib at the doses evaluated. Exposure of each drug was consistent with observed monotherapy exposure levels. Updated data will be presented. Citation Format: Virginia Borges, Carlos Alemany, Nancy Lin, Sara Nunnery, Cynthia Ma, Margaret Tonda, Morena Shaw, Arlene Chan. A Phase 1b/2 study of palazestrant (OP-1250) in combination with ribociclib or alpelisib in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative, advanced and/or metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-04-12.

Abstract PO2-15-06: ctDNA-based DNADX in hormone receptor-positive and HER2-negative (HR+/HER2-) advanced breast cancer following endocrine therapy and CDK4/6 inhibition: a correlative analysis from the randomized phase 2 PARSIFAL trial

Abstract ctDNA-based DNADX in hormone receptor-positive and HER2-negative (HR+/HER2-) advanced breast cancer following endocrine therapy and CDK4/6 inhibition: a correlative analysis from the randomized phase 2 PARSIFAL trial Background: DNADX, a novel machine learning-based approach, utilizes DNA from tumor tissue or plasma ctDNA to identify clinically relevant phenotypic tumor features and classify breast cancer into 4 subtypes (Nat Comm 2023). Here, we evaluated DNADX's ability to predict prognosis and treatment benefit in HR+/HER2- advanced breast cancer following endocrine therapy and a CDK4/6 inhibitor. Methods: DNADX was evaluated centrally in available baseline plasma ctDNA samples from PARSIFAL trial (NCT02491983) which randomized 486 patients (pts) with HR+/HER2- advanced breast cancer to receive (1:1 ratio) first line palbociclib with either fulvestrant or letrozole. Shallow whole genome sequencing was performed on ctDNA, and the 4 DNA-based subtypes (Clusters-1, -2, -3, and -4) were identified if the ctDNA tumor fraction (TF)≥3%. The main objective was to evaluate the association of DNADX subtypes with progression-free survival (PFS) and overall survival (OS). Secondary objective was to identify the subgroup of pts who benefit more from each endocrine treatment. Uni- and multi-variable Cox regression models were used after adjusting for TF, menopausal status, ECOG status, de novo metastasis (vs. recurrence), visceral disease and number of metastatic sites. Results: DNADX was evaluated in plasma ctDNA samples from 122 pts (25.1%). Clinical variables and median PFS (27.6 months) were similar as the overall PARSIFAL population. DNADX identified 56.6% pts with TF of < 3%, 14.8% with Cluster-1, 19.7% with Cluster-2, 5.7% with Cluster-3 and 3.3% with Cluster-4. In terms of PFS, pts classified with TF< 3% had a lower risk of progression compared to Cluster-1, Cluster-2, Cluster-3, Cluster-4 subtypes (pairwise PFS hazard ratios [HRs] of 1.88, 2.02, 3.15, and 5.62, respectively, with a global log-rank test of p=0.010). Similar results were obtained after adjusting for other clinical-pathologic variables. A numerical benefit of fulvestrant in comparison with letrozole was observed in pts classified in Cluster-1 and Cluster-4 (HR=0.42, 95% CI 0.14-1.24) in contrast to the other groups (HR=1.21, 95% CI 0.68-2.18), and the interaction test was statistically significant after adjusting for clinical-pathologic variables (anova p-value=0.037). In terms of OS, pts classified with TF< 3% had a lower risk of death compared to Cluster-1, Cluster-2, Cluster-3, and Cluster-4 subtypes (pairwise OS HRs of 1.90, 4.23, 11.13, and 6.80, respectively, with a global log-rank test of p=0.003). In the multivariable analysis, results were consistent after adjusting for clinical-pathologic variables and TF. Conclusions: Liquid biopsy-based DNADX subtypes predict outcomes in pts with HR+/HER2- advanced breast cancer on endocrine therapy and CDK4/6 inhibitors, potentially identifying the most optimal endocrine treatment for each pt. Citation Format: Fara Brasó-Maristany, Javier Cortés, José Manuel Pérez-García, Rosario Vega-León, Laia Paré, Guillermo Villacampa, Judit Matito, Francisco Pardo, Marina Gomez-Rey, Mario Mancino, Elena Martínez-García, Carmen Mora Gallardo, Leonardo Mina, Florence Dalenc, Meritxell Bellet- Ezquerra, Manuel Ruíz - Borrego, Miguel Gil-Gil, Peter Schmid, Charles M. Perou, Joel S. Parker, Patricia Villagrasa, Ana Vivancos, Aleix Prat, Antonio Llombart-Cussac. ctDNA-based DNADX in hormone receptor-positive and HER2-negative (HR+/HER2-) advanced breast cancer following endocrine therapy and CDK4/6 inhibition: a correlative analysis from the randomized phase 2 PARSIFAL trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-15-06.

Abstract RF01-06: Efficacy and safety of toripalimab plus metronomic chemotherapy in HER2 negative metastatic breast cancer: a multicenter phase II trial based on a Bayesian adaptive randomized design

Abstract Background: Combining Immune checkpoint blockade (ICB) with chemotherapy may significantly improve efficacy in patients with breast cancer. Metronomic chemotherapy is based on more frequent and low-dose drug administrations compared with conventional chemotherapy. Some clinical studies with small samples have tried the combination of metronomic chemotherapy and ICB in patients with advanced tumors. However, whether metronomic chemotherapy is more suitable for ICB than conventional chemotherapy is still unclear. Thus, we performed the first clinical trial, to our knowledge, of metronomic chemotherapy combined with PD-1 blockade comparing with the efficacy of combined conventional chemotherapy and ICB. Methods: This study is a multicenter randomized phase 2 trial using a multi-arm design with Bayesian adaptive randomization and efficacy monitoring. Eligible patients have advanced HER2 negative breast cancer, with no more than one prior line of standard chemotherapy. Patients were randomized to 5 groups: ① metronomic vinorelbine (NVB, 40 mg/day, TIW) monotherapy (the control cohort); ② NVB + Toripalimab (anti-PD1 antibody, 240 mg Q3W); ③Bevacizumab (5 mg/kg Q3W) + NVB+ Toripalimab (the BEV cohort); ④ Cisplatin (50mg/m Q3W) + NVB + Toripalimab (the DDP cohort), ⑤Cyclophosphamide (50mg/day, QD) + Capecitabine (500 mg, TID) + NVB+ Toripalimab (the VEX cohort). The primary endpoint is disease control rate (DCR), and secondary endpoints are objective response rate (ORR), progression free survival (PFS), and overall survival (OS). The safety profile has also been assessed. Mass cytometry time-of-flight (CyTOF) analyses of paired blood samples were performed to demonstrate dynamic changes in systemic immune profile. Results: A total of 103 patients were randomized. Characteristics were as expected for advanced breast cancer and balanced between cohorts. Adverse events of any grade occurred in 64 patients, with 5.2% grade >3. The rate of nausea was significantly higher in the cisplatin cohort than in the others (P< 0.001). Toripalimab was not associated with any previously unreported toxicity. Among the five treatment cohorts, the VEX cohort and the cisplatin cohort had the highest DCR, 69.7% (95% CI 51.7–85.9%) and 73.7% (95% CI 56.1–88.7%), respectively. Followed by the bevacizumab cohort, DCR is 55.7% (95% CI 37.4%–73.6%). Most objective responses were observed in the VEX cohort (ORR: 18.5%; 95% CI 5.6–34.1%), followed by cisplatin (ORR 14.5%; 95% CI 3.3–29.0%). It is worth noting that the PFS of patients in the VEX cohort was the longest, reaching 6.6 months (95% CI 4.0-5.9), followed by 4.0 months (95% CI 2.4-10.4) in patients of the bevacizumab cohort. The PFS of patients receiving the cisplatin regimen was relatively short, only 3.5 months (95% CI 2.2-5.3). Similarly, patients in the cisplatin cohort had shorter OS than those in the VEX and bevacizumab cohorts. In the TNBC subgroup, again, patients in the VEX cohort had the highest DCR (74.1%, 95%CI 47.9%-95.4%) and longest PFS (9.8 months, 95%CI 3.8-21.9). We obtained over 63 million cells in total and clustered CD45+ immune cells into 32 clusters. The systemic immune profile of patients changed dramatically over 2 cycles of PD-1 blockade. However, only the change of cluster 30 differed between responders and non-responders. This is a group of intermediate monocytes with a high expression of CD38, which decreased in responders but significantly increased in non-responders. CD38-NAD+ axis regulates the PD1+ exhausted T cell function. Meanwhile, the overall expression of CD38 in monocytes was significantly increased by DDP and BEV treatment compared with baseline, but not in the VEX groups. DDP significantly increased the expression level of CD38 on NK cells, while BEV or VEX treatment did not affect it. Conclusions: These data suggest promising clinical efficacy and evidence of cooperativity between metronomic VEX chemotherapy and PD-1 blockade. Citation Format: Hongnan Mo, Xiaoying Sun, Jingtong Zhai, Jiashu Han, Hewei Ge, Yuhan Wei, Xiuwen Guan, Haili Qian, Fei Ma. Efficacy and safety of toripalimab plus metronomic chemotherapy in HER2 negative metastatic breast cancer: a multicenter phase II trial based on a Bayesian adaptive randomized design [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 RF01-06.

Abstract PS15-09: Imlunestrant monotherapy and in combination with abemaciclib, with or without an aromatase inhibitor, in estrogen receptor-positive (ER+), HER2-negative (HER2-) advanced breast cancer (aBC): updated results from the EMBER study

Abstract Background: Imlunestrant is an oral, brain-penetrant selective estrogen receptor degrader, designed to deliver continuous ER target inhibition, including in ESR1-mutant breast cancer. In the first-in-human dose escalation/expansion (Phase 1a/1b) study of the EMBER trial (NCT04188548), imlunestrant showed favorable safety, pharmacokinetics, and clinical benefit in pre-treated patients with ER+, HER2- aBC when administered as monotherapy (Jhaveri, ASCO 2022) or with abemaciclib ± aromatase inhibitor (AI) (Jhaveri, SABCS 2022). Here, we report updated data from Phase 1a/1b of imlunestrant monotherapy as well as from Phase 1b of imlunestrant with abemaciclib ± AI in EMBER. Methods: Phase 1a/1b enrolled patients with ER+ aBC (prior endocrine therapy (ET) sensitivity or untreated de novo aBC). Prior aBC therapy allowance was ≤3 (no restrictions on the type of prior therapies) in Phase 1a and ≤2 (only 1 prior ET) in Phase 1b for patients receiving imlunestrant monotherapy; and ≤1 (no prior CDK4/6 inhibitors) in Phase 1b for patients randomized to receive imlunestrant + abemaciclib ± AI. Key endpoints included safety and tolerability, objective response rate (ORR: complete response (CR) or partial response (PR) in patients with measurable disease), clinical benefit rate (CBR: CR or PR, or stable disease ≥24 weeks) per RECIST v1.1, and progression-free survival (PFS). Results: As of March 2023, 114 patients received imlunestrant monotherapy (200mg n=21; 400mg (RP2D) n= 51; ≥600mg n=42), and 85 patients received imlunestrant (400mg n=80; 800 mg n=5) in combination with abemaciclib ± AI (both at labeled doses). At the RP2D, the most common all-grade/Grade 3 treatment-emergent adverse events (TEAEs) with imlunestrant monotherapy were fatigue (39%/4%), nausea (39%/2%), and diarrhea (29%/2%). With the combination of imlunestrant + abemaciclib ± AI, the most common all-grade/Grade 3 TEAEs were diarrhea (88%/9%), nausea (61%/0%), fatigue (51%/5%), and neutropenia (44%/16%). No safety signals of ocular or cardiac toxicity (bradycardia/QTc prolongation) were observed. Baseline characteristics, safety, and preliminary efficacy are presented in Table 1. Combination therapy of imlunestrant and abemaciclib ± AI improved ORR and CBR. Conclusion: With longer follow-up, imlunestrant alone or in combination with abemaciclib ± AI continues to demonstrate a tolerable safety profile along with favorable preliminary efficacy in patients with ER+, HER2- aBC. Further data will be presented at the meeting. The Phase 3, EMBER-3 study is ongoing; evaluating imlunestrant, investigator’s choice ET, and imlunestrant plus abemaciclib in ET pre-treated ER+, HER2- aBC patients (NCT04975308). Table. Baseline characteristics, safety and preliminary efficacy a, in patients with available ctDNA data. Citation Format: Komal Jhaveri, Elgene Lim, Rinath Jeselsohn, Cynthia Ma, Erika Hamilton, Cynthia Osborne, Manali Bhave, Peter Kaufman, J. Thaddeus Beck, Luis Manso, Ritesh Parajuli, Hwei-Chung Wang, Jessica Tao, Ajay Dhakal, Jean-Yves Pierga, Yen-Shen Lu, Tim Larson, Yolanda Jerez Gilarranz, Roohi Ismail-Khan, Francesca Bacchion, Claudia Karacsonyi, Yujia Li, Shawn T. Estrem, Bastien Nguyen, Muralidhar Beeram. Imlunestrant monotherapy and in combination with abemaciclib, with or without an aromatase inhibitor, in estrogen receptor-positive (ER+), HER2-negative (HER2-) advanced breast cancer (aBC): updated results from the EMBER study [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 PS15-09.

Abstract PS15-02: A Phase Ⅰb Study of D-0502 as Monotherapy for Advanced or Metastatic ER-Positive and HER2-Negative Breast Cancer: Results from the Dose-Expansion Stage

Abstract Background: Endocrine therapy is the mainstay treatment for estrogen receptor (ER)-positive advanced breast cancer (BC). D-0502, an orally bioavailable selective estrogen receptor degrader (SERD), has previously demonstrated antitumor activity in various ER-positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-) breast cancer cell lines and xenograft models. The phase Ⅰ open-label study (NCT03471663) evaluated the safety, tolerability, pharmacokinetics (PK) and efficacy of D-0502 as monotherapy and in combination with palbociclib in female patients with ER+ and HER2- breast cancer. The dose escalation part of D-0502 monotherapy (phase Ⅰa) has been presented before (SABCS 2021, PS11-26 Abstract #1348). Here, we present the results of D-0502 monotherapy from the dose-expansion stage in phase Ⅰb study. Methods: In the single-agent dose-expansion stage of phase Ⅰb study, patients (n=60) received D-0502 (400 mg QD) in 28-day cycles. Eligible patients included females with confirmed ER+, HER2- locally advanced, or metastatic BC; ECOG 0-1; measurable disease (RECIST v1.1); premenopausal or postmenopausal status; adequate hematologic, hepatic and renal functions. The primary objectives are to characterize the safety of D-0502. The secondary objectives are to evaluate the preliminary anti-tumor activity and the PK characteristic. Results: As of April 07, 2023, 60 female patients were enrolled and treated with 400mg single-agent D-0502. Median age was 57 (range: 32-82) years, 55.0% had an ECOG PS of 1. Disease progression resulting in treatment discontinuation occurred in 66.7% (40/60) of patients, and 6.7% (4/60) of patients discontinued treatment because of AEs. Treatment-related adverse events (TRAEs) were reported in 57 pts (95.0%), most of which were grade 1-2. No grade 4/5 TRAE has been reported. The incidence of serious adverse events was 6.7% (4/60). The most common (≥ 15%) TRAEs included vomiting, dizziness, nausea, increased aspartate aminotransferase and alanine aminotransferase, anaemia, decreased appetite, diarrhoea, and malaise. In the 51 efficacy evaluable patients, 8 patients had partial response (PR) and 27 had stable disease (SD); objective response rate (ORR) and disease control rate (DCR) were 15.7% (8/51) and 68.6% (35/51), respectively. The clinical benefit rate (CBR: CR + PR + SD ≥24 weeks) was 47.1% (24/51). The median PFS was 5.6 months (95% Cl: 2.0, 10.0). Conclusion: D-0502 monotherapy showed promising antitumor activity and tolerable toxicity in female patients with ER+ and HER2- locally advanced or metastatic BC. Currently this treatment is being evaluated in a phase Ⅲ study for patients with ER+ and HER2- locally advanced or metastatic BC in China. Citation Format: Jiayu Wang, Tao Sun, Qingyuan Zhang, Yanxia Shi, Xu Wang, Yiding Chen, Quchang Ouyang, Kunyan Li, Manojkumar Bupathi, w. Jeffery Edenfield, Andrea L.M. Silber, Hong Zong, Erika Hamilton, Dejan Juric, Kate Lathrop, Yihong Zhang, Kathryn Stazzone, Zhe Shi, Yaolin Wang, Ling Zhang, Binghe Xu. A Phase Ⅰb Study of D-0502 as Monotherapy for Advanced or Metastatic ER-Positive and HER2-Negative Breast Cancer: Results from the Dose-Expansion Stage [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 PS15-02.

Abstract PO3-18-09: OPERA-01: A randomized, open-label, phase 3, study of palazestrant (OP-1250) vs standard-of-care treatment for ER+, HER2- advanced or metastatic breast cancer after endocrine and CDK4/6 inhibitor therapy

Abstract Background: In estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC), adding a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor to endocrine therapy (ET) has improved outcomes and is the current standard-of-care treatment in the first-line setting. However, resistance to first-line treatment develops in most patients (pts), which is often attributed to acquired mutations in ESR1. Limited data exist for ET-based treatment options after progression on prior ET and CDK4/6 inhibitors, and most pts will transition to chemotherapy for further treatment. Therefore, there is a significant unmet need for more effective ET in pts with ER-positive, HER2-negative MBC to improve outcomes and delay time to chemotherapy. Palazestrant (OP-1250) is a small molecule oral complete ER antagonist (CERAN) and selective ER degrader (SERD) that binds the ligand binding domain of ER and completely blocks ER-driven transcriptional activity in both wild-type (ESR1-wt) and mutant (ESR1-mut) forms of ER. In preclinical studies, palazestrant demonstrated better tumor shrinkage in ESR1-wt and ESR1-mut models when compared to fulvestrant; it also showed efficacy in brain metastasis models. In a phase 1/2 monotherapy study in pts with heavily pretreated ER-positive, HER2-negative advanced breast cancer (BC) or MBC (NCT04505826), palazestrant showed a tolerable safety profile, promising antitumor efficacy, and favorable pharmacokinetics (PK) supporting once a day (qd) dosing. The recommended Phase 2 dose of palazestrant is 120 mg qd. Methods: The OPERA-01 trial is an international, multicenter, randomized, open-label, phase 3 clinical trial comparing the efficacy and safety of palazestrant as a single agent to standard-of-care ET (fulvestrant, anastrozole, letrozole, or exemestane) in pts with ER-positive, HER2-negative advanced BC or MBC that has relapsed or progressed on 1 or 2 prior lines of ET for MBC, which includes a CDK4/6 inhibitor. Eligible pts are women (pre- or post-menopausal) or men who have a confirmed diagnosis of ER-positive, HER2-negative locally advanced evaluable BC or MBC not amenable to curative therapy. ER and HER2 status are determined according to the American Society of Clinical Oncology/College of American Pathologists guidelines. Patients must have Eastern Cooperative Oncology Group performance status 0 or 1. Prior treatments must include 1 or 2 prior lines of ET as monotherapy or in combination with a CDK4/6 inhibitor for MBC; must have received CDK4/6 inhibitor in combination with ET and have disease progression during or within 28 days of completion of each line of prior treatment for MBC; most recent ET given for ≥6 months. Prior chemotherapy in the metastatic setting is not permitted. Patients (N∼500) are randomized to palazestrant or standard-of-care ET monotherapy, and are stratified by ESR1 mutation status, prior lines of ET for advanced disease (1 vs 2 lines), and presence or absence of visceral disease. The primary endpoint of progression-free survival will be assessed by blinded independent central review in pts with and without ESR1 mutations in the intent-to-treat population. Secondary endpoints include overall survival, antitumor activity (objective response rate, clinical benefit rate, and duration of response), safety, patient-reported outcomes, and PK in pts with and without ESR1 mutations. The study is planned to be conducted globally. Citation Format: Arlene Chan, Jane Meisel, Komal Jhaveri, Joo Hyuk Sohn, Meritxell Bellet- Ezquerra, Jason Schroeder, Mark Shilkrut, Barbara Pistilli. OPERA-01: A randomized, open-label, phase 3, study of palazestrant (OP-1250) vs standard-of-care treatment for ER+, HER2- advanced or metastatic breast cancer after endocrine and CDK4/6 inhibitor therapy [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 PO3-18-09.

Abstract PO1-05-07: Circulating tumor DNA dynamics in acelERA Breast Cancer: a Phase II study of giredestrant for estrogen receptor-positive, HER2-negative, previously treated advanced breast cancer

Abstract BACKGROUND Giredestrant (GIR) is a highly potent, oral, selective estrogen receptor antagonist and degrader (SERD) that exhibits robust estrogen receptor (ER) occupancy. The Phase II, randomized, open-label acelERA Breast Cancer (BC) study (NCT04576455) assessed GIR vs physician’s choice of endocrine therapy (PCET) in second- or third-line ER-positive, HER2-negative advanced BC (ER+, HER2– aBC). The study did not reach statistical significance for the primary endpoint of investigator-assessed progression-free survival (PFS); however, the benefit of GIR was of larger magnitude among patients (pts) with ESR1-mutated tumors (ESR1m; a common cause of acquired resistance to endocrine therapy [ET]). We present an exploratory biomarker analysis of circulating tumor (ct)DNA dynamics. METHODS Pts (n = 303) were randomized 1:1 to GIR or PCET (75% of pts had fulvestrant [FUL]; 25%, an aromatase inhibitor). Partial response (PR), stable disease (SD), and progressive disease (PD) were categorized by RECIST v1.1. Plasma samples taken at Cycle 1, Day 1 (C1D1; n = 229), while on treatment (tx) at C2D1 (n = 220), and at the end of therapy (EOT; n = 155) were evaluated with the FoundationOne Liquid CDx next-generation sequencing assay. Gene mutations were defined as variants with known or likely impact on protein function. Composite tumor fraction (cTF) was defined as the total estimated tumor ctDNA content in each sample, and was only evaluable for a subset of samples (137 C1D1; 136 C2D1; 99 EOT). cTF or ESR1 mutant allele frequency (MAF) changes were calculated as a percent change from C1D1. ESR1m clonality was estimated as variant tumor fraction/estimated tumor fraction. Statistical significance was evaluated using the Mann–Whitney test. RESULTS The overall mutation landscape remained relatively unchanged with GIR tx at C2D1 or EOT, except for ESR1m prevalence, which declined from 43% at C1D1 to 26% on tx and 27% at EOT. With PCET, ESR1m prevalence decreased from 34% at C1D1 to 29% on tx, but increased to 43% by EOT. There were no concordant changes for other top mutated genes in this study, including PIK3CA, TP53, or DNMT3A. cTF decreased on tx in 38/65 (59%) and 32/59 (54%) of evaluable pts with GIR and PCET, respectively; the median change from C1D1 was –23% with GIR compared with –5% with PCET or –15% with FUL. The median change in cTF levels on tx with GIR was significantly greater in pts with a PR (–88%) vs PD (+6%, p = 0.002) or SD (–19%, p = 0.004). The degree of cTF decline on tx with GIR was significantly higher in pts with baseline ESR1m (median change –58%) vs no ESR1m detected (+5%, p = 0.012). Pts with a clonal ESR1m had higher levels of cTF decline on tx vs pts with subclonal ESR1m, suggesting cTF dynamics are a function of tumor heterogeneity. ESR1 MAF decreased on tx in 93% of pts with baseline ESR1m on GIR, vs 60% with PCET and 70% with FUL. ESR1 MAF decline on tx was significantly higher with GIR vs PCET at both C2D1 and EOT (p < 0.0001). The average ESR1 MAF decline on tx with GIR was greater in pts with a PR (–97%) vs PD (–54%, p = 0.025) or SD (–48%, p = 0.051), and all seven GIR-treated pts with a PR showed a near or total loss of ESR1 MAF by C2D1. The ESR1m variants D538G and Y537X had a significantly greater decline in MAF on tx with GIR vs PCET or FUL (p < 0.0001). CONCLUSIONS Data show that cTF and ESR1m ctDNA dynamics were associated with clinical response to GIR in ER+, HER2– aBC. ESR1 MAF decline was significantly greater with GIR vs PCET or FUL. ESR1 MAF declined to a greater degree with GIR compared with cTF, which is consistent with the larger magnitude of PFS benefit seen with GIR in pts with ESR1m tumors. The specific ESR1 variants D538G and Y537X showed greater sensitivity to GIR compared with PCET or FUL. Citation Format: Ann Collier, Aditya Bardia, Joo Hyuk Sohn, Elgene Lim, Marianna Chavez, Miguel Martín, Jorge Martinalbo, Pablo Perez-Moreno, Heather Moore. Circulating tumor DNA dynamics in acelERA Breast Cancer: a Phase II study of giredestrant for estrogen receptor-positive, HER2-negative, previously treated advanced breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-05-07.

Abstract PO2-02-05: CDK4/6 inhibitor dalpiciclib combined with letrozole as neoadjuvant therapy in postmenopausal patients with hormone receptor-positive, HER2-negative stage II-III breast cancer: a single-arm exploratory trial

Abstract Background: Patients with HR-positive, HER2-negative breast cancer respond poorly to neoadjuvant chemotherapy. The phase 3 DAWNA-1 and DAWNA-2 studies have proved that adding dalpiciclib (a CDK4/6 inhibitor) to endocrine therapy can significantly improve progression-free survival in patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer. However, the evidence of dalpiciclib in the neoadjuvant setting is limited. This study aimed to explore the efficacy and safety of dalpiciclib plus letrozole as neoadjuvant therapy in in patients with HR-positive, HER2-negative stage II-III breast cancer. Methods: In this multicenter, single-arm exploratory trial (NCT05512780), adult postmenopausal women with HR-positive (estrogen receptor >10%), HER2-negative stage II-III invasive breast cancer were enrolled. Patients received oral dalpiciclib (150 mg on days 1-21 of each 28-day cycle) and oral letrozole (2.5 mg once daily) for 4 cycles, followed by surgery. The primary endpoint was objective response rate (ORR), assessed by investigator according to the Response Evaluation Criteria In Solid Tumors version 1.1. Secondary endpoints included complete cell cycle arrest (CCCA, defined as Ki-67 < 2.7% on day 15 of the first cycle) rate, total pathological complete response (tpCR; ypT0/is ypN0) rate, residual cancer burden (RCB) 0-I rate, and safety. Results: Between June 2022 and January 2023, 41 patients were screened at 9 sites, and 35 patients were enrolled and received at least one dose of study drug. The median age was 66 years (range, 52-83), and the median baseline Ki-67 level was 20% (range, 4%-40%). The majority of patients had T2 disease (65.7%), lymph node-positive disease (88.6%), and stage II disease (IIA: 45.7%; IIB: 40.0%). The ORR was 35.5% (11/31) at 8 weeks and 51.7% (15/29) at 16 weeks in patients with evaluable response. The CCCA rate was 70.0% (21/30) in patients with available data. Four patients refused surgery and chose to continue the drug therapy. Of 27 patients who had undergone surgery, one (3.7%) patient had tpCR and RCB 0. Of 35 patients, the most common adverse events were neutrophil count decreased (74.3%), white blood cell decreased (68.6%), anemia (34.3%), and fatigue (31.4%). The most common grade 3 or higher adverse event was neutrophil count decreased (45.7%). No febrile neutropenia or treatment-related deaths occurred. Conclusions: This is the first prospective study of neoadjuvant dalpiciclib in patients with HR-positive, HER2-negative breast cancer. The findings suggest the promising tumor response to neoadjuvant dalpiciclib plus letrozole in postmenopausal patients with HR-positive, HER2-negative breast cancer, with a manageable safety profile. This combination can effectively suppress the tumor cell proliferation, as reflected by change in Ki-67 level. Citation Format: Lina Zhang, Chao Yang, Jie Ma, Yuntao Li, Ruizhen Luo, Jianjun Han, Xiaochun Wang, Zhisheng Zhang, Li Ma, Haifeng Cai, Xiangshun Kong, Zunyi Wang, Xinping Zhou, Yueping Liu, JiaJie Shi, Yanshou Zhang, Meiqi Wang, Jiaxing Wang, Cuizhi Geng. CDK4/6 inhibitor dalpiciclib combined with letrozole as neoadjuvant therapy in postmenopausal patients with hormone receptor-positive, HER2-negative stage II-III breast cancer: a single-arm exploratory trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-02-05.

Abstract PO3-05-06: Targeting PAM50 HER2-Enriched intrinsic subtype with enzalutamide in hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer: results of the SOLTI-1502 ARIANNA trial

Abstract Background Pre-clinical evidence and retrospective studies suggest that PAM50 HER2-Enriched (HER2-E), HR+/HER2- tumors have estrogen receptor (ER) independence and poor prognosis but seem to have androgen receptor (AR)-addiction. Enzalutamide (ENZ) is a potent inhibitor of AR signaling. We hypothesized that ENZ may induce a significant proliferative arrest in PAM50 HER2-E, HR+/HER2-negative advanced breast cancer (ABC), leading to clinical benefit in this poor prognosis population. Methods Eligible patients (pts), males or pre/post-menopausal women with advanced HR+/HER2- ABC resistant to endocrine therapy, received ENZ 160 mg/day until disease progression. Pts were assigned to different cohorts according to PAM50 intrinsic subtypes identified in the pre-treatment tumor biopsy: Cohort A included pts with HER2-E and Cohort B pts with Luminal A/B tumors. Centralized molecular assessment of pre-treatment and C1D15 tumor biopsies were required for the primary endpoint evaluation. After C1D15 biopsy, exemestane 50mg QD could be added to ENZ at physician’s discretion. Tumor assessments were performed every 8 weeks. Primary efficacy endpoint was the relative change in the PAM50 11-gene proliferation-related signature in Cohort A. Secondary objectives included anti-proliferative effect of ENZ in Cohort B, overall response rate (ORR), Clinical benefit rate (CBR; partial response [PR] + stable disease ≥ 24 weeks) progression-free survival (PFS), and safety. Results From June 2020 to October 2022, 47 tumors were screened, and 6 PAM50 HER2-E tumors were identified (13%). A total of 34 pts were enrolled: 6 pts in Cohort A and 28 pts in Cohort B. Among them, 4 pts from Cohort A received ENZ plus exemestane and 23 pts in Cohort B. Mean age was 59 (range 39-76), 89% of pts were postmenopausal, 74% had liver disease, and 59% received (neo)adjuvant treatment. The median number of lines for ABC was 4 (1-8). Mean Ki67 (central assessment) in Cohort A was 37% (5%-70%), while in Cohort B it was 30% (3%-90%). Mean central AR in Cohort A was 66% (30-100), while in Cohort B it was 55% (1-100). The mean suppression of PAM50 11-gene proliferation-signature after 2 weeks of treatment with ENZ was 3.7% (p=0.848) in Cohort A and 1.2% (p=0.909) in Cohort B. The median change in Ki67 levels in Cohort A was -0.43% (p=0.812), while in Cohort B it was +3.86% (p=0.081). No statistically significant differentially expressed genes or changes in intrinsic subtypes were observed. Overall, the median PFS was 1.8 months (95% CI 1.6-1.8). In Cohort A, median PFS was 1.6 months (95% CI 1.0-1.9), and in Cohort B, it was 1.8 months (95% CI 1.6-1.8). CBR was 0% and 11% (n=3, 95% CI 2.8-25.9%) in Cohorts A and B, respectively. A PR with 16 months duration in cohort B was observed in a patient with an AR-mutated tumor (AR c. 689C >T). Regarding safety, grade 1-2 and 3-4 toxicities occurred in 94.1% and 35.3% of patients, respectively. ENZ dose reduction and discontinuation occurred in 2 (5.9%) and 3 (8.8%) pts, respectively. The most common toxicities related to ENZ were nausea (n=8, 24%), decreased appetite (n=8, 24%), AST increase (n=6, 18%) and vomiting (n=6, 18%). Conclusions The hypothesis that ENZ could induce proliferation arrest in HR+/HER2-, PAM50 HER2-E tumors was not confirmed, and ARIANNA was prematurely closed due to the lack of efficacy. Additional research is needed to explore if ENZ may benefit specific populations of pts with breast cancer (e.g. AR-mut tumors) and whether alternative AR modulators are more effective in blocking AR signaling in HR+/HER2-, PAM50 HER2-E tumors Citation Format: Mafalda Oliveira, Tomás Pascual, Sonia Pernas, Mireia Margelí, Salvador Blanch, Barbara Adamo, Francisco Javier Salvador Bofill, Xavier Gonzalez-Farré, Samyukta Chillara, Patricia Galván, Esther Sanfeliu, Paula Blasco, Valeria Sirenko, Alejandra Espinosa, Charles M Perou, Aleix Prat, Luis Manso. Targeting PAM50 HER2-Enriched intrinsic subtype with enzalutamide in hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer: results of the SOLTI-1502 ARIANNA trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-05-06.

Abstract PO5-16-12: EFFICACY AND TOLERABILITY OF METRONOMIC CHEMOTHERAPY (mChT) WITH CYCLOPHOSPHAMIDE, METHOTREXATE AND CAPECITABINE (CMX) IN PATIENTS WITH HEAVILY PRETREATED ADVANCED BREAST CANCER. RESULTS FROM A MULTICENTER RETROSPECTIVE STUDY

Abstract BACKGROUND mChT consists on the administration of repetitive, low doses of chemotherapy drugs and represents an attractive and active therapeutic strategy in cancer patients. Beyond the traditional cytotoxic effect of each drug on tumor cells, mChT seems to play a role in the modulation of angiogenesis and immune-regulation. mChT has demonstrated promising clinical activity and low toxicity in patients with advanced breast cancer (ABC). The aim of this study is to describe the safety and efficacy of CMX in a retrospective cohort of heavily pretreated HER2-negative ABC patients. METHODS This is a multicenter, retrospective study that included patients with HER2-negative ABC who received treatment with CMX (capecitabine 500 mg thrice daily, methotrexate 2.5 mg twice a week, and cyclophosphamide 50 mg daily). Demographic data, tumor characteristics, previous therapies, efficacy, and toxicity of the CMX treatment were collected. Statistical analyses were performed with Stata v.14. For standard summary statistics, mean and range for continuous data and relative and absolute frequencies for categorical data were used while for survival analysis Kaplan Meier approach was employed. RESULTS A total of 25 patients from 4 centers in Spain treated between October 2016 and February 2023 were included in this analysis. Median age was 63 years (range: 37-87), 68% had visceral disease, and 48% had triple-negative tumors. All patients previously received a median of 5 prior lines of systemic therapy in the metastatic setting and 80% of patients had been treated with capecitabine, most of them in the metastatic scenario with a median treatment duration of 6.2 months. Dose reductions were necessary in 5 patients and 1 patient discontinued treatment due to toxicity. No grade 3-4 hand-foot syndrome or diarrhea were reported. Objective response rate was 20.8% and disease control rate was 54.2%. Median progression-free survival was 6.1 months (95% confidence interval [CI] 95%; 4.3 - 12.4) and median overall survival was 12.3 months (95% CI; 6.8 - 24.7). Neither the number of previous lines of treatment nor the prior use of capecitabine showed a negative impact on the efficacy of CMX. CONCLUSIONS CMX is an effective and well-tolerated scheme of mChT and may represent an adequate treatment option for patients with heavily pretreated HER2-negative ABC, including those patients that previously received capecitabine as single agent. These encouraging data warrant further investigation. Citation Format: Cristina Saavedra, María Gion, Alfonso Cortés, Patricia Cortez, Laia Garrigós, José Manuel Pérez-García, Gabriele Antonarelli, Javier Cortés. EFFICACY AND TOLERABILITY OF METRONOMIC CHEMOTHERAPY (mChT) WITH CYCLOPHOSPHAMIDE, METHOTREXATE AND CAPECITABINE (CMX) IN PATIENTS WITH HEAVILY PRETREATED ADVANCED BREAST CANCER. RESULTS FROM A MULTICENTER RETROSPECTIVE STUDY [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 PO5-16-12.

Abstract PO1-06-05: Heterogeneity and prognostic characteristics of HER2-low breast cancer: A retrospective analysis of patients with HER2-negative metastatic breast cancer

Abstract Background: It remains uncertain as to whether low levels of HER2 positivity have any prognostic implications in breast cancer patients, whether HER2 levels can be inconsistent between primary tumors and metastatic lesions in individuals with advanced HER2-negative breast cancer, and how such inconsistencies may impact patient prognosis. Methods: A retrospective analysis of advanced breast cancer patients admitted to our hospital from from January 1st, 2010 to January 1st, 2019 was performed, with all patients that underwent at least one metastatic lesion biopsy being screened. The hormone receptor (HR) and HER2 profiles of both primary and metastatic lesions from these patients were confirmed, and HER2-positive patients (HER2 3+ immunohistochemistry [IHC] results or HER2 2+ IHC results with positive in situ hybridization [ISH] results) were excluded from further analyses. To examine the prevalence of HER2-low status across primary and metastatic cancers, the current study set out to detect inconsistencies between these two tumor compartments with respect to HER2-low status and to examine the prognostic implications of these findings in patients. Results: The median follow-up duration for this study at the cutoff date (December 31, 2021) was 49.3 (45.8-52.8) months. The current study examined 1,031 participants with HER2 and HR status data from both primary and metastatic tumors. The proportion of HER2-low expression was significantly higher in metastatic lesions than primary tumors (34.7% vs 25.7%), with a corresponding drop in the proportion of HER2-zero metastatic lesions (FIGURE 1). In a multivariate analysis, HER-2 upregulation was linked to HR status, which was established as an independent influencing factor, with such upregulation being most common in HR-positive individuals (P= 0.004). With respect to HER2 status of primary lesions, the medianl survival of patients in the HER2-zero was similar to HER2-low patients, regardless of HR status [44.8 months (95% CI 38.2-54.1) vs 41.5 months (95% CI 35.0-48.0)] (P = 0.954)(FIGURE 2A). However, when the HER2 status of metastatic lesions was examined, patients with HER2-low expression had a greater median OS than HER2-zero patients [47.6 months (95% CI 39.6-48.0) vs. 32.2 months (95% CI 24.6-40.0)] (P < 0.001)(FIGURE 2B). The median OS of patients that exhibited HER2 upregulation (zero→low) was longer than that of patients without such upregulation (zero-zero) (55.8 months (95% CI 45.0-66.6) vs. 32.4 months (95% CI 23.8-41.0)) (P < 0.001)(FIGURE 3A). Among HR-positive patients, HER2 upregulation was associated with significantly prolonged OS relative to patients without such upregulation [56.6 months (95% CI 44.6-68.6) vs. 41.7 months (95% CI 31.1-52.3)] (P=0.006)(FIGURE 3B), whereas survival outcomes were similar in these two groups in the HR-negative subgroup [44.8 months (95% CI 25.6-64.0) and 25.3 months (95% CI 20.4-30.3)] (P=0.103)(FIGURE 3C). However, independent of HR status, the median OS of patients who had HER2 downregulation (low→zero) was similar to those without downregulation (low→low)(FIGURE 3 D, E, F). Conclusion: These results support inconsistencies in HER2-low expression status between primary and metastatic lesions, with low HER2 levels in metastatic tumors being associated with improved survival outcomes. HR-positive patients are more likely to exhibit HER2 upregulation within metastatic lesions and experience corresponding prognostic benefits. Keywords: HER2-low, inconsistency, survival, prognosis, advanced breast cancer Citation Format: Huimin Lv, Min Yan, Mengwei Zhang, Limin Niu, Huiai Zeng, Huihui Sun, Shengnan Zhao, Jing Wang. Heterogeneity and prognostic characteristics of HER2-low breast cancer: A retrospective analysis of patients with HER2-negative metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-06-05.

Abstract PO4-15-06: Genomic landscape characterization after exposure to cyclin dependent kinase 4/6 inhibitors: a retrospective multi-institutional consortium analysis

Abstract Background: Limited data are available to determine the best therapeutic strategy for hormone-receptor positive (HR+) HER2 negative (HER2-) advanced breast cancer (ABC) after progression on cyclin dependent kinase 4/6 inhibitors (CDK4/6i). The aim of this study was to characterize the genomic and prognostic profile of patients (pts) that experienced disease progression after first-line therapy with a CDK4/6i. Methods: The study retrospectively analyzed a multi-institutional cohort of 75 patients (pts) with HR+/HER2- ABC after experiencing progression on first-line endocrine therapy (ET) with CDK4/6i and characterized by circulating tumor DNA (ctDNA) next-generation sequencing (Guardant 360). Oncogenic pathways (i.e., RTK, RAS, RAF, MEK, NRF2, ER, WNT, MYC, p53, cell cycle, notch, and PI3K) were defined based on previous research (Sanchez-Vega et al. Cell, 2018). Associations across single nucleotide variations (SNVs), copy number variations (CNVs), and pathway classification were tested by uni- and multivariable logistic regression with respect to a CDK4/6i naïve group comprising 247 patients with HR+/HER2- ABC (control). Prognosis was analyzed through Cox regression for overall survival (OS). Result: Our study cohort included 75 ABC pts who experienced progression after first line CDK4/6i plus ET: 43 pts (57.3%) were treated with ET while 31 (41.3%) with a non-ET- second line therapy. The most common histology was invasive ductal carcinoma (70.6%), 37.3% of pts were negative for progesterone expression and 26.7% had de novo metastatic disease. The PI3K (33.3%), p53 (28%) and ER (25.3%) pathways were the most mutated in the CDK4/6i-treated cohort. Comparing our population with a CDK4/6i naïve cohort (N=247), the multivariate analysis showed a higher prevalence in the study cohort of SNVs mutations in: i) ESR1 gene [Odds ratio (OR) 2.93; p=0.005]; ii) cell-cycle pathway (OR 4.24; p=0.033); iii) ER pathway (OR 2.04; p= 0.034). Moreover, in the study cohort a numerical but not significant increase of RB1 SNVs was also observed. Multivariable analyses of the 43 pts that received ET second line therapy showed a negative prognostic impact with TP53 SNVs in both progression-free survival (PFS) [Hazard ratio (HR) = 3.34; 95% CI: 1.15-9.66, p=0.026] and OS (HR = 3.85; 95% CI: 1.52-9.77, p=0.005). The prognostic role of p53 pathway mutations was also confirmed for both PFS (HR = 4.71, 95% CI: 1.64-13.50; p=0.004) and OS (HR = 3.25; 95% CI: 1.27-8.3; p=0.014). The potential interaction between the prognostic oncogenic pathways and the outcome was investigated according to the treatment strategy (ET vs non-ET). A consistent impact was observed across the above prognostic pathways both for PFS and OS. A numerical difference was observed in terms of PFS in pts with p53 pathway mutations that underwent non-ET second line. Conclusions: The genomic landscape of progressive disease after CDK4/6i exposure is significantly different from the genomic alterations detectable in treatment-naïve pts, which could potential impact future treatment strategies for patients with disease progression after adjuvant CDK4/6i exposure. Our data suggest that the choice of second-line treatment could potentially be guided by the identification of actionable mutation by ctDNA, although further prospective studies are needed to validate the clinical utility of this approach. Citation Format: Letizia Pontolillo, Carolina Reduzzi, Andrew Davis, Lorenzo Gerratana, Arielle Medford, Katherine Clifton, Whitney L. Hensing, Marko Velimirovic, Ami N. Shah, Jeannine Donahue, Laura Munoz Arcos, Charles S. Dai, Jennifer Keenan, Amir Behdad, William Gradishar, Emilio Bria, Cynthia Ma, Aditya Bardia, Massimo Cristofanilli. Genomic landscape characterization after exposure to cyclin dependent kinase 4/6 inhibitors: a retrospective multi-institutional consortium 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 PO4-15-06.

Abstract PO3-19-12: Evaluating the impact of ePRO-based follow-up system (Pink Ribbon Diary) on quality of life and treatment adherence in patients with breast cancer receiving CDK4/6 inhibitors: a single center, randomized controlled study (JPRO-B)

Abstract Background: Treatment-related toxicities (TRT) may decrease patient’s quality of life (QOL) and may result in a decrease of adherence to the therapy. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is), such as palbociclib (PAL) and abemaciclib (ABM) improved patients’ outcomes with estrogen receptor-positive (ER+) HER2 negative (HER2-) advanced breast cancer (ABC), however, majority of patients who undergo CDK4/6i therapy experience ≥ Grade 2 TRTs, such as hematological abnormalities, gastrointestinal disorders or general fatigue. While prompt management of those TRTs is mandatory to prevent patients from discontinuing the therapy, real-time monitoring of TRTs has been warranted. Recently, efforts have been made to monitor symptoms using electronic patient-reported outcome (ePRO) to detect side effects as early as possible and to provide timely support. However, the efficacy of ePRO in daily clinical practice for those receiving CDK4/6is is still unclear. In addition, the researches in the field of ePRO to date have only focused on drugs administered intravenously in hospitals, where patients’ adherence has no clinical importance. Study design and eligibility criteria: This randomized, open-label, controlled phase 2 trial is designed to assess the efficacy of a new proprietary ePRO system, the Pink Ribbon Diary (PRD), compared with placebo (usual care without the ePRO system) in breast cancer patients with ER+HER2-ABC receiving oral CDK4/6i-based therapy aged ≥ 20 years. All eligible patients who complete training on how to use ePRO system are randomly allocated to either arm A using ePRO system or arm B receiving usual care (1:1). Participants in the arm A are required to record medication taken and physical condition every day for 3 months, and report adverse events using PRO-CTCAETM once a week. Patients in the arm B are also asked to answer to questions concerning adverse events using PRO-CTCAETM at monthly hospital visit for 3 months. All participants are asked to respond to the EORTC QLQ-C30 at their monthly visit and a questionnaire survey on adherence before the study and after completion of the study. Participants in the arm A and healthcare providers, will answer the questionnaire about the feeling of using the PRD. Primary endpoint is the change in global health status/QOL (EORTC QLQ-C30) at 3 months from baseline. Secondary endpoints are RDI (relative dose intensity), other domains of EORTC QLQ-C30, number of days missed medication, PDC (proportion of days covered), survey of medication compliance awareness using MMAS-8 (Morisky Medication Adherence Scale), questionnaire on use of PRD, and comparison between two groups of occurrence of adverse events and incidence of missed medication. Study objective: To assess the clinical efficacy of PRD in patients with ER+HER2-ABC undergoing CDK4/6i-based therapy. Statistical methods: For analysis of QOL, the primary endpoint, the differences in global health status/QOL (EORTC QLQ-C30) before and after the study will be compared between the two groups using the t-test. Present accrual and target accrual: The study was approved by institutional review board in December 2022, and is open for enrollment. The target sample size is 70. The study is on-going and 22 patients have been accrued to date. Trial registration numbers: Japan Registry of Clinical Trials (jRCT) jRCT1030220626 (https://jrct.niph.go.jp/re/reports/detail/30182). Citation Format: Rie Ozeki, Hideo Shimizu, Kotaro Iijima, Misato Okazaki, Junichiro Watanabe, Mitsue Saito. Evaluating the impact of ePRO-based follow-up system (Pink Ribbon Diary) on quality of life and treatment adherence in patients with breast cancer receiving CDK4/6 inhibitors: a single center, randomized controlled study (JPRO-B) [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 PO3-19-12.

Abstract RF01-03: PARSIFAL-LONG: Extended follow-up of hormone receptor-positive/HER2-negative advanced breast cancer patients treated with fulvestrant and palbociclib vs. letrozole and palbociclib in the PARSIFAL study

Abstract Background: The Phase 2 PARSIFAL study assessed whether fulvestrant (FUL) or letrozole (LET) was the optimal endocrine partner for the cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) palbociclib (PAL) in patients (pts) with untreated, endocrine-sensitive, hormone receptor-positive (HR+)/HER2-negative (HER2-) advanced breast cancer (ABC) in the first-line setting. This trial failed to demonstrate an improvement in progression-free survival (PFS) of PAL+FUL over PAL+LET (Llombart-Cussac et al. Jama Oncol 2021). Following progression on CDK4/6i-based regimens in the metastatic setting, the EMERALD study (Bardia et al, SABCS 2022 GS3-01) identified early progressions (< 12 months [mo]) as a strong predictor of resistance to subsequent endocrine therapies. Here, we report updated PFS and overall survival (OS) from PARSIFAL, exploring a PFS <12 mo threshold as a prognostic factor for poor outcomes. Methods: This was an observational, international, multicenter study that included pts from the prospective PARSIFAL study, in which pts were randomly assigned (1:1) to receive PAL (oral 125 mg/day, 28-day cycles; 3 weeks on, 1 week off) plus FUL or LET at conventional doses. The primary objective was to extend the assessment of OS of PARSIFAL study with a longer median follow-up. Secondary objectives included extended PFS, other post-progression efficacy data, and the identification of new prognostic and predictive markers. The design had a planned recruitment of at least 388 pts with 195 deaths. The 2-sided stratified log-rank test (α = 0.05) had a 70% power to detect a hazard ratio ≤0.70 in favor of FUL + PAL arm. Results: A total of 389 pts (80.5%) from the PARSIFAL study were included in this analysis, involving 32 of the 47 original sites. Pts signed a new informed consent form according to local regulations. Demographic and baseline disease characteristics were similar between the PARSIFAL-LONG and the overall PARISFAL intention-to-treat populations. At the time of analysis, after a median follow up of 5.0 years (range, 0.1-7.3), 241 and 213 events were reported for PFS and OS, respectively. No differences in efficacy were observed between treatment arms whether for PFS (hazard ratio, 1.0, p=0.985) or OS (hazard ratio, 0.94, p=0.635). In accordance with the protocol for PARSIFAL-LONG, both arms were combined for subsequent analysis. The median PFS (mPFS) for the first-line PAL-based regimen population was 33.2 mo (95%CI, 27.7-39.5), with a median OS (mOS) of 65.4 mo (95%CI, 57.8-72.0). A total of 86 pts (22.1% of the population) had a mPFS time <12 mo (early progressors). mOS and mPFS for this early progressor subgroup were 24.0 mo (95%CI, 17.3-30.1) and 7.0 mo (95%CI, 5.6-8.3), respectively, and only 11 pts (12.8%) were still alive at the time of analysis. The remaining 303 pts (77.9%) were progression-free on PAL-based regimens at 12 mo (PFS≥12). The number of events for PFS and OS at this time were 165 (54.5%) and 138 (45.5%), respectively. mOS from randomization for the PFS≥12 subgroup was 81.5 mo (95%CI, 70.2-not achieved) and the mPFS was 49.8 mo (95%CI, 40.9-59.8). Following progression on PAL-based regimens, the PFS≥12 criteria was a strong predictor for mOS, with 27.0 vs 18.0 mo (hazard ratio, 0.67, 95%CI, 0.51-0.90, p=0.007) for PFS≥12 and early progressors, respectively. These differences may increase in the future, as 54.5% of pts with PFS≥12 are still alive compared to 12.8% of pts with an early progression. Conclusions: Extended follow-up analysis from PARSIFAL study confirms no major differences between LET or FUL when combined with PAL. mPFS and mOS results are consistent with those reported in other first-line trials involving different CDK4/6i. Progression within the first year of first-line CDK4/6i-based regimen for HR+/HER2- ABC pts may be prognostic of less favorable outcomes. Citation Format: Antonio Llombart-Cussac, José Manuel Pérez-García, Meritxell Bellet- Ezquerra, Florence Dalenc, Miguel Gil-Gil, Manuel Ruíz - Borrego, Joaquín Gavilá, Peter Schmid, Pilar Zamora, Duncan Wheatley, Eduardo Martínez-de Dueñas, Kepa Amillano, Antonio Antón, Paul Cottu, Gemma Viñas, Thierry Petit, Petra Tesarová, Juan Cueva, Marco Colleoni, Maria Purificación Martínez del Prado, Raquel Andrés, Marta Díaz Cabo, Susana Victorino, Miguel Sampayo-Cordero, Javier Cortés. PARSIFAL-LONG: Extended follow-up of hormone receptor-positive/HER2-negative advanced breast cancer patients treated with fulvestrant and palbociclib vs. letrozole and palbociclib in the PARSIFAL study [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 RF01-03.

Abstract PO5-13-09: Clinical usage of a CLIA accredited protein/phosphoprotein assay for breast cancer: Primary usage cases and significant findings in the HER2- setting

Abstract Background: A CLIA-accredited assay that measures the expression and/or activation levels of 32 clinically actionable protein and phosphoprotein analytes in clinical tissue biopsy samples was launched in January 2021. The current intended use population for the assay is for patients with late/advanced stage breast cancer wherein molecular profiling is being utilized for clinical decision making. Assessment of physician ordering practices, clinical use dynamics as well as protein/phosphoprotein actionability frequencies were determined for clinically actionable biomarkers. Methods: A total of 219 cases have been processed to date, with mean turn-around time of 16.4 days. The assay utilizes laser capture microdissection to enrich tumor epithelium from FFPE core needle biopsy and resection material coupled to reverse phase protein array. Results for each of the 32 analytes are generated by comparing each patient to a reference population and reported both as a relative quartile and as a continuous percentile compared to the reference population (0-100%). For the purposes of this analysis, significant expression/activation cutpoints were set at the 40th percentile threshold. Results: To date, clinicians have requested the test most frequently to identify potential therapeutic targets in patients with HER2-negative disease (84% of all tested patients, 36% were triple-negative). Despite the majority of cases being HER2-negative, we found that phosphorylated (p) HER2 (Y1248) was found to be activated in 17% of all HER2-negative cases and 19% of triple negative breast cancer cases (TNBC). pHER2 was concurrently activated with pHER3 (Y1289) in 15% (12/80) of TNBC cases and 13% (24/187) of all HER2-negative cases. pHER2 presented concurrently with pEGFR (Y1068 or T654) in 14% (11/80) of TNBC cases and 14% (26/187) of all HER2- cases. Expression of TROP2 was observed in 16% of HER2-negative patients including 11% of ER+/HER2- and 23% of TNBC cancers. MHCII expression, a recently described candidate predictive biomarker of anti-PDL1/PD1 response in TNBC, was found to be expressed in 29% of TNBC patients. Activation frequencies of other clinically relevant drug targets in HER2-negative disease such AKT and mTOR pathway activation was also assessed. We found that pAKT (S473 and/or T308) was activated in 7% of ER+/HER2- cases and 14% of TNBC. Concurrent with AKT activation, at least one additional member of the AKT-mTOR pathway (mTORC1 (S2448), 4E-BP1 (S65), p70S6K (T389), or S6RP (S235/S236) was co-activated in 50% and 45% of ER+/HER2- and TNBC cancers respectively. Conclusion: This initial assessment of a CLIA LDT protein/phosphoprotein assay utilized to date found that physicians most often order the test for advanced stage HER2-negative breast cancer. Activation/expression of clinically important protein drug targets with potential actionability in HER2-negative disease was observed in a significant number of cases and demonstrates the power of the assay to elucidate actionable targets for potential therapeutic intervention. Citation Format: Claudius Mueller, Brian Corgiat, Emanuel Petricoin, Kayla Sparks, Joyce O'Shaughnessy, Chelsea Gawryletz, Matthew Schwartz, Justin Davis. Clinical usage of a CLIA accredited protein/phosphoprotein assay for breast cancer: Primary usage cases and significant findings in the HER2- setting [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 PO5-13-09.