Hormone Receptor-positive Advanced Breast Cancer Research Articles

Vitreoretinal Traction Syndrome, Nitrituria and Human Epidermal Growth Factor Receptor Negative Might Occur in the Aromatase-Inhibitor Anastrozole Treatment

Background. Anastrozole has been approved for treatment of hormone receptor-positive advanced or metastatic breast cancer by FDA. This study was to assess Anastrozole-related adverse events (AEs) of real-world through data mining of the US Food and drug administration adverse event reporting system (FAERS). Methods. Four different disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN) and the multiitem gamma Poisson shrinker (MGPS) algorithms were employed to quantify the signals of Anastrozole-associated AEs. Results. A total 25 system organ class (SOCs) and 300 significant disproportionality Preferred Terms (PTs) were found in this study. The top 5 most significant SOCs were Eye disorders, renal and urinary disorders, respiratory, thoracic and mediastinal disorders, investigations, and cardiac disorders. Unexpected significant AEs was vitreoretinal traction syndrome (ROR = 1108.22, PRR = 1103.98, IC025 = 9.51, EBGM05 = 389.98), nitrituria (ROR = 3561.82, PRR = 3557.28, IC025 = 10.38, EBGM05 = 318.83) and human epidermal growth factor receptor negative (ROR = 675.04, PRR = 674.01, IC025 = 9, EBGM05 = 204.57). Conclusion. The Unexpected significant AEs associated with anastrozole were identified in this study, warrants urgent clarification through additional prospective studies.

Abstract PO5-21-10: Efficacy and Safety of Alpelisib in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor: An Open-label, Multi-centre, Prospective, Single Arm Clinical Trial

Abstract Introduction: Currently, patients with luminal metastatic breast cancer receive a CDK4/6 inhibitor in combination with endocrine therapy as a first or second line of treatment. When tumors become resistant to the CDK4/6 inhibitors, treatment with alpelisib (PI3K inhibitor) in combination with an endocrine agent can be a next treatment option if an activating PIK3CA mutation is confirmed (cfr. SOLAR-1 trial). However, limited data is available after treatment with CDK4/6 inhibitors (cfr. BYLieve trial) and even less about alpelisib in later lines of therapy. Therefore, we aim to investigate the therapeutic efficacy and safety of alpelisib in combination with an endocrine agent in PIK3CA-mutated advanced breast cancer patients in later lines after prior CDK4/6i treatment. Methods: This is an open-label, prospective, multi-centre, single arm clinical trial enrolling patients from both the University Hospital of Leuven (UHL) and Ghent University Hospital (GUH). For each patient, metastatic tumor was tested for PIK3CA mutations using the UHL 96 gene panel. Our endpoints are clinical benefit rate, progression-free survival, time to treatment discontinuation (defined as the date of starting alpelisib to the date of treatment discontinuation or death) and safety. Descriptive statistics were used. Results: Between June 18th 2019 and August 23rd 2021, 38 patients have been included with confirmed PIK3CA hotspot mutations. All patients had CDK4/6 inhibitor in an earlier treatment line. Median age at alpelisib initiation was 64 years (range: 39-82 years). Included patients had a median of four lines of systemic therapy for advanced disease prior to starting alpelisib (range: 1- 11). Clinical benefit rate (patients receiving ³ 6 months of treatment) was 26.3% (10/38). The median progression-free-survival as well as time to treatment discontinuation were 3 months (range: 1 – 18). Dose reduction due to toxicity occurred in 11 patients (29%), of which 7 due to hyperglycemia grade 3, 2 due to diarrhea grade 3, 1 due to rash grade 2 and 1 due to anorexia. Finally, 84% of patients (32/38) stopped alpelisib treatment because of progressive disease, 8% (3/38) because of intolerance, one patient died because of cerebral hemorrhage during treatment, one patient withdrew their informed consent and one patient is still ongoing with the treatment. Conclusion: Our trial demonstrates activity of alpelisib in patients with PIK3CA mutated advanced breast cancer in later lines of treatment after treatment with CDK4/6 inhibitors with a clinical benefit rate of 26.3%. Discontinuation of therapy due to toxicity was seen in only 8% of patients, although toxicity induced dose reduction was needed in 29% of patients. These findings support the results of the BYLieve trial and additionally show efficacy of alpelisib in later lines of treatment for hormone receptor-positive advanced breast cancer. Citation Format: Rik Van Severen, Anne-Sofie De Crem, Hava Izci, Laurence Slembrouck, Isabelle Vanden Bempt, Hans Wildiers, Kevin Punie, Eline Naert, Ingeborg Hilderson, Ann Smeets, Ines Nevelsteen, Anne Deblander, Nynke Willers, Patrick Berteloot, Ignace Vergote, Sileny Han, Adriaan Vanderstichele, Giuseppe Floris, Christine Desmedt, Hannelore Denys, Patrick Neven. Efficacy and Safety of Alpelisib in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor: An Open-label, Multi-centre, Prospective, Single Arm Clinical 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 PO5-21-10.

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 PO4-05-09: Phase I study of the FGFR inhibitor rogaratinib, fulvestrant and palbociclib in advanced hormone receptor-positive (HR+) breast cancer (BC) with FGFR1/2 amplification and/or overexpression (FGFR1/2+)

Abstract Background: Novel therapies are needed upon progression to first-line CDK4/6 inhibitor (CDK4/6i) plus aromatase inhibitor (AI) in advanced HR+ BC. One frequent alteration driving resistance to CDKi plus AI is FGFR1/2 amplification or overexpression. In preclinical FGFR1/2+ HR+ BC models, combined CDK4/6, ER and FGFR blockade was more effective than single- or double combinations (Breast Cancer Res; 23:21-37; 2021). Rogaratinib (ROGA) is a selective FGFR1-4 kinase inhibitor with significant activity in FGFR-aberrant tumors. We aimed to study the tolerability and preliminary efficacy of ROGA added to fulvestrant (FUL) and palbociclib (PAL) in patients (pts) with FGFR1/2+ HR+ BC progressing on first-line CDK4/6i plus AI. Methods: ROGABREAST (NCT04483505) was a single-arm, prospective, multicentric, open-label, phase I dose-escalation trial following a classic 3+3 schedule. Pts were pre-screened for FGFR1/2 amplification and/or overexpression by FISH and RNAScope. Women >18 year-old with advanced HR+ BC progressing on first-line CDI4/6i plus AI, and adequate organ function were included. Pts received ROGA monotherapy q12 hours in day 1. In day 2, pts continued ROGA and started FUL (500 ug IM) plus PAL (100 mg/day on days 1-21). FUL was repeated in day +15. Cycle 1 was 29 days-long and followed by 28-day cycles (continuous ROGA q12 hours days 1-28, FUL 500 ug day 1, and PAL 100mg/d days 1-21). Level 1 was ROGA 400 mg/bid and escalated 200 mg/bid increments. FUL dose was not modified. PAL was allowed to escalate intrapatient to 125 mg/d after cycle 2 in pts experiencing ≤ grade 1 tolerable side effects as the greatest toxicity in cycle 1. PK and PD (FGF23 and phosphate levels) profiles were obtained in days +1 and +15. DLT-assessment period was cycle 1-2. Results: from 12/2020 to 5/2022, 67 pts were screened; 29 were FGFR1/2+ (22 and 5 RNAscope-positive for FGFR1 and FGFR2; 17 and 3 FISH-positive for FGFR1 and FGFR2). Nine pts entered the study. Six were enrolled in level 1, where 1 DLT (grade 3 diarrhea) occurred, and 3 in level 2 (600 mg ROGA bid; no DLTs). Grade 3 hyperphosphatemia, adequately controlled with diet and chelants (33% of the patients) and grade 2 non-tolerable dactylitis/onycholysis (11%) were the most frequent severe toxicities after the DLT period. Other toxicities were mild and well-tolerated (grade 1-2 diarrhea and hyperphosphatemia occurred in 66 and 44% of the pts, respectively). Median PFS was 113 days and 44% of the pts had a PFS > 180 days, with no apparent relationship with FGFR1 or 2 status, or mutations found via WES. The trial was terminated after completion of level 2 due to rogaratinib development discontinuation. Conclusions: Triple FGFR1/2, CDK4/6 and ER blockade appears safe at standard drug dosages and shows promising clinical activity in second-line HR+ FGFR1/2+ BC patients progressing on CDK4/6i plus AI. Citation Format: Noelia Martínez-Jáñez, Sonia Pernas, José Ángel García-Sáenz, Serafin Morales Murillo, Begoña Bermejo, Juan A Guerra, Silvana Mouron, Miguel Quintela-Fandino. Phase I study of the FGFR inhibitor rogaratinib, fulvestrant and palbociclib in advanced hormone receptor-positive (HR+) breast cancer (BC) with FGFR1/2 amplification and/or overexpression (FGFR1/2+) [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 PO4-05-09.

Abstract PO4-01-14: Effects of neoadjuvant endocrine therapy on early-stage breast cancer: a retrospective cohort study of patients during the COVID19 pandemic

Abstract Background: At the height of the COVID19 pandemic, many surgical procedures across the country including at Dartmouth-Hitchcock Medical Center (DHMC) were postponed to redirect resources. The American Society of Breast Surgeons shared guidelines to manage patients experiencing surgical delays. For estrogen receptor positive (ER+), HER2- early-stage tumors, recommendations were to use neoadjuvant endocrine therapy (NET). NET is usually under-utilized for locally advanced hormone receptor-positive breast cancer (BC) despite literature concluding that chemotherapy and NET have comparable clinical response rates but with lower toxicity for the latter. The COVID19 pandemic thus presented a unique occasion to extend the use of NET for localized BC. Herein, we examined the rate of adoption of NET and associated patient/tumor characteristics at DHMC during the lockdown. Methods: A retrospective analysis of patients diagnosed with early-stage ER+, HER2- BC between December 2019 and June 2020. Data extracted from chart review included age, menopausal status, tumor stage/grade, body mass index (BMI), and adherence to adjuvant endocrine therapy (ET). A “delay in surgery” was defined as days between surgical consult and surgery over 14 days. Descriptive statistics were applied to data collected on patient/tumor characteristics, and the number of patients accepting or declining NET. Results: 109 cases were identified within the study period, with 42 found with surgical delay. The median age of the delayed group was 62 and the majority of patients were post-menopausal. 36 patients received NET with most started on an aromatase inhibitor. Median BMI was 28.5. Median duration of treatment was 39.5 days. Three cases were noted to have some decrease in cellularity for pathologic partial response and four had no definite response. The majority of patients on NET had no change in pathological grade. Out of the 36 patients who had NET, 30 (83.3%) remain on adjuvant ET. In contrast, only 59% (43 out of 73 patients) of those who did not receive NET were on adjuvant ET at the median follow up time of 2.75 years post-therapy initiation. Of note, 16 (out of 73) patients who were not on NET were either lost to follow up, had their care transferred to another health network or were not offered ET. Results are reported in Tables 1 and 2. Conclusions: Delays in surgery during the COVID19 crisis resulted in increased use of NET in early-stage BC. Impact of NET use includes possible increase in long-term adherence to adjuvant ET with a trend towards statistical significance (odds ratio of 3.25, p=0.08). A larger sample size is needed to evaluate this finding and a prospective trial is in progress (NCT04568616). NET is a viable treatment option during surgical delays and may help increase long-term adherence to adjuvant ET. Table. Patient and tumor characteristics Table. Number of patients on adjuvant ET Citation Format: Mary Chamberlin, Todd Miller, Marie Anne Christine Buteau, Steven Tau. Effects of neoadjuvant endocrine therapy on early-stage breast cancer: a retrospective cohort study of patients during the COVID19 pandemic [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 PO4-01-14.

Abstract 804: Temporal trends and disparities by race and ethnicity in treatment of women diagnosed with advanced hormone receptor-positive breast cancer: A SEER-Medicare analysis

Abstract Background: The clinical guidelines for management of advanced hormone receptor-positive (HR+) breast cancer (BC) have changed in the past decade with the addition of novel drug classes. We assessed temporal patterns of treatment initiation among women diagnosed with advanced HR+ BC and examined disparities in treatment initiation by race and ethnicity. Methods: Women aged ≥65 years diagnosed with stage IV or metastatic HR+ BC between 2010-2019 were identified in SEER-Medicare. Poisson models were used to estimate age-adjusted annual incidence rates (IR) and 95% confidence intervals (CIs) for treatment initiation within 12 months of BC diagnosis independently by human epidermal growth factor receptor 2 (HER2) status. Age-adjusted incidence rate ratios (IRR) and 95% CIs were estimated to compare rates of initiation among non-Hispanic Black (NHB) and Hispanic patients with non-Hispanic White (NHW) patients. Results: Among 3,476 eligible patients with a mean age of 76.7 (SD: 7.5) years at diagnosis, 79.6% were NHW, 9.5% were NHB, and 6.0% were Hispanic. Among 2,668 women with HR+/HER2- BC, most initiated on aromatase inhibitors (AIs) alone (56.7%), followed by AIs with palbociclib (12.6%). There was a temporal increase in rates of initiation of AIs with palbociclib (IR [95% CI] per 1000 person-years: 252.8 [240.8, 265.4] in 2015 and 343.9 [330.8, 357.7] in 2019. We did not observe significant differences in rates of initiation of AIs alone or with palbociclib by race and ethnicity. Among 537 HR+/HER2+ patients, 25.0% initiated on AIs alone, 24.6% on pertuzumab and trastuzumab with chemotherapy, 14.3% on trastuzumab with chemotherapy, and 9.1% on AIs and trastuzumab with chemotherapy. IRs (95% CI) for initiation of pertuzumab and trastuzumab with chemotherapy increased from 175.6 (146.3, 210.9) in 2013 to 756.5 (698.3, 819.5) in 2019, while rates for trastuzumab with chemotherapy declined from 963.1 (809.4, 1146.0) in 2010 to 88.4 (72.6, 107.5) in 2019. Rates of initiation of AIs and trastuzumab with chemotherapy remained constant over time. Compared to NHW, NHB and Hispanic women were less likely to initiate pertuzumab and trastuzumab with chemotherapy (IRR [95% CI]: 0.52 [0.27, 1.00] and 0.54 [0.24, 1.23] respectively) and more likely to initiate AIs alone (IRR [95% CI]: 2.23 [1.39, 3.55] and 2.98 [1.69, 5.24] respectively). Conclusions: We observed a temporal increase in the initiation of AIs with palbociclib among patients with advanced HR+/HER2- BC. Among patients with HR+/HER2+ BC, rates of initiating pertuzumab and trastuzumab with chemotherapy increased while rates of trastuzumab with chemotherapy declined. The observed differential management of NHB and Hispanic compared with NHW patients with HR+/HER2+ BC using pertuzumab and trastuzumab with chemotherapy and AIs alone requires further investigation. Citation Format: Kexin Zhu, Elisa Bandera, Farzin Khosrow-Khavar. Temporal trends and disparities by race and ethnicity in treatment of women diagnosed with advanced hormone receptor-positive breast cancer: A SEER-Medicare analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 804.

Abstract 4424: Differential metabolic response of triple-negative and estrogen receptor-positive breast cancer cells to abemaciclib, a CDK4/6 inhibitor

Abstract Background: Inhibition of the cell cycle kinases CDK4/6 is the standard-of-care for advanced hormone receptor-positive breast cancer. The clinical efficacy of CDK4/6 inhibitors in triple-negative breast cancer remains uncertain. Mechanisms of sensitivity and resistance are not fully understood. This study comprehensively investigated the metabolic response of triple-negative and estrogen receptor-positive breast cancer cells to abemaciclib (Abe), with the aim of providing metabolic insights for resistance mechanisms. Methods: MCF-7 (MCF) and MDA-MB-231 (MDA) cells were treated with Abe (0, 100, and 500 nM) for 1, 2, or 7 days. Cell cycle and cell senescence analyses were performed to assess drug effects. Cellular metabolism was investigated using the Seahorse assay, LC-MS/MS based targeted metabolomics, and stable isotope-assisted metabolic flux analyses with [U-13C]glutamine, [1,2-13C]glucose, and [U-13C]glucose as the tracers. Results: Abe induced cell cycle arrest at G0/G1 in both cell lines, more pronounced in MCF. Dose- and time-dependent cell senescence occurred in both treated cell lines, more pronounced in MDA. The Seahorse assay indicated that energy metabolism (assessed by oxygen consumption rate and extracellular acidification rate) was reduced in both treated cell lines. Targeted metabolomics revealed that post Abe treatment, intracellular lactate significantly decreased in both cell lines; intracellular TCA intermediates significantly decreased in MCF while being unchanged in MDA; intracellular deoxynucleotides decreased in both cell lines, to a lesser extent in MDA; cellular energy levels (assessed as the ratios of ATP/AMP, ATP/ADP, CTP/CMP, CTP/CDP) were significantly lower in MCF while remaining unchanged or increased in MDA; intracellular levels of many amino acids significantly increased in MDA while decreasing in MCF. [U-13C]glutamine flux revealed a significant decrease of intracellular glutamine-derived TCA intermediates in both treated cell lines. [1,2-13C]glucose flux indicated an enhanced oxidate pentose phosphate pathway (PPP) activity and increased de novo syntheses of purine nucleotides (ATP and GTP) in treated MDA (but not MCF). [U-13C]glucose flux suggested that while both cell lines responded to Abe with decreased anaerobic glycolysis (pyruvate converting to lactate), MDA (but not MCF) showed an enhanced capability of utilizing glucose-derived carbon to replenish TCA intermediates and increased amino acid synthesis. Conclusion: Adaptive cellular metabolism, characterized by enhanced utilization of glucose-derived carbon to replenish TCA intermediates and increased PPP activity, thus promoting biosynthesis of amino acids and purine nucleotides to maintain cellular energy and redox balance, may contribute to the intrinsic resistance of triple-negative breast cancer to CDK4/6 inhibitors. Citation Format: Jun Jiang, Xun Bao, Yuanyuan Jiang, Yang Yue, Maik Huettemann, Jing Li. Differential metabolic response of triple-negative and estrogen receptor-positive breast cancer cells to abemaciclib, a CDK4/6 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4424.

CD63+ cancer-associated fibroblasts confer CDK4/6 inhibitor resistance to breast cancer cells by exosomal miR-20

Cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (CDK4/6i) have rapidly received Food and Drug Administration (FDA) approval as a new type of therapy for patients with advanced hormone receptor-positive breast cancer. However, with the widespread application of CDK4/6i, drug resistance has become a new challenge for clinical practice and has greatly limited the treatment effect. Here, the whole microenvironment landscape of ER+ breast cancer tumors was revealed through single-cell RNA sequencing, and a specific subset of cancer-associated fibroblasts (CD63+ CAFs) was identified as highly enriched in CDK4/6i resistant tumor tissues. Then, we found that CD63+ CAFs can distinctly promote resistance to CDK4/6i in breast cancer cells and tumor xenografts. In addition, it was discovered that miR-20 is markedly enriched in the CD63+ CAFs-derived exosomes, which are used to communicate with ER+ breast cancer cells, leading to CDK4/6i resistance. Furthermore, exosomal miR-20 could directly target the RB1 mRNA 3′UTR and negatively regulate RB1 expression to decrease CDK4/6i sensitivity in breast cancer cells. Most importantly, we designed and synthesized cRGD-miR-20 sponge nanoparticles and found that they can enhance the therapeutic effect of CDK4/6i in breast cancer. In summary, our findings reveal that CD63+ CAFs can promote CDK4/6i resistance via exosomal miR-20, which induces the downregulation of RB1 in breast cancer cells, and suggest that CD63+ CAFs may be a novel therapeutic target to enhance CDK4/6i sensitivity.

Expression of concern—Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study

Expression of concern—Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study

Efficacy and safety of tucidinostat in patients with advanced hormone receptor-positive human epidermal growth factor receptor 2-negative breast cancer: real-world insights.

Tucidinostat, which is a subtype-selective histone deacetylase inhibitor, has been approved in China for the treatment of hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). However, existing evidence mainly stemmed from randomized controlled trials, and might have limitations in representing the complexities of clinical practice and diverse patient populations. Therefore, there is a need to explore the efficacy and optimal therapeutic modality for tucidinostat in real-world clinical settings. The objective of this real-world study was to analyze the clinical data of 47 patients with HR+/HER2- ABC who received tucidinostat treatment at West China Hospital, Sichuan University, between August 2020 and May 2023. The primary outcomes were progression-free survival (PFS) and clinical benefit rate [CBR; defined as partial response (PR) and stable disease (SD) for ≥6 months on clinical evaluation]. A total of 47 patients were included, and the median follow-up time was 18.20 months. The median line of tucidinostat therapy was 3 (range, 1-9). In all, 52.17% patients were treated with tucidinostat plus fulvestrant, while 38.30% were treated with tucidinostat plus aromatase inhibitors. Notably, 10.64% of the patients with rapidly progressing visceral metastases received tucidinostat plus endocrine therapy as maintenance treatment after achieving disease control with chemotherapy. The median PFS was 4.43 months [95% confidence interval (CI), 2.77-10.53], and the median overall survival was 19.57 months (95% CI, 12.83-not reached). The 6-month CBR for the overall population was 41.86%. Patients undergoing maintenance therapy demonstrated a significantly longer PFS than did those who did not receive it as maintenance therapy (14.13 vs. 3.93 months; P=0.01). Univariate Cox regression analysis showed that use of tucidinostat in lines 1-2, use of tucidinostat plus fulvestrant, presence of one metastatic site, and lack of brain metastasis were favorable factors for PFS. Thrombocytopenia was the most frequently reported adverse event, with an incidence rate of 31.91% at all grades and 14.89% at grade ≥3. Four (8.51%) patients discontinued the treatment. For patients with HR+/HER2- ABC, tucidinostat combination therapy offers certain survival benefits with controllable safety. Furthermore, compared with non-maintenance therapy, maintenance therapy after chemotherapy may have promising efficacy.

Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia.

Treatments for PIK3CA-mutant cancers are limited by toxicities associated with the inhibition of WT PI3Kα. Molecular dynamics, cryo-electron microscopy, and DNA-encoded libraries were used to develop RLY-2608, a first-in-class inhibitor that demonstrates mutant selectivity in patients. This marks the advance of clinical mutant-selective inhibition that overcomes limitations of orthosteric PI3Kα inhibitors. See related commentary by Gong and Vanhaesebroeck, p. 204 . See related article by Varkaris et al., p. 227 . This article is featured in Selected Articles from This Issue, p. 201.

The Evolving Pathways of the Efficacy of and Resistance to CDK4/6 Inhibitors in Breast Cancer.

The approval of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) has remarkably improved the survival outcomes of patients with advanced hormone receptor-positive (HR+) breast cancer (BC), becoming the new standard of care treatment in these patients. Despite the efficacy of this therapeutic combination, intrinsic and acquired resistance inevitably occurs and represents a major clinical challenge. Several mechanisms associated with resistance to CDK4/6i have been identified, including both cell cycle-related and cell cycle-nonspecific mechanisms. This review discusses new insights underlying the mechanisms of action of CDK4/6i, which are more far-reaching than initially thought, and the currently available evidence of the mechanisms of resistance to CDK4/6i in BC. Finally, it highlights possible treatment strategies to improve CDK4/6i efficacy, summarizing the most relevant clinical data on novel combination therapies involving CDK4/6i.

384MO Final overall survival analysis for fulvestrant vs anastrozole in endocrine therapy (ET)-naïve, hormone receptor-positive (HR+) advanced breast cancer (FALCON)

384MO Final overall survival analysis for fulvestrant vs anastrozole in endocrine therapy (ET)-naïve, hormone receptor-positive (HR+) advanced breast cancer (FALCON)

Synergistic efficacy of PI3Kδ inhibitor with anti-PD-1 mAbs in immune-humanized PDX model of endocrine resistance hormone receptor-positive advanced breast cancer

PurposeEndocrine resistance hormone receptor-positive (HR+) advanced breast cancer (ABC) is generally insensitive to immunecheckpoint inhibitors (ICIs). This study sought to determine whether PI3Kδ inhibitor could enhance the sensitivity of endocrine resistance HR + advanced BC to ICIs by reducing immune evasion. MethodsPatient-derived HR + ABC xenografts were implanted into immune-humanized NSG mice and subsequently treated with YY20394 (PI3Kδ inhibitor) and camrelizumab. The mice were monitored for tumor progression, biochemical blood indicators, and peripheral blood T-cell subsets. The xenografted tumors were collected at the end of the treatment cycle and subjected to HE staining, immunohistochemistry and protein phosphorylation analysis. Besides, the xenografted tumors were also used to isolate primary breast cancer cells (BCCs) and regulatory T-cells (Tregs), which were subsequently used to evaluate drug sensitivity in vitro. ResultsThe humanized PDX model showed a favorable initial treatment response to camrelizumab combined with YY20394 and manageable toxicity. YY20394 plus camrelizumab showed a strong inhibitory effect on HR + BC in vivo mediated by suppression of Treg activity and an increased proportion of CD8+ T cells. Mice bearing tumors treated with YY20394 and camrelizumab had less invasion, mitotic figures, and ki67 expression, while having higher IL-12 expression compared with other groups. Mechanistically, YY20394 only effectively inhibited the PI3K pathway and proliferation activity in Tregs but not in BCCs. ConclusionOur study suggests PI3Kδ inhibitor could the enhance the efficacy of ICIs in HR + BC PDX models by combating immune suppression and provides a feasible approach that may overcome the resistance of ICIs in HR + BC patients.

Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer: a long-term safety and overall survival update from the randomised, double-blind, placebo-controlled, phase 3 trial.

The ACE study previously demonstrated that tucidinostat (chidamide), a subtype-selective histone deacetylase (HDAC) inhibitor, plus exemestane significantly improved progression-free survival (PFS) in advanced hormone receptor-positive (HR+) breast cancer patients with a manageable safety profile. The analysis of long-term safety and overall survival (OS) is presented here. ACE is a randomized, double-blind, placebo-controlled, phase 3 trial comparing tucidinostat 30 mg/twice weekly plus exemestane 25 mg/day versus placebo plus exemestane 25 mg/day in postmenopausal patients with advanced, HR+ breast cancer. The primary endpoint was PFS, and OS was the secondary endpoint. Of the 365 patients enrolled between July 2015, and June 2017, 244 were assigned to tucidinostat plus exemestane (tucidinostat group) and 121 to placebo plus exemestane group (placebo group). Baseline characteristics were well balanced between groups. The median follow-up from randomization to data cut-off (February 25, 2021) of this analysis was 26.5 months (range, 13.9-45.5 months). A total of 231 deaths (63.3%) from 365 patients occurred, including 155 deaths (63.5%) in the tucidinostat group and 76 deaths (62.8%) in the placebo group. The median OS was 30.3 months (95% CI, 26.7-36.7) in the tucidinostat group and 30.3 months (95% CI, 24.8-38.1) in the placebo group. The safety profiles of both tucidinostat and placebo groups remained consistent with those previously reported, and no new safety signals were observed with longer follow-up. Neutropenia of grade 3 or 4 occurred in 51.6% of the patients in the tucidinostat group and 2.5% of the patients in the placebo group. Adverse events (AEs) that led to treatment discontinuations from any cause occurred in 28 (11.5%) patients in the tucidinostat group and 4 (3.3%) in the placebo group. Although tucidinostat in combination with exemestane had produced a clinically meaningful and statistically significant improvement in the primary endpoint PFS, the ACE study did not show a prolongation of the secondary endpoint OS in the tucidinostat combination regimen. Ongoing studies have been considered in terms of potential identification of what patient subpopulations could benefit most from the tucidinostat combination regimens in advanced HR+ breast cancer.

Capivasertib in Hormone Receptor–Positive Advanced Breast Cancer

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

First-line systemic treatment with palbociclib in women aged ≥70 years presenting with hormone receptor-positive advanced breast cancer: Results from the PALOMAGE program.

1018 Background: Endocrine therapy (ET) combined with a CDK4/6 inhibitor is standard of care for hormone receptors-positive (HR+) advanced breast cancer (ABC). In France, 33% of BC are diagnosed in women aged 70 and older, contrasting with their constant underrepresentation in clinical trials. PALOMAGE, a prospective, observational, longitudinal real-life program, assessed the feasibility of ET combined with palbociclib (PAL), specifically in women aged ≥70 years with HR+ HER2- ABC. Methods: Depending on prior treatment for ABC and time of relapse, women were enrolled in two cohorts: ET-sensitive disease (no prior systemic treatment for ABC and no relapse within 1 year after adjuvant ET, cohort A) or ET-resistant disease (relapse on adjuvant ET or &lt; 1 year after completion, or prior treatment for ABC, cohort B). Data collected at baseline and then every 3 months included: sociodemographic, clinical, biological, disease- and treatment-related, response, quality of life (QoL; EORTC QLQ-C30 and ELD14), geriatric (G8 and Geriatric-COre DatasEt [G-CODE]) and safety. Results of feasibility in cohort B (rate of PAL discontinuation at 6 months 28.8%) were reported at SABCS 2021. Here, we report results in cohort A, based on the rate of PAL discontinuation at 18 months for any reason as the primary endpoint. Secondary endpoints included time-to-treatment failure (TTF), progression-free survival (PFS), QoL, and safety. Results: For this analysis, 362 patients (from 130 sites) with sufficient data were considered: median age was 78 years (range: 70-94), ECOG was ≥2 in 19.2%, and visceral metastases was present in 39.8%. PAL starting dose was 125 mg, 100 mg, and 75 mg in 80.0%, 14.4%, and 5.6% of patients, respectively, and combined with an aromatase inhibitor in 93.6% or fulvestrant in 6.4%. Baseline scores showed G8 ≤14, ADL ≤5 and IADL ≤3 in 68.2%, 15.5% and 29.4% of patients, respectively. Among the 362 patients, 327 were evaluable for the primary endpoint. With a median follow-up of 20.7 months (95% CI: 18.8-22.0), the 18-month discontinuation rate for PAL was 41.9% (95% CI: 36.6%-47.2%), due to disease progression (20.8%), toxicity (7.7%), patient’s choice (6.7%), death (4.6%), or other reason (2.1%). Median TTF and PFS were 22.7 months (95% CI: 19.1–26.0) and 28.1 months (95% CI: 25.6-not reached), respectively. Safety profile showed (360 patients evaluable) 54.4% all grade neutropenia (1.1% febrile neutropenia). Impact of geriatric status on effectiveness and safety will be presented, together with the evolution of QoL. Conclusions: In a large real-life population of older women with G8 impaired in two thirds and with ET-sensitive ABC, discontinuation rate of PAL at 18 months was 41.9%, with a median PFS of 28.1 months, consistent with PALOMA2 results. Optimized ET combined with PAL is feasible in unselected older women with HR+ ET-sensitive ABC.

Phase 2 study of HDAC inhibitor tucidinostat in combination with anti-PD-1 antibody in patients with locally advanced or metastatic urothelial carcinoma.

e16563 Background: Tucidinostat (also known as chidamide), a novel histone deacetylase (HDAC) inhibitor, has been approved for treatment of patients (pts) with relapsed or refractory peripheral T-cell lymphoma and advanced hormone receptor-positive breast cancer in China. Tislelizumab (a PD-1 checkpoint inhibitor) is currently approved for pts with PD-L1-high locally advanced or metastatic urothelial carcinoma (UC) who progressed during/following platinum-containing therapy in China. However, the response rate of tislelizumab as monotherapy is limited in UC. The aim of this study was to evaluate the efficacy and safety of tucidinostat combined with tislelizumab in pts with locally advanced or metastatic UC. Methods: This study is an open-label, single-center, phase Ⅱ trial. Patients who previously failed systemic platinum-based chemotherapy with UC were included, regardless of PD-L1 status. Eligible pts received 30 mg oral tucidinostat twice weekly (BIW) in combination with 200 mg tislelizumab by intravenous drip every three weeks (Q3W). This is a Simon's two-stage design. All pts were treated until progression or unacceptable toxicity in two years. The primary endpoint was objective response rate (ORR). The secondary endpoints included progression free survival (PFS), disease control rate (DCR), overall survival (OS), the safety and tolerability. Results: From Jan. 2021 to Sep. 2022, 26 pts were enrolled (median age 62 y, range 31-74y), of whom 24 were evaluable for response per RECIST 1.1 criteria. One pt was lost to follow-up and one withdrew the group due to sudden cerebral infarction. Complete response (CR) was observed in 2 pts, while partial response (PR) was observed in 8 pts, with an ORR of 41.7% (10/24). The DCR was 62.5%. The median PFS was 4.6 months. Most adverse events (AEs) were grade 1 or 2. The most common grade 3 AEs were neutropenia 11.5%, thrombocytopenia 11.5%, leukopenia 7.7%, anemia 7.7%, anorexia 7.7%, creatinine increased 3.8%. One pt experienced grade 4 immuno-pneumonia was permanently discontinued. One pt was on maintenance therapy of tucidinostat without immunotherapy because of interstitial pneumonia. Conclusions: The preliminary data indicate that tucidinostat combined with tislelizumab might be a potentially effective regimen with a manageable safety profile in UC. The study remains ongoing and updated results will be presented later. Clinical trial information: NCT04562311 .

Tolerability and effectiveness of fulvestrant as first-line endocrine therapy in unselected patients with advanced breast cancer (ABC): Results of a multicenter, single arm, non-interventional study.

e13061 Background: Fulvestrant, a selective estrogen receptor (ER) down-regulator, is a standard of care for first-line treatment in hormone receptor-positive (HR+) advanced breast cancer. This study is to assess the safety profile and effectiveness of fulvestrant 500mg as the first-line endocrine therapy of post-menopausal women with HR+ locally advanced or metastatic breast cancer. Methods: The study is an open-label, multicentre, prospective, observational study in China. Chinese patients receiving fulvestrant 500mg as the first endocrine agent after relapse according to investigator’s clinical practice were enrolled. Primary variable is the frequency and severity of adverse events (AEs). Secondary variables were objective response rate (ORR), clinical benefit rate (CBR), progress free survival (PFS) and overall survival (OS). Predictive effects of endocrine resistance, chemotherapy for advanced disease and adjuvant endocrine therapy on the effectiveness were prespecified as exploratory variables. Results: From November 2017 to December 2020, 461 patients were enrolled by 29 Chinese centers. Median age was 56 years and the ECOG score was: 0, 165 (35.8%); 1, 281 (60.9%); 2, 12 (2.6%); and 3, 3 (0.7%). 20 (4.3%) patients had the Kaplan-Feinstein index ≥2. Majority (77.0%) of the patients were ER+ and PgR+, and 190 (41.2%) had visceral metastasis. In total, 91 (19.7%) patients were primary endocrine resistant, 202 (43.8%) were secondary endocrine resistant and 123 (26.7%) were endocrine-therapy naïve. 147 (31.9%) patients received previous chemotherapy for advanced disease, while 101 (21.9%) patients had anti-estrogen drugs as adjuvant therapy. 54 (11.7%) patients had concurrent CDK4/6 inhibitors. After a median follow-up of 26.8 months (IQR 18.7-38.2), median PFS was 13.0 months (95% CI 9.8-16.4) and median OS was 41.2 months (95% CI 37.3-NE). ORR was 11.3% (95% CI 8.2-15.1) and CBR was 60.6% (95%CI 55.2-65.8). Patients with endocrine-therapy naïve tumor, no previous chemotherapy for advanced disease and adjuvant anti-estrogen treatment had a longer PFS of first-line fulvestrant 500mg. 67 (14.5%) patients had at least one AE, with 1 (0.2%) patient withdrawing because of AEs. Drug-related serious AEs (SAEs) were rare, occurring in 2 (0.4%) patients. No patient died as a result of a drug-related AE. Neutropenia, increased ALT/AST, and anemia were the most commonly reported AEs in this study. Conclusions: This is the first prospective real-world study confirming that fulvestrant 500mg is a well-tolerated treatment option in unselected ABC in China. In the real clinical practice, fulvestrant 500mg can achieve the consistent anti-tumor activity as in clinical trials. Patients with endocrine-therapy naïve status and no prior chemotherapy tend to have a longer control time. Clinical trial information: NCT02909361 .

Optimal Treatment of Hormone Receptor-positive Advanced Breast Cancer Patients With Palbociclib.

Palbociclib was the first cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor approved worldwide. Currently, CDK4/6 inhibitors are strongly recommended for endocrine therapy in the first or second line with hormone receptor-positive advanced breast cancer. It is expected the use of CDK4/6 inhibitor will further increase. Therefore, the aim was to investigate and better understand the use of palbociclib. We retrospectively analyzed the data of patients with advanced breast cancer who were treated with palbociclib in three hospitals between 2018 and 2022. Clinical data were obtained from the patients' medical electronic records. A total of 143 patients were enrolled. The median age was 66 years (range=33-89), and the majority (90.9%) were postmenopausal patients. In total, median time-to-treatment discontinuation (TTD) (95% confidence interval, CI) was 7 (6-10) months. Median TTD (95% CI) was 13 (7-20) months for the first or second line, and significantly prolonged compared to TTD for the third or later lines with palbociclib (p<0.0001). The importance of front-line use was indicated. Multivariate analyses showed that no visceral metastasis or first or second line therapy influenced the longer TTD. Between patients above or below 70 years of age, older age did not negatively affect TTD, though there were significantly more cases of dose reduction or withdrawal in patients over 70 years old. The variation of adverse events (AEs) among hospitals was very large (9.0%, 31.3%, 4.5%). We found that understanding of AE management was important. This study showed that dose reduction or withdrawal of palbociclib had no harmful effects in Japanese patients. Efficacy was also high in older patients. It is important to manage palbociclib administration more safely and appropriately. A combination of dose reduction and withdrawal is key to this therapeutic strategy.