Factor Receptor 2-negative Breast Cancer Research Articles

Adjuvant treatment strategy evolution and risk stratification for hormone receptor-positive, human epidermal growth factor receptor-2 negative early breast cancer in China.

Patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2 negative (HER2-) early breast cancer (EBC) with high-risk clinicopathological features face an increased risk of recurrence. This study explored the evolving treatment landscape and clinical outcomes in patients with EBC using a nationwide database. The study cohort comprised HR+/HER2-, stages 1-3, patients with EBC who underwent surgery and received adjuvant endocrine therapy (AET) from January 2013 to March 2021. High-risk patients were defined by ≥4 positive axillary lymph nodes, or 1-3 positive lymph node(s) with at least one high-risk feature (histologic grade 3, tumor size ≥5cm, or Ki-67 ≥20%). A low-risk cohort included patients not meeting the criteria. Survival analysis was conducted with a cutoff of September 2021. The study included 4088 eligible patients (1310 high-risk patients and 2778 low-risk patients). High-risk patients were more likely to receive adjuvant chemotherapy and radiotherapy compared to low-risk patients. From 2013 to 2021, an increasing proportion of patients received aromatase inhibitors and ovarian function suppression as part of their AET. The 2-, 5-, and 7-year invasive disease-free survival for high-risk cohort were 90.67%, 75.26%, and 57.10%, respectively, these rates were notably higher for low-risk cohort at 97.14%, 89.85%, and 84.83%. High-risk patients demonstrated a higher risk of recurrence or death compared with low-risk patients (hazard ratio, 2.38; 95% CI, 1.82-3.12). In the setting of standard or even intensive AET, patients with EBC with high-risk features still present high recurrence risk, highlighting the urgent need for innovative adjuvant treatment strategies.

Prognostic and Predictive Significance of HER2-low Expression in Metastatic Hormone Receptor Positive Breast Cancer Patients Receiving CDK4-6 Inhibitor Therapy

Objective: This study aimed to analyze the predictive and prognostic value of HER2-low expression in hormone receptor (HR) positive human epidermal growth factor receptor-2 (HER2) negative metastatic breast cancer patients receiving cyclin-dependent kinase-4/6 inhibitor (CDK4/6i) therapy. Methods: This retrospective study included patients who received CDK4/6i plus endocrine therapy (ET). The pathological and clinical characteristics and survival times of the patients were compared and analyzed. Results: Our study included 122 patients. There were HER2-zero 88(72%) and HER2-low 34 (28%) patients. The median progression free survival (mPFS) of all patients who received CDK4/6i+ET was 21 (95% confidence interval (CI),18.5–23.5) months, while mPFS was not reached in the HER2-zero group, and mPFS in the HER2-low group was 12 (95%CI, 6.8–17.1) months (p=0.001). The mPFS was shorter in patients with primary endocrine resistance (6 vs. 21 months, p=0.001). There was a change in the HER2-low status of 26(45%) patients with recurrence compared to the first biopsy. In the HER2-zero and HER2-low groups, 22(25%) and 24(71%) patients, respectively, progressed with CDK4/6i+ET (p=0.001). Estrogen receptor (ER) levels less than and greater than 50% resulted different mPFS (6 and 21 months, respectively) (p=0.025). Median PFS differed based on CDK4/6i+ET combination, treatment line, and best treatment response (all p=0.001). In multivariate analysis, HER2 status(p=0.018), chemotherapy status(p=0.006), best response status with CDK4/6i (p=0.001) for PFS, and best response status with CDK4/6i therapy (p=0.007) for OS were significant. Conclusions: In patients with HR+HER- metastatic breast cancer receiving CDK4/6i therapy, the duration of mPFS was lower in the HER2-low group than that in the HER2-zero group. HER2-low expression is a predictive biomarker of response to CDK4/6 inhibitor therapy.

Final results of RIGHT Choice: Ribociclib plus endocrine therapy vs combination chemotherapy in premenopausal women with clinically aggressive HR+/HER2- advanced breast cancer.

A head-to-head comparison of efficacy between a cyclin-dependent kinase 4/6 inhibitor plus endocrine therapy (ET) versus combination chemotherapy (CT) has never been reported in patients with clinically aggressive hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). In this open-label, multi-center, randomized phase 2 trial, pre/perimenopausal women with clinically aggressive HR+/HER2- ABC were randomized 1:1 to first-line ribociclib (600 mg daily; 3-weeks-on, 1-week-off) plus letrozole/anastrozole and goserelin or investigator's choice of combination CT (docetaxel plus capecitabine, paclitaxel plus gemcitabine, or capecitabine plus vinorelbine). The primary endpoint was progression-free survival (PFS). Among 222 patients randomized to ribociclib plus ET (n=112) or combination CT (n=110), 150 (67.6%) had symptomatic visceral metastases, 41 (18.5%) had rapid disease progression per investigator's judgment, and 31 (14.0%) had symptomatic non-visceral disease. Overall, 106 (47.7%) patients had investigator-assessed visceral crisis. Median follow-up time was 37.0 months. At data cutoff, 31.3% (ribociclib arm) and 15.5% (CT arm) of patients had completed study treatment and transitioned to post-trial access. The median PFS was 21.8 months (ribociclib plus ET; 95% CI, 17.4-26.7 months) and 12.8 months (combination CT; 95% CI, 10.1-18.4 months); hazard ratio [HR], 0.61; 95% CI, 0.43-0.87; P=.003. The overall response rates and the median time to response in the ribociclib versus CT arms, respectively, were 66.1% and 61.8% and 4.9 months and 3.2 months (HR, 0.76; 95% CI, 0.55-1.06). Lower rates of symptomatic adverse events were observed in the ribociclib versus CT arm. First-line ribociclib plus ET showed a significant PFS benefit, similar response rates, and better tolerability over combination CT in patients with clinically aggressive HR+/HER2- ABC.

CDK4/6 inhibitors: The Devil is in the Detail.

Update on the most recent clinical evidence on CDK4/6 inhibitors (CDK4/6i) in the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor (HER)2-negative breast cancer. Over the past decade, CDK4/6i have become part of the standard of care treatment of patients with both metastatic and high-risk early HR + /HER2- breast cancers. The three available CDK4/6i (palbociclib, ribociclib and abemaciclib) have been extensively studied in combination with endocrine therapy (ET) in metastatic breast cancer (mBC) with consistent prolongation of progression free survival; however, ribociclib has emerged as the preferred first line agent in mBC given overall survival benefit over endocrine monotherapy. In early BC, abemaciclib is the only currently approved agent while ribociclib has early positive clinical trial data. Toxicities and financial burden limit the use of CDK4/6i in all patients and resource-poor settings, and optimal timing of their use in mBC remains unclear. There is considerable evidence for the use of CDK4/6i in metastatic and early HR + /HER2- breast cancer, but knowledge gaps remain, and further research is necessary to better define their optimal use.

Statin use and risks of breast cancer recurrence and mortality.

Preclinical evidence suggests improved breast cancer survival associated with statin use, but findings from observational studies are conflicting and remain inconclusive. The objective of this study was to assess the association between statin use after cancer diagnosis and cancer outcomes among breast cancer patients. In this retrospective cohort study, 38,858 women aged ≥66 years who were diagnosed with localized and regional stage breast cancer from 2008 through 2017 were identified from the linked Surveillance, Epidemiology, and End Results Medicare database. Statin use was ascertained from Medicare Part D pharmacy claims data. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between post-diagnosis statin use and risks of breast cancer recurrence and breast cancer-specific mortality. Over a median follow-up of 2.9 years for recurrence and 3.7 years for mortality, 1446 women experienced a recurrence, and 2215 died from breast cancer. The mean duration of post-diagnosis statin use was 2.2 years. Statin use post-diagnosis was not associated with recurrence risk (HR, 1.05; 95% CI, 0.91-1.21), but was associated with a reduced risk of cancer-specific mortality (HR, 0.85; 95% CI, 0.75-0.96). The reduction was more pronounced in women with hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer (HR, 0.71; 95% CI, 0.57-0.88). These findings suggest that post-diagnosis statin use is associated with improved cancer-specific survival in women with breast cancer and should be confirmed in randomized trials of statin therapy in breast cancer patients.

Abstract PO2-05-02: Real-world experience of patients receiving treatment for hormone receptor-positive/human epidermal growth factor receptor-2 negative metastatic breast cancer: A global analysis of symptoms and side effects

Abstract Background: Advances in treatment for patients (pts) with hormone receptor-positive (HR+)/human epidermal growth factor receptor-2 negative (HER2–) metastatic breast cancer (mBC) have improved overall survival, but treatment resistance is common and median survival remains only a few years. These pts usually need chronic therapy and often experience symptoms and side effects. There is limited knowledge on pts’ experiences outside the clinical trial setting, largely because this information is not routinely reported. This analysis leverages a unique database of physician- and pt-reported data to describe symptoms and side effects among a real-world, geographically diverse population of pts receiving treatment for HR+/HER2– mBC. Methods: This retrospective cohort study used Adelphi Disease Specific Programme Real World Data, comprising validated, linked pt and physician questionnaire data from the US, France, Germany, Italy, Spain, and UK. Eligible pts were ≥18 y, currently receiving treatment for advanced BC and not enrolled in a clinical trial. Data were collected between August 2022 and February 2023. Physician surveys provided data on individual pt demographics and disease characteristics, comorbidities, treatment history, and treatment (including adherence). Physicians also reported presence or absence of symptoms and side effects after treatment initiation for each pt they considered. A subset of pts completed one-time validated quality of life (QOL) instruments, including the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) and EORTC QLQ-breast (BR23). Results: Data from 1578 pts receiving treatment for HR+/HER2– mBC were analyzed. Mean age was 65-y, 91% were white, 71% had de novo mBC, and 82% had ECOG performance status 0-1 at the start of current treatment. Across all lines of therapy, 71% of pts were receiving endocrine-based therapy, 16% were receiving chemotherapy only, and 13% were receiving other therapies; 40% of all pts were receiving second or later lines of any systemic therapy (2L+). Among all pts, the most common physician-reported symptoms and side effects (in ≥10% of pts) were bone pain (30%), change in appetite (13%), weight loss (12%), neutropenia (11%), and joint/muscle pain (11%). Pts on 2L+ therapy experienced a greater frequency of symptoms and side effects than those on first-line therapy (Table). Of 220 pts who completed QOL questionnaires, the most commonly reported symptoms and side effects (in ≥70% of pts) were feeling tired (87%), worry about future health (80%), general worrying (79%), needing to rest during the day (74%), feeling weak (74%), having trouble doing strenuous activity (71%), and trouble taking a long walk (71%). These were common irrespective of pt age, disease state (recurrent vs de novo), current treatment regimen, and line of therapy. Conclusions: This real-world analysis shows that both physicians and pts identified substantial symptoms and side effects during treatment. These were pervasive across the population and more common in those receiving 2L+ therapy, although it remains unclear which were due to treatment or disease. Thus, it is important to continue to develop treatments and supportive care to improve both clinical outcomes and pt QOL. Citation Format: MK Rehnquist, Ann Partridge, Annabel Lambert, Allison Kurian, Natalia Sadetsky, Emily Freeman, Lisa Carey. Real-world experience of patients receiving treatment for hormone receptor-positive/human epidermal growth factor receptor-2 negative metastatic breast cancer: A global analysis of symptoms and side effects [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 PO2-05-02.

Abstract PO2-05-03: Costs associated with adverse events in patients receiving treatment for hormone receptor positive/human epidermal growth factor receptor-2 negative metastatic breast cancer

Abstract Background:Adverse event (AE)-related health care resource utilization (HCRU) and costs are an important component in understanding the economic burden associated with managing patients (pts) with cancer and can inform treatment decision-making and access for pts, providers, and payers. At present, there are little data on AE-related HCRU and costs among pts receiving late-line treatment for hormone receptor positive (HR+)/human epidermal growth factor receptor-2 negative (HER2–) metastatic breast cancer (mBC). As such, the objective of this analysis was to describe the AE-related HCRU and costs among pts with HR+/HER2– mBC receiving chemotherapy (CT) who have received prior CT and endocrine-based therapies (ET). Methods: This retrospective study included pts who had at least 1 prior ET, had completed at least 2 CTs, had initiated their third (or greater) CT (post-ET) in the metastatic setting between Jan 2016 and Mar 2022, and were included in the Optum Research Database. The start date for the current line of CT was the index date. Pts were followed until disenrollment from health plan, study end date (Jun 2022), or death. AEs included in this study were based on clinical impact; these AEs were then organized into categories. AE-related HCRU and costs were reported as per pt per month (PPPM) and included outpatient visits, office visits, emergency room visits, inpatient stays, other medical costs (eg, laboratory/ancillary costs), and pharmacy costs. Costs were adjusted to 2021 US dollars using the Consumer Price Index. Results: A total of 769 pts were included with a mean age of 64 y (standard deviation: 13 y) and baseline National Cancer Institute comorbidity score of 0 (44%) or 1–2 (39%). 51% were commercially insured. A total of 715 (93%) pts had ≥1 AE during the follow-up period; the mean total PPPM cost associated with AEs was $7421 (Table 1) and the majority of costs were driven by ambulatory visits (office and outpatient visits: $3846 PPPM; Table 1) and inpatient stays ($3042 PPPM; Table 1). Among pts who experienced AEs, AEs that were associated with the highest mean total PPPM costs included infections, hepatoxicity, gastrointestinal toxicity and renal failure events. The costs associated with infections and renal failures were predominantly driven by inpatient stay costs ($5540 and $3298 PPPM, respectively; Table 1). Conclusions: This real-world analysis suggests that there is high prevalence of AEs associated with CTs in late-line (≥3 CTs) HR+/HER2– mBC, which may lead to a substantial economic burden and suboptimal treatment outcomes. Newer, effective therapies with manageable AE profiles may offer a better benefit-to-risk profile and improve outcomes compared with chemotherapies. Citation Format: Anju Shah, Amy Sainski-Nguyen, Kristin Moore, MK Rehnquist, Rita Nanda. Costs associated with adverse events in patients receiving treatment for hormone receptor positive/human epidermal growth factor receptor-2 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 PO2-05-03.

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 PS06-02: Circulating tumor DNA (ctDNA) monitoring of estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) high risk breast cancer during adjuvant endocrine therapy

Abstract Background: ctDNA monitoring during adjuvant endocrine therapy provides an opportunity to detect molecular relapse before clinically apparent recurrence. The rate and dynamics of ctDNA positivity and the frequency of asymptomatic but imaging detectable metastatic disease at the time of ctDNA detection remain unknown in high-risk ER+/HER2- breast cancers. We present results of ctDNA positivity rates in 508 and imaging results in ctDNA+ patients from a prospective, multicenter, randomized ctDNA surveillance and intervention trial, DARE (NCT04567420). Patients and methods: Patients receiving adjuvant endocrine therapy for > 6 months but < 7 years, with either (i) risk of recurrence > 15% calculated by PREDICT, RSPC, or CTS5, or (ii) > 4 positive axillary lymph nodes, or (iii) primary tumor > 5 cm, or (iv) 1-3 positive nodes with grade 3 histology, or > 3 cm tumor, or Oncotype Dx RS > 26, MammaPrint high risk, EndoPredict > 4, Prosigna score > 60 were eligible for ctDNA surveillance with the SignateraTM assay (Natera Inc.) every 4-6 months during routine follow up visits. ctDNA+ patients underwent systemic staging with imaging and randomized to continuation of adjuvant therapy versus switching to fulvestrant plus palbociclib if there was no evidence of distant metastatic disease. The primary objectives are to assess the incidence of ctDNA positivity in the surveillance phase and to assess if palbociclib plus fulvestrant improves relapse-free survival in 100 randomized patients. This is an updated, protocol-driven interim report to determine if screening eligibility criteria needs to be revised to keep randomization rate > 15% of the screened population. Results: The trial is open at 15 sites and enrolled 508 patients between May 2021 and June 2023; 882 plasma ctDNA tests were performed successfully in 364 patients (72%). The most common reason for failure to generate a personalized ctDNA assay was insufficient tissue submitted, 78% of failed tests were due to preanalytical failure, the technical failure rate was 22%. Thirty patients, 8.2% of those with results available, had >1 positive ctDNA result, the overall positivity rate across all assays was 3.4% (n=30/882). Patient characteristics are shown in the table (not all patients have complete data), 47% of ctDNA+ cases had >4 + lymph nodes. ctDNA positivity rate in the first test was 3.8%, and anytime ctDNA detection rate among those with serial testing was 7.2%. Among ctDNA+ patients, the first ctDNA draw was positive in 23 of 30 cases (77%) with 36.5 months median time (range 6-102 months) from surgery to testing. Using 12 months interval brackets from surgery to 1st ctDNA positivity, annual detection rates were 2,3% (1/44), 8.5% (7/82), 10.8% (9/83), 7.5% (4/53), 13,2% (5/38), and 6.2% (4/64), at 1st, 2nd, 3rd, 4th and > 5th year post-surgery, respectively, due to small sample sizes, 95% confidence broadly overlap. Five ctDNA+ patients (16.7%) had asymptomatic, imaging-detectable metastatic disease, 22 ctDNA+ patients were randomized, the goal is to accrue a total of 100 patients. Conclusions: ctDNA surveillance of ER+/HER2- breast cancers during adjuvant endocrine therapy indicate 8.3% detection rate at patient level and 3.4% at assay level. Serial screening increases detection rates as 23% of positive ctDNA tests occurred after an initial negative result. 83% of ctDNA+ patients had true molecular relapse without imaging detectable metastatic disease. Eligibility for screening on the trial is now restricted to patients with >4 + lymph nodes, randomization is open for any patients who are ctDNA+ including routine commercial screening. Table of patient characteristics with ctDNA result (n=364) ctDNA+ (n=30) Age < 50 29% 23% Age >50 71% 77% PR + 78% 73% PR - 7% 17% HER2 IHC negative 79% 77% Grade 1 8% 7% Grade 2 53% 50% Grade 3 29% 37% T 1 19% 17% T2 43% 43% T3 27% 27% T4 2% 7% 0 +nodes 12% 12% 1 +node 24% 10% 2 +nodes 15% 13% 3 +nodes 8% 13% >4 +nodes 0 47% Citation Format: Lajos Pusztai, Ekaterina Kalashnikova, Evthokia Hobbs, Ursa Brown-Glaberman, Monica Mita, Paula Klein, Fengting Yan, Sima Ehsani, Wajeeha Razaq, Alison Stopeck, Manali Bhave, Michelle Loch, Sagar Sardesai, Evanthia Roussos Torres, Mark Burkard, Femi Okubanjo, Eric Gauthier, Angel Rodriguez, Minetta Liu, Peter Kabos. Circulating tumor DNA (ctDNA) monitoring of estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) high risk breast cancer during adjuvant endocrine 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 PS06-02.

Abstract PO3-14-01: Heterogeneity of tumor immune microenvironment to predict everolimus efficacy in premenopausal women with hormone receptor-positive/human epidermal growth factor receptor 2-negative adavanced breast cancer

Abstract Objective Everolimus (EVE), a mammalian target of rapamycin (mTOR) inhibitor, has been shown to prolong survival of patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-), advanced breast cancer (ABC) with endocrine resistance. Preclinical studies have suggested that mTOR is closely associated with the tumor immune microenvironment (TME). We aimed to explore the tumor heterogeneity of TME between patients with different response to everolimus (EVE), and identify potential markers to predict efficacy of EVE in premenopausal patients with HR+/HER2−, advanced breast cancer (ABC) suffering endocrine resistance. Methods Patients were divided into two groups according to the best response to EVE: the responsive subgroup (RS) and the non-responsive subgroup (NRS). Postoperative tumor tissue from patients who received EVE was collected for whole exome sequencing. Transcript abundance of 126 distinct tumor regions of interest (ROIs) were quantitated using digital spatial profiling, including 42 tumor cell zones (TCZs), 42 immune cell zones (ICZs), and 42 stroma cell zones (SCZs). Based on investigation in multiple discrete areas, differences in cell components, function and pathway, gene expression and immune cell infiltration between RS and NRS were investigated. Results Totally, 93 differentially expressed genes (DEGs) were identified in the ICZs, 174 DEGs in the TCZs, and 197 DEGs in the SCZs, using p< 0.05 and |log2FC >1| as the screening criterion. Among all the subgroup analyses on different ROIs, the statistical significance of PIP gene was the highest (ICZs: p=2.6E-12, TCZs: p=1.25E-20, SCZs: p=2.0E-18) in the comparison of RS and NRS. Moreover, we found that PIP was highly expressed in NRS and patients with a progression-free survival < 1 year. The receptor-legend analysis showed that, the intra-and inter-cellular communication in RS was mainly mediated by interaction between CCL-CCR family, while NRS mainly by COL family complex. Comparing all cell components extracted from each ROI, no statistical differences were found between RS and NRS, only a statistical trend in the SCZs (p=0.098). Further cell classification analysis showed fibroblasts highest in TCZs and SCZs, macrophages in ICZs. Compared to NRS, in TCZs, fibroblasts were significantly increased (p=0.01), and plasma cells (p=0.02) and neutrophils (p=0.03) were decreased in RS. In SCZs, the downregulated fibroblasts (p=0.04) and enhanced plasma cells (p=0.01) were observed in NRS. In ICZs, pDCs (p=0.048) and neutrophils (p=0.006) were significantly elevated in NRS compared with RS. Conclusion The utility of digital spatial gene expression profiling might provide some references to predict the efficacy of EVE in premenopausal patients with HR+/HER2- ABC with endocrine resistance. Citation Format: Yujing Tan, Fei Ma, Jiayu Wang, Pin Zhang, Binghe Xu, Liyan Xue, Ying Fan. Heterogeneity of tumor immune microenvironment to predict everolimus efficacy in premenopausal women with hormone receptor-positive/human epidermal growth factor receptor 2-negative adavanced 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 PO3-14-01.

Abstract PS12-09: Capivasertib plus cyclin-dependent kinase 4/6 inhibitor and fulvestrant in hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: updated Phase 1b analysis from CAPItello-292

Abstract Background AKT pathway activation is implicated in endocrine therapy (ET) and cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) resistance in patients (pts) with HR+/HER2– advanced breast cancer (ABC). In CAPItello-291, capivasertib (C, a potent inhibitor of all 3 AKT isoforms) + fulvestrant (F) significantly improved PFS versus placebo F in pts with aromatase inhibitor-resistant HR+/HER2– ABC. Simultaneous inhibition of AKT and CDK4/6 pathways may delay CDK4/6i resistance or re-sensitize tumors to ET plus CDK4/6i, leading to improved clinical outcomes. CAPItello-292 (NCT04862663) is an ongoing Phase 1b/3 study examining the efficacy and safety of C + CDK4/6i (palbociclib [P], ribociclib [R]) + F in HR+/HER2– ABC. The recommended Phase 3 dose (RP3D) of C+P+F has been determined (C 400 mg BID, 4 days on/3 days off, P 125 mg, F 500 mg). Here we report ongoing Phase 1b data on C+P+F and C+R+F. Methods: Phase 1b of CAPItello-292 uses a keyboard design (mTPI-2) with the following planned doses: C 200 mg, 320 mg, 400 mg; P 75 mg, 100 mg, 125 mg; R 200 mg, 400 mg, 600 mg; F is fixed at 500 mg every 28 days + loading dose on cycle 1 day 15. Starting doses for C+P+F were C 320 mg BID, 4 days on/3 days off, P 125 mg QD) for 21 days of each 28-day cycle. Starting doses for C+R+F (ongoing) are C 400 mg BID, 4 days on/3 days off, R 400 mg QD for 21 days of each 28-day cycle. Eligible pts have HR+/HER2− ABC and ≥1 prior ET in the advanced setting or disease recurrence within 12 months of completing (neo)adjuvant ET (HER2− defined as immunohistochemistry [IHC] 0, or 1-positive or IHC2-positive/in situ hybridization-negative). Prior use of CDK4/6i, selective estrogen receptor degraders, and chemotherapy is permitted in Phase 1b. Phase 1b primary objectives: assess safety/tolerability; confirm RP3D. Objective response and clinical benefit rates (24 weeks; RECIST v1.1) were also assessed. Results: At data cut-off (Apr 21, 2023), 40 pts (median age: 58.5 years [range 38–82]) who were heavily pre-treated (as follows: 82.5% [33/40] prior CDK4/6i; 47.5% [19/40] prior F; 70.0% [28/40] prior chemotherapy [median 1.5 lines]) were treated with C+P+F. No new dose-limiting toxicities (DLTs) were observed since determination of RP3D. The most frequent adverse events (AEs) occurring in >40% of pts were diarrhea (70.0% [28/40]; 1/28 grade [G] ≥3), neutropenia (55.0% [22/40]; 20/22 G≥3), fatigue, and nausea (both 42.5% [17/40]; all G1/2). Hyperglycemia occurred in 17.5% (7/40) pts (1/7 G3). No treatment-related deaths or new safety risks were identified. At the RP3D, the median (range) duration of exposure to C was 8.6 months (1.7–14.1); 5/8 pts with measurable disease at baseline had confirmed partial response (objective response rate: 62.5%, 95% confidence interval [CI] 24.5–91.5). Two additional pts had stable disease ≥7 weeks as a best objective response. At 24 weeks, the clinical benefit rate was 53.8% (7/13; 95% CI 25.1–80.8).Enrollment into C+R+F is ongoing: as of May 05, 2023, 8 pts had been dosed (6/8 pts had completed cycle 1). Based on clinical and safety review, the safety review committee has endorsed dose escalation to the highest dose level of R; no DLTs have been reported so far, although data are preliminary.Preliminary ctDNA analyses of pts treated with C+P/R+F will be presented. Conclusions: C+P+F was tolerable in heavily pre-treated pts with HR+/HER2– ABC at all dose levels; AEs were as expected, given the known safety profile of the individual treatments. Evidence of clinical activity has been observed in pts treated with the RP3D; data collection is ongoing. Preliminary safety analysis of C+R+F suggests no critical tolerability concerns; more pts and longer follow-up is required to characterize the safety of the combination. Updated data will be presented. Funding: AstraZeneca Capivasertib was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited) Citation Format: Erika Hamilton, Patrick Neven, Barbara Pistilli, Muralidhar Beeram, Virginia Borges, Mario Campone, José Luiz Miranda Guimarães, Theodoros Foukakis, Annette Raskov Kodahl, Peter Lau, Elgene Lim, Iwona Ługowska, Greg Rychlik, Christopher Gresty, Claire Miller, Roberto Sommavilla, Dhivya Sudhan, Hope Rugo. Capivasertib plus cyclin-dependent kinase 4/6 inhibitor and fulvestrant in hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: updated Phase 1b analysis from CAPItello-292 [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 PS12-09.

Abstract PO3-04-09: Prognoses of Patients with Hormone Receptor-Positive andHuman Epidermal Growth Factor Receptor 2-Negative BreastCancer Receiving Neoadjuvant Chemotherapy before Surgery:A Retrospective Analysis

Abstract Abstract: Purpose: To evaluate the clinical characteristics, pathological response, and prognostic significance of hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2−) breast cancer (BC) after neoadjuvant chemotherapy (NAC). Methods: A survival analysis was performed to detect the factors related to recurrence and death in 3070 consecutive patients with HR+/HER2− BC who received NAC from 2011 to 2022. All patients received current “standard of care” following neoadjuvant therapy based on guidelines, including surgery and adjuvant endocrine therapy. HER2-low was defined as immunohistochemistry (IHC) 1+ or IHC 2+ and fluorescence in-situ hybridization-negative. Results: The complete pathological response (pCR) (ypT0/is ypN0) rate was 14.5%. The clinical tumor size (cT), ER scores, PR status, and Ki67 levels were related to pCR. The 5-year disease-free survival (DFS) and overall survival (OS) rates were 82.6% and 90.4%, respectively. PR, Ki67 levels, and postmastectomy radiotherapy were independent factors for DFS and OS, and the extranodal extension (ENE) correlated with DFS. However, pCR and HER2 status were related to OS. The pCR rate in PR negativity BC was significantly higher than that in PR positivity BC (21.1% vs. 12.2%, p = 0.000), but PR negativity BC had a poorer prognosis than PR positivity BC. HER2-low BC showed high ER scores (over 50%), PR positivity, large ypT, ENE, and lymphovascular invasion but a lower pCR rate than HER2-zero BC. Patients with HER2-low BC had shorter OS than those with HER2-zero BC (p = 0.037). However, there was no difference in DFS. Conclusions: Depending on PR status and HER2 status, patients with ER positivity and HER2 negativity exhibit different pathologic complete response rates to neoadjuvant chemotherapy and long-term outcomes, especially patients with PR negativity or HER2-low status. Keywords: breast cancer; neoadjuvant chemotherapy; survival; prognosis; PR; HER2-low Citation Format: Jin Zhang, Yan Liu, Shichao Zhang. Prognoses of Patients with Hormone Receptor-Positive andHuman Epidermal Growth Factor Receptor 2-Negative BreastCancer Receiving Neoadjuvant Chemotherapy before Surgery:A Retrospective 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 PO3-04-09.

Abstract PO1-13-01: Safety profiles of Chinese breast cancer patients who received abemaciclib in MONARCH plus and monarchE study

Abstract Aim: Abemaciclib demonstrated efficacy with tolerable safety profile in Chinese patients (CN pts) with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC) and high-risk early breast cancer (EBC). The overall safety profile of abemaciclib in Chinese ABC and EBC pts was consistent with overall population in the MONARCH plus and monarchE studies. To better understand the safety of abemaciclib in CN pts, beyond the previously reported most frequent adverse events (AEs), we report a comprehensive summary of other selected AEs in CN pts in the two trials. Methods: Study designs of MONARCH plus (NCT02763566) and monarchE (NCT03155997) studies were reported previously. To report detailed characteristics of a selected AE profile, including alanine aminotransferase increased, aspartate aminotransferase increased, blood creatinine increased, fatigue, nausea, and vomiting, data were pooled across all CN pts from these two phase 3 studies. The safety population was defined as all randomized patients receiving at least 1 dose of Abemaciclib or endocrine therapy. Data cutoff time is May 18, 2020 and July 1, 2022, respectively. Results: Among 6052 participants in the overall safety population, 875 CN pts (14.5%) were included (512/3100 abemaciclib, 363/2952 placebo). CN pts treated with abemaciclib indicated consistent AE profiles in combination with different endocrine therapies (aromatase inhibitors or Fulvestrant). Detailed characteristics of selected AEs are summarized in table. No deaths due to the selected AEs were reported in CN pts. Conclusion: The selected AEs of abemaciclib group were in low severity with limited grade 3-4 events. Those AEs were tolerable and generally manageable in CN pts in the MONARCH plus and monarchE trials. Citation Format: Zhimin Shao, Qingyuan Zhang, Quchang Ouyang, Qiang Liu, Jifeng Feng, Hui-Ping Li, Xiaojia Wang, Ning Liao, Liu Yang, Qinyi Zhu, Chenxi Qian, Zefei Jiang. Safety profiles of Chinese breast cancer patients who received abemaciclib in MONARCH plus and monarchE 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 PO1-13-01.

Abstract PO1-14-01: Clonal Architecture of circulating tumor DNA predicts Early Progression on Tamoxifen With or Without Palbociclib in Hormone Receptor-Positive Advanced Breast Cancer: NCCH1607/PATHWAY trial

Abstract Objective: Some patients with poor prognosis hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC) experience early disease progression on the combination of CDK4/6 inhibitors and endocrine therapy. We aimed to determine whether clonal architecture assessed by circulating tumor DNA (ctDNA) could identify patients at higher risk of early progression on tamoxifen therapy with or without palbociclib. Methods: PATHWAY trial is a randomized, placebo-controlled, Asian international, double-blind, phase 3 study evaluating palbociclib plus tamoxifen (PAL+TAM) versus placebo plus tamoxifen (PLB+TAM) in pre/perimenopausal and postmenopausal women with HR+/HER2- ABC (NCT03423199). The study was conducted as a Clinical Research Collaboration with the National Cancer Center Hospital as the regulatory study sponsor and Pfizer providing drug and financial support. The primary endpoint was investigator assessed progression-free survival (PFS). Genomic profiling by next-generation sequencing was an exploratory endpoint to characterize molecular alterations in ctDNA and correlate these with clinical outcomes. Plasma samples were collected at cycle 1-day 1 (pre-treatment) and cycle 2-day 15 and sequenced with the Guardant360 assay (Guardant Health). Patients were included if they had a minimum of 14 days of treatment in the first cycle. The variant allele frequency (VAF) was defined as number of mutant molecules at a specific nucleotide location over the total number of molecules present in the background at a specific given genomic location. We assessed the gene with highest VAF as the dominant clone allele frequency (DCAF). The association of changes in ctDNA alterations with PFS was evaluated to identify biomarkers of early progression. Results: Pre-treatment plasma was successfully sequenced in 177 of the 184 patients; 88 patients treated with PAL+TAM, and 89 with PLB+TAM. ctDNA was detected in 144 (81.4%) patients; the median number of genetic abnormalities was 2 (range, 0-19). PIK3CA, TP53, ERBB2, ESR1, AKT1, EGFR and PTEN were the genes with highest VAF as the dominant clone (24.3%, 11.9%, 4.5%, 4.5%, 3.4%, 3.4%, 3.4%, respectively). The median DCAF was 1.79 (range, 0.1-81.23); PAL+TAM, 2.53 (range, 0.1-63.5) and PLB+TAM, 1.65 (range, 0.08-81.23). Patients with ≥ 2 detectable genomic alterations and DCAF ≥ 1.8% had worse PFS (hazard ratio (HR) 1.93 [95% confidence interval (CI): 1.375 to 2.721], p = 0.0003 and HR 1.95 [95% CI: 1.345 to 2.834], p < 0.0001, respectively) compared to all other patients. In addition, we evaluated whether changes of clonal architecture in ctDNA at early treatment time point (ie. Cycle 2 Day 15) are associated with PFS. Patients with increased DCAF had worse PFS on both PAL+TAM (HR 2.80 [95% CI: 0.552 to 14.15], p = 0.04) and PLB+TAM (HR 2.02 [95% CI: 1.022 to 3.990], p = 0.01). All patients with high pretreatment DCAF (≥ 1.8%) and increase in DCAF progressed within 1 year (n=5, 2 patients treated with PAL+TAM, and 3 with PLB+TAM). Conclusion: Evaluation of clonal architecture in ctDNA could support identification of HR+/HER2- ABC patients with poorer prognosis, who may be at higher risk of early progression, regardless of CDK4/6 inhibitor use. Citation Format: Yoon-Sim Yap, Yuki Kojima, Akinobu Hamada, Hirofumi Mukai, Yen-Shen Lu, Joo Hyuk Sohn, Yoshiko Umeyama, Emi Noguchi, Kazuki Sudo, Tomomi Hata, Aya Kuchiba, Taro Shibata, Shigehiro Yagishita, Masayuki Yoshida, Shinji Kohsaka, Kouya Shiraishi, Kenichi Nakamura, Kenji Tamura, Kan Yonemori. Clonal Architecture of circulating tumor DNA predicts Early Progression on Tamoxifen With or Without Palbociclib in Hormone Receptor-Positive Advanced Breast Cancer: NCCH1607/PATHWAY trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-14-01.

Abstract PO3-16-08: Real-World Treatment Patterns in Elderly Patients with HER2-Negative Early Breast Cancer

Abstract Background: As the treatment landscape of human epidermal growth factor receptor 2-negative (HER2–) early breast cancer (BC) evolves, an understanding of treatments given in real-world settings to elderly patients with HER2– early BC is needed to gain insight into the potential unmet needs of this population for whom clinical data are limited. This study described demographics, clinical characteristics, and neoadjuvant and adjuvant treatment patterns in elderly patients with HER2– early BC in the United States. Methods: This retrospective study used SEER-Medicare data (2010–2019) to identify patients aged ≥66 years with HER2– early (Stage I–III) BC receiving primary surgery. Patient characteristics were evaluated at primary surgery or at BC diagnosis. Neoadjuvant and adjuvant therapies were defined as any National Comprehensive Cancer Network-recommended regimens received between BC diagnosis and primary surgery, and during the 180-day period following primary surgery, respectively. Patient characteristics were described using means and standard deviations (SDs) for continuous characteristics, and frequencies and proportions for categorical characteristics. Neoadjuvant and adjuvant therapies were summarized using frequencies and proportions. All analyses were conducted for the overall population and stratified by breast cancer subtype (hormone receptor-positive [HR+]/HER2– vs. triple negative BC [TNBC]) and stage at diagnosis (Stage I vs. Stage II/III). Results: Of 28,655 eligible patients, 25,899 (90.4%) had HR+/HER2– BC and 2,756 (9.6%) had TNBC; 17,961 (62.7%) had Stage I BC and 10,694 (37.3%) had Stage II/III BC. Mean (SD) age at diagnosis was 75.8 (6.4) years, mean (SD) National Cancer Institute comorbidity index was 1.9 (2.1), and 23.7% received single or multi-gene testing for a breast cancer gene 1 and/or 2 (BRCA1/2) mutation (HR+/HER2– BC: 24.6%; TNBC: 15.5%), with most (86.3%) testing occurring after primary surgery. Relative to HR+/HER2– BC patients, TNBC patients were less likely to present with Stage I disease (46.7% vs. 64.4%), had a larger mean tumor size at diagnosis (2.6 cm vs. 1.9 cm), and higher-grade tumors (Grade III or IV: 70.6% vs. 14.6%). TNBC patients were also more likely to receive neoadjuvant chemotherapy (90.9% vs. 35.3%) and adjuvant radiation therapy (81.2% vs. 66.4%) than HR+/HER2– BC patients (Table 1). By BC stage, neoadjuvant therapy was more common among Stage II/III patients relative to Stage I patients (12.3% vs. 2.7%), with most (90.4%) neoadjuvant chemotherapy use observed among Stage II/III patients. Adjuvant therapy use was similar between Stage I and Stage II/III patients (87.4% vs. 88.1%) and the most common adjuvant therapies across both subgroups were endocrine therapy (85.2% vs. 82.2%) and radiation therapy (68.5% vs. 66.1%). Conclusion: In elderly patients with HER2– early BC, treatment with adjuvant therapy was common, while neoadjuvant therapy was limited. Moreover, one in four HER2– early BC patients were tested for a BRCA1/2 mutation in real-world clinical practice. Our findings highlight the need for a better understanding of the role of increased and timely BRCA1/2 testing to inform optimal treatment strategies across neoadjuvant and adjuvant settings in this population. Table 1. Treatment Patterns Among Patients with TNBC and HR+/HER2– Early Breast Cancer Citation Format: Jagadeswara Earla, Allison Kurian, Kalé Kponee-Shovein, Ambika Satija, Yan Song, Nathaniel Downes, Malena Mahendran, Qi Hua, Arun Kumar, Jaime Mejia. Real-World Treatment Patterns in Elderly Patients with HER2-Negative Early 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 PO3-16-08.

Abstract PO3-04-10: Real-world progression-free survival and overall survival of palbociclib plus endocrine therapy in Japanese patients with HR+/HER2- ABC in the first- or second-line setting: A multicenter observational study

Abstract Introduction Palbociclib (PAL), a selective, oral inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), plus (+) endocrine therapy (ET) is standard therapy for the treatment of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) and was launched in December 2017 in Japan. Efficacy and safety of PAL + ET was shown by randomized clinical studies, PALOMA-2 and PALOMA-3. Further, recent large real-world studies, P-REALITY/P-REALITY X, confirmed effectiveness of PAL+ aromatase inhibitor (AI) for HR+/HER2- ABC in routine United States clinical practice. However, there is limited real-world evidence (RWE) for PAL in Japan. To strengthen the RWE of PAL+ET for HR+/HER2- ABC treatment under different clinical practice and healthcare system, we examine the real-world effectiveness of PAL + ET as 1st line (1L) and 2nd line (2L) treatment for HR+/HER2- ABC in Japan. Methods In this multicenter, observational study, patients with HR+/HER2- ABC, who initiated PAL + ET from 15 December 2017 to 31 December 2020 were enrolled. To reduce selection bias, all patients who started PAL during the above period were listed and their eligibility confirmed. Eligible patients had 1) diagnosis of HR+/HER2- ABC; 2) received PAL + ET as 1L or 2L treatment; 3) at least 6 months of follow up from start of PAL or died within that period. The 1L treatment was defined as the first systemic therapy received for ABC regardless of recurrence timing if receiving adjuvant treatment. The subsequent treatment after 1L treatment was defined as a 2L treatment. The primary endpoint was real-world progression-free survival (rwPFS) defined as the time from PAL+ET start to physician-documented disease progression or death due to any cause, whichever occurs first. Secondary endpoints included overall survival (OS), and chemotherapy-free survival (CFS). Results were stratified by treatment line (ie. 1L or 2L). rwPFS, OS, and CFS were analyzed with the Kaplan-Meier method (NCT05399329). Results In this study, 677 patients were enrolled. Among them, 419 (62%) patients and 258 (38%) patients received PAL + ET as 1L and 2L, respectively. The median age was 59.0 (range 29-87) and 470 patients (69.8%) were postmenopausal. 49.0% patients had visceral involvement and 63.8% had a disease-free interval >24 months, defined as date of breast cancer surgery to the diagnosis date of recurrence, and 26.9% had de novo metastatic disease. The starting dose of PAL was 125 mg (89%), 100mg (9%), and 75mg (2%); dose reductions during the treatment period were required for 72% of patients. The most common ET combined with PAL was fulvestrant (FUL; 56.3% in 1L, 76.7% in 2L) followed by letrozole (LET; 37.9% in 1L, 16.3% in 2L). After a median follow-up of 36.2 months, the median rwPFS (95% CI) was 24.5 months (19.9-29.4) for 1L treatment and 14.5 months (10.2-18.3) for 2L treatment. Among the 604 patients initiating at 125 mg/day, the median rwPFS was 25.6 months (21.3-30.4) for 1L treatment and 14.3 months (9.7-18.3) for 2L treatment. Although median OS was not reached (NR) in 1L, median OS of 2L was 44.1 months (39.2 -NR). The 48-months OS rates for 1L and 2L treatment were 62.0% (55.4-67.9) and 48.4 % (40.4-55.9), respectively. The median CFS was 36.7 months (31.8-43.9) for 1L treatment and 23.8 months (20.5-27.3) for 2L treatment. Conclusions Our real-world data are consistent with findings form the PALOMA-2 and PALOMA-3 studies and those from RWE in routine United States clinical practice. FUL was the most commonly endocrine partner with PAL regardless of treatment lines. These observations add to the body of evidence supporting PAL effectiveness in clinical practice for Japanese ABC patients. Citation Format: Norikazu Masuda, Masaya Hattori, Tersuhiro Yoshinami, Takuho Okamura, Ken-ichi Watanabe, Takahiro Nakayama, Hiroko Masuda, Michiko Tsuneizumi, Daisuke Takabatake, Michiko Harao, Hiroshi Yoshino, Natsuko Mori, Hiroyuki Yasojima, Chiya Oshiro, Madoka Iwase, Miki Yamaguchi, Takafumi Sangai, Shinsuke Sasada, Takanori Ishida, Manabu Futamura, Nobuyoshi Kosaka, Yoshiyuki Shibasaki, Shigenori Nagai. Real-world progression-free survival and overall survival of palbociclib plus endocrine therapy in Japanese patients with HR+/HER2- ABC in the first- or second-line setting: A multicenter observational 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 PO3-04-10.

Abstract PO1-15-09: Vitamin A Metabolism Induces Ferroptosis to Enhance Immune Therapy Efficacy in HR+/HER2- Breast Cancer

Abstract Background: Immune checkpoint blockade (ICB) has substantially improved patient overall and progression-free survival in triple-negative breast cancer (TNBC), but its efficacy remains to be elucidated in the hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer, which is characterized by generally impotent lymphocytic infiltration. In the I-SPY2 trial (NCT01042379), pembrolizumab- or durvalumab-containing neoadjuvant therapy increased the pathologic complete response of HR+/HER2- patients. However, pembrolizumab-containing therapy failed to improve the survival of metastatic HR+/HER2- breast cancer patients (NCT03051659). These inconsistent results underscored the necessity of the investigation of predictive biomarkers to pinpoint potential ICB responders in HR+/HER2- breast cancer. Method: In this study, we collected pretreatment tumor samples from 16 patients in two respective clinical trials (NCT: 04215003 and 04355858) and profiled droplet-based single-cell sequencing, bulk RNA-Seq. Patients were treated with camrelizumab (PD-1 inhibitor)-containing therapy, and five of them achieved partial relief after an 8-week course. We also leveraged the bulk RNA-Seq data from the I-SPY2 trial and Fudan University Shanghai Cancer Center (FUSCC) TNBC ICB trials (NCT04418154 and NCT04613674) for external validation. Another FUSCC transcriptome dataset consisting of 933 treatment-naïve HR+/HER2- or TNBC breast cancer patients was used to detect the abundance of cell types. In vitro and in vivo experiments were used to explore mechanisms of anti-tumor immune response. Results: Based on the single-cell sequencing results, we comprehensively delineated the microenvironmental landscape of HR+/HER2- breast cancer. We discovered responders of immunotherapy showed a higher presence of CXCL9/10+ M1-like macrophages and exhibited enrichment of tumor cells with ferroptosis. We further identified the upregulation of vitamin A metabolism and the vitamin A metabolic gene CRABP1 in tumor cells with ferroptosis. We verified the vitamin A metabolism could induce ferroptosis in HR+/HER2- breast cancers rather than TNBC by CRABP1-ERK axis, which could further recruit CXCL9/10+ M1-like macrophages and promote anti-tumor immune response in HR+/HER2- breast cancer. Combining anti-PD1 with enhancing vitamin A metabolism via retinoid acid possessed greater therapeutic efficacy than monotherapy in HR+/HER2- breast cancers. Finally, we developed an immune therapy response score and validated its reliability in predicting the immunotherapy efficacy for HR+/HER2-breast cancers through both internal and external cohorts. Conclusion: Our study represents the earliest efforts to decipher the microenvironmental landscape and the mechanisms underlying the response to ICB in HR+/HER2- breast cancer at single-cell resolution. We unraveled a HR+/HER2- breast cancer-specific Vitamin A-ferroptosis axis that mediated immunotherapy response and constructed a robust immunotherapy efficacy prediction score based on this Vitamin A-ferroptosis axis. Citation Format: Yi-Fan Zhou, Hu-Yun-Long Zhang, Xi Jin, Yi-Zhou Jiang, Zhi-Ming Shao. Vitamin A Metabolism Induces Ferroptosis to Enhance Immune Therapy Efficacy in HR+/HER2- 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 PO1-15-09.

Abstract PO4-02-04: Overall survival and disease recurrence rates in patients with invasive lobular breast cancer of the PenelopeB cohort

Abstract Background: In the PENELOPEB trial, the addition of 1-year of cyclin-dependent kinase 4/6 (CDK4/6) inhibitor palbociclib to standard endocrine therapy (ET) for women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) early breast cancer at high risk of recurrence after neoadjuvant chemotherapy (NACT) did not improve invasive disease-free survival (iDFS) or overall survival (OS) in the main study analysis. Invasive lobular breast cancer (ILC) accounts for ~15% of all breast cancers (BC) and represents an underinvestigated subtype of BC with typically less sensitivity to (neo)adjuvant chemotherapy, and poor distant disease-free survival (DDFS) irrespective of response to NACT. Here, we report the post-hoc analysis results of iDFS, DDFS and OS in pre- and postmenopausal women enrolled on PENELOPEB and with ILC. Methods: Patients with HR+/HER2-negative BC without pathological complete response (pCR) after taxane-containing NACT and at high risk of relapse (CPS-EG score ≥3, or 2 and ypN+) were randomized (1:1) to receive 13 cycles of palbociclib 125mg daily or placebo on days 1-21 of a 28-day cycle in addition to standard ET with tamoxifen (TAM) +/- gonadotropin-releasing hormone analogue (GnRHa) or aromatase inhibitor (AI) +/- GnRH. Randomization was stratified by nodal status at surgery, age at first diagnosis (< 50 vs. ≥50 years), Ki-67, region, and CPS-EG score. ILC diagnosis was locally assessed and reported by the investigators on the pathology case report form. The primary objective of this post-hoc analysis was to evaluate iDFS, DDFS and OS by treatment arm in patients with high risk ILC. Results: A total of 1,250 patients were randomized, of whom 110 had ILC and were nearly uniformly distributed between both treatment arms (palbociclib n=58 vs. placebo n=52), with a higher proportion of postmenopausal women (58.6% in the palbociclib arm vs. 53.8% in the placebo arm) compared to premenopausal women (41.4% in the palbociclib arm vs. 46.2% in placebo arm). There was no difference in the distribution of AI/TAM use between the treatment arms. An estimated absolute 3-year-iDFS difference of 18.3% with palbociclib compared to placebo (iDFS 88.4% [95% CI 76.0-94.6] vs. 70.1% [95% CI 55.3-80.7]) with a HR of 0.66 [95% CI 0.27 – 1.61, log-rank p=0.354]) was observed. A comparable 3-year-DDFS difference of 16.3% was observed. An estimated 3-year-OS difference of 16.4% (98.0% [95% CI 86.6 – 99.7] vs. 81.6% [95% CI 67.5 – 90.0]) with a hazard ratio (HR) of 0.27 (95% CI 0.05 – 1.43, log-rank p=0.108) was observed. Out of 12 observed deaths (n=2 palbociclib vs. n=10 placebo), 11 (in placebo arm) were related to metastasic BC. Conclusions: In this post-hoc analysis, a trend towards improvement in OS and a trend in favor of iDFS and DDFS for the addition of palbociclib to ET was observed among women with HR+/HER2- ILC at high risk of recurrence after NACT, but these differences were not statistically significant. This could represent a valuable treatment option for patients with high risk ILC. Due to the small sample size of the ILC subgroup, further follow-up evaluation is necessary. Moreover, analyses in the ILC subgroup from other adjuvant CDK4/6 inhibitor trials could substantiate these findings. Table. Overall survival and disease recurrence rates in patients with invasive lobular breast cancer of the PenelopeB cohort Results of iDFS, DDFS and OS. Citation Format: Hervé Bonnefoi, Frederik Marmé, Miguel Martín, Michael Untch, Sung-Bae Kim, Harry Bear, Nicole McCarthy, Karen Gelmon, José Ángel García-Sáenz, Catherine M. Kelly, Toralf Reimer, Zhe Zhang, Masakazu Toi, Hope Rugo, Michael Gnant, Andreas Makris, Nader Hirmas, Valentina Nekljudova, Johannes Holtschmidt, Sibylle Loibl. Overall survival and disease recurrence rates in patients with invasive lobular breast cancer of the PenelopeB 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 PO4-02-04.

Abstract PO2-18-09: A phase 3 randomized open-label study of extended adjuvant therapy with camizestrant vs standard endocrine therapy in patients with ER+/HER2– early breast cancer and an intermediate or high risk of recurrence (CAMBRIA 1)

Abstract Background: Definitive locoregional (surgery ± radiotherapy) and standard adjuvant endocrine therapy (ET) (± chemotherapy or cyclin-dependent kinase 4/6 inhibitor [CDK4/6i]) can achieve cure in many patients (pts) with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2–) early breast cancer (BC). Nevertheless, a significant proportion of pts with stage I–III disease will experience recurrence to metastatic, incurable disease (5- and 10-year cumulative incidences of recurrence of 8.3% and 14.0%, respectively). There is evidence that incorporating a more effective endocrine therapy after 2 years of standard adjuvant ET can result in clinical benefit for high-risk individuals. Camizestrant is a next-generation oral selective ER degrader and pure ER antagonist. In SERENA-2, camizestrant 75 mg and 150 mg significantly prolonged progression-free survival vs fulvestrant in postmenopausal women with ER+/HER2– advanced BC with disease recurrence or progression after ET. The CAMBRIA-1 study (NCT05774951) is evaluating the potential of extended adjuvant therapy with camizestrant to improve outcomes in pts with ER+/HER2– early BC with an intermediate or high risk of recurrence after definitive locoregional therapy and standard adjuvant ET. Trial design: This phase 3 randomized, open-label study is enrolling women (pre- or postmenopausal) and men with ER+/HER2– (immunohistochemistry 0/1+/2+/in situ hybridization-negative) early BC who have completed definitive locoregional therapy and standard adjuvant ET (± CDK4/6i) for ≥2 and ≤5 years (+ 3 months) without disease recurrence. Pts must be considered at intermediate or high risk of recurrence based on clinical, biological, and genomic factors. Pts are randomized (1:1) to continue standard ET of the investigator’s choice (tamoxifen or aromatase inhibitor ± luteinizing hormone-releasing hormone [LHRH] agonist) or camizestrant ± LHRH agonist for up to 60 months. The primary endpoint is invasive BC-free survival (STEEP 2.0 criteria). Secondary endpoints include invasive disease-free survival and distant relapse-free survival (STEEP 2.0 criteria), overall survival, safety, and health-related quality of life. Primary endpoint analysis will use a stratified log-rank test adjusting for stratification factors, assuming a two-sided significance level of 5%. Approximately 4300 pts will be randomized; enrollment is ongoing. Clinical trial identification: NCT05774951 Editorial acknowledgment: Writing assistance was provided by Alison Lovibond, PhD, of BOLDSCIENCE Inc., funded by AstraZeneca. Legal entity responsible for the study: AstraZeneca Funding: This study was supported by AstraZeneca. Citation Format: Erika Hamilton, Sibylle Loibl, Naoki Niikura, Priya Rastogi, Kamal S. Saini, Ioanna Gioni, Teresa Klinowska, Ingrid A. Mayer, Mary Stuart, Emilia Syta, Andrew Walding, Thomas Bachelot. A phase 3 randomized open-label study of extended adjuvant therapy with camizestrant vs standard endocrine therapy in patients with ER+/HER2– early breast cancer and an intermediate or high risk of recurrence (CAMBRIA 1) [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 PO2-18-09.

Abstract PO2-09-03: Twenty-one gene recurrence scores in individuals with breast cancer associated with PALB2 germline pathogenic variants

Abstract Background: The 21-gene recurrence score assay (Oncotype DX, Genomic Health Inc., CA) is prognostic, quantifies predicted benefit of adjuvant chemotherapy, and informs clinical decisions for patients with early-stage, hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer (BC). Differences in Oncotype recurrence scores (RS) in individuals with and without BRCA1 and BRCA2 (BRCA1/2) pathogenic variants (PV) have been demonstrated, but the results of this assay in patients with BC and germline PALB2 PV have not previously been described. This is of particular relevance as PALB2 BC has demonstrated biologic features similar to BRCA1/2 BC such as poly(adenosine diphosphate ribose) polymerase inhibitor (PARPi) sensitivity. Methods: Patients with early-stage, HR+, HER2-, invasive breast cancer and a germline PALB2 PV were ascertained from academic cancer center databases and the Prospective Registry of MultiPlex Testing (PROMPT), an online research registry for individuals who have had multigene panel testing for inherited cancer susceptibility. Study participants (pts) were categorized by age < 50 and ≥50. Oncotype DX RS were retrospectively reviewed and categorized as those that would and would not warrant consideration of chemotherapy (≥16 and < 16, respectively, for pts < 50; ≥26 and < 26, respectively, for pts ≥50). Yates corrected Chi-square tests were used to compare RS distributions between carriers and a previously published genetically unselected reference population. Results: Oncotype DX reports were reviewed for 20 pts with BC and germline PALB2 PV. Median RS was 19 (range 6-41) overall. Four patients were diagnosed under the age of 50 (range 33-48); median RS for these individuals was 19 (range 12-41). Sixteen patients were diagnosed at age 50 or greater (median 59, range 50-70); median RS for these individuals was also 19 (range 6-31). Compared to the genetically unselected reference population, Oncotype DX RS in pts with PALB2-associated BC demonstrated a numerical but not statistically significant shift in distribution towards categories in which chemotherapy would be considered. Among pts under the age of 50, 75% had Oncotype DX RS for which chemotherapy would be considered and 25% had Oncotype DX RS for which endocrine therapy alone would likely be recommended (p=0.726 compared to reference). Among pts aged 50 and older, 25% had Oncotype DX RS for which chemotherapy would be considered and 75% had Oncotype DX RS for which endocrine therapy alone would likely be recommended (p=0.579 compared to reference). Conclusions: Compared to data from the published genetically unselected commercial database, BC associated with PALB2 PV may have higher Oncotype DX RS reflective of intrinsically less favorable biology and greater therapeutic sensitivity. Larger datasets are forthcoming to confirm presence of significant differences in Oncotype DX RS distributions between BC with and without PALB2 PV. Table 1. Oncotype DX RS distribution by age among pts with gPALB2 PV and genetically unselected reference *Jakubowski et al., J Surg Oncol 2020. PMID 3249731 Citation Format: Payal Shah, Siddhartha Yadav, Jamie Brower, Jada Hamilton, Erica Simmons, Judy Garber, Kenneth Offit, Mark Robson, Fergus Couch, Susan Domchek. Twenty-one gene recurrence scores in individuals with breast cancer associated with PALB2 germline pathogenic variants [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 PO2-09-03.