Hormone Receptor-positive Advanced Breast Cancer Research Articles

Mechanisms of endocrine resistance in hormone receptor-positive breast cancer.

Hormone receptor-positive breast cancer may recur or metastasize years or decades after its diagnosis. Furthermore, hormone receptor expression may persist in relapsed or metastatic cancer cells. Endocrine therapy is one of the most efficacious treatments for hormone receptor-positive breast cancers. Nevertheless, a considerable proportion of patients develop resistance to endocrine therapy. Previous studies have identified numerous mechanisms underlying drug resistance, such as epigenetic abnormalities in the estrogen receptor (ER) genome, activation of ER-independent ligands, and alterations in signaling pathways including PI3K/AKT/mTOR, Notch, NF-κB, FGFR, and IRE1-XBP1. This article reviews the mechanisms of endocrine resistance in hormone receptor-positive advanced breast cancer, drawing from previous studies, and discusses the latest research advancements and prospects.

Pathological complete response after neoadjuvant cyclin-dependent kinase 4/6 inhibitor and neoadjuvant endocrine therapy in locally advanced hormone receptor-positive breast cancer

Breast cancer (BC) comprises different molecular subtypes, each having its own individual prognostic factors and thus having a distinct treatment algorithm. With the advent of cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors, hormone receptor-positive (HR+) BC now has an additional targeted therapeutic option apart from endocrine therapy. As of now, CDK 4/6 inhibitors are Food and Drug Administration (FDA) approved in the metastatic and adjuvant settings. However, for the neoadjuvant setting, systemic chemotherapy is the standard of care. Systemic chemotherapy may not be a suitable option for elderly and frail patients in terms of associated side effects. Thus, due to tailored oncological management, many phase II and III trials of neoadjuvant CDK 4/6 inhibitors are ongoing. CDK 4/6 inhibitors are better tolerated than systemic chemotherapy and have less reported adverse events. Here, we report a case of locally advanced BC (HR+) achieving pathological complete response from neoadjuvant CDK 4/6 inhibitor with minimal toxicity. Thus, CDK 4/6 inhibitors appear to have a promising and upcoming role in the neoadjuvant setting for hormone-positive BC.

A plain language summary of the CAPItello-291 study: Capivasertib in hormone receptor-positive advanced breast cancer.

This is a summary of the article discussing the results of the CAPItello-291 study. In the study, participants had advanced breast cancer that could not be completely removed with surgery, and that was diagnosed as a type of breast cancer where tumor cells had hormone receptors (HR-positive) but did not have HER2 receptors (HER2-negative). All participants were also required to have previously received treatment with a type of therapy called an aromatase inhibitor (with or without a CDK4/6 inhibitor), but over time their cancer cells had still grown or spread. The CAPItello-291 study researchers wanted to find out if a treatment combination of the medications capivasertib plus fulvestrant worked better than placebo plus fulvestrant. Capivasertib is a drug that blocks the activity of a protein called AKT, which is found inside breast cancer cells. The main finding was that participants who took capivasertib plus fulvestrant lived longer without their disease getting worse (progressing) compared with those treated with placebo plus fulvestrant. This is called progression-free survival. This result was seen across all participants (median progression-free survival of 7.2months with capivasertib plus fulvestrant vs 3.6months with placebo plus fulvestrant). It was also seen in participants whose tumors had detectable genetic alterations in genes called PIK3CA, AKT1, and/ or PTEN (median progression-free survival of 7.3months with capivasertib plus fulvestrant vs 3.1months with placebo plus fulvestrant). The most common side effects experienced by participants included diarrhea and different types of rash. These were as expected (given how capivasertib works). The CAPItello-291 study is still ongoing, and more results are expected to be released in the future. Results from the CAPItello-291 study showed that capivasertib plus fulvestrant compared with placebo plus fulvestrant improved progression-free survival in participants with HR-positive/ HER2-negative advanced breast cancer whose cancer had grown or spread despite hormone therapy (with/without a CDK4/6 inhibitor).Clinical Trial Registration: NCT04305496 (CAPItello-291) (ClinicalTrials.gov).

AI-based big data analysis of user-generated content to understand adherence in oral hormone receptor-positive advanced breast cancer treatment: A literature review and patient-centered approach using natural language processing

AI-based big data analysis of user-generated content to understand adherence in oral hormone receptor-positive advanced breast cancer treatment: A literature review and patient-centered approach using natural language processing

Palbociclib in adults aged 70 years and older with advanced breast cancer: A phase 2 multicenter trial (Alliance A171601)

IntroductionPalbociclib is a widely used treatment for advanced breast cancer in older adults. However, the existing evidence regarding its safety and tolerability in this age group is inconsistent and limited to retrospective subgroup or pooled analyses. Materials and MethodsWe conducted a prospective single-arm multicenter phase 2 study to evaluate the safety and tolerability of palbociclib in participants aged 70 years or older with advanced hormone receptor-positive breast cancer. Participants were given palbociclib in combination with their physician's choice of endocrine therapy (letrozole or fulvestrant). The primary endpoint was the incidence of grade 3+ adverse events (AEs) by six months. Secondary endpoints included AE-related dose delays, dose reductions, early discontinuations, and hospitalizations. Additionally, we compared these endpoints by age groups (70–74 and ≥ 75 years). ResultsOf the 90 participants (median age 74 years [70–87]) enrolled, 75.6% (95% confidence interval [CI], 65.4–84.0) had grade 3+ AEs by six months. The most frequent grade 3+ AEs were neutropenia (61%), fatigue (4%), and nausea (3%). Febrile neutropenia was uncommon (1.1%). Due to AEs, 36% had dose delays, 34% had dose reductions, 10% had early discontinuations, and 10% had hospitalizations. Compared to those aged 70–74 years, participants aged ≥75 years had higher rates of early discontinuations (5.9% vs 15.9%, a difference of 9.5% [95% CI 3.5%–22.5%]). DiscussionPalbociclib has an overall favorable safety profile in adults aged ≥70 with advanced breast cancer. However, adults ≥75 years had a trend toward higher rates of AE-related early discontinuations compared to those 70–74 years. Further research is needed to evaluate tolerability and improve the delivery of palbociclib in older adults.ClinicalTrials.gov:NCT03633331

Entinostat, a class I selective histone deacetylase inhibitor, plus exemestane for Chinese patients with hormone receptor-positive advanced breast cancer: An overall survival update and long-term safety from the randomised, double-blind, placebo-controlled, phase 3 trial.

1050 Background: Entinostat, a synthetic benzamide derivative HDAC inhibitor, selectively targets Class I HDAC enzymes. In a randomized, double-blind, phase 3 trial, entinostat with exemestane demonstrated a statistically significant progression-free survival (PFS) benefit compared to placebo, with a median PFS of 6.32 months versus 3.72 months (HR 0.76, 95% CI 0.58-0.98, p=0.046; Binghe Xu, et al. Acta Pharm Sin B. 2023). This analysis focus on the results of overall survival (OS) and long-term safety. Methods: Patients eligible for this study had HR+/HER2– advanced breast cancer (ABC) with disease relapse or progression following at least one prior endocrine therapy (ET). They were randomly assigned in a 2:1 ratio to receive either entinostat (5mg, weekly) or placebo in combination with exemestane until disease progression or unacceptable toxicity. The primary endpoint of the study was PFS. Secondary endpoints included OS, objective response rate, clinical benefit rate and safety. Median OS was estimated using the Kaplan-Meier method and the HR and its 95% CI were calculated using the multivariate Cox proportional hazard regression model. Results: A total of 354 patients were randomized to receive either entinostat (n=235) or placebo (n=119). As of the data cutoff date (July 31, 2023), 196 (55.4%) OS events had occurred, with a median follow-up of 31.83 months. There were 127 (54.0%) deaths in the entinostat arm compared to 69 (58.0%) deaths in the placebo arm. The entinostat demonstrated improved OS compared to placebo, with a median OS of 38.39 months versus 29.18 months (HR 0.837, 95% CI 0.624-1.124, p=0.237) in the full analysis set (FAS). The results of the per-protocol analysis set (PPS) were consistent with those of the FAS, showing a median OS of 39.01 months versus 33.98 months (HR 0.796, 95% CI 0.588-1.079, p=0.142). Notably, 179 (76.2%) patients in the entinostat arm and 100 (84%) patients in the placebo arm received new anti-cancer regimens, including CDK4/6 inhibitors (14.5% vs 24.4%), chemotherapy (54.9% vs 63.9%), endocrine therapy (40.4% vs 42.9%), and herbal medicines (9.8% vs 3.4%). After adjusting for the imbalance in the use of CDK4/6 inhibitors and chemotherapy between the treatment arms, the HR for overall survival was 0.78 (95% CI 0.58-1.05, p=0.097). The updated safety results were generally consistent with the previous analysis. Conclusions: The combination of entinostat with exemestane has provided clinically meaningful OS benefit in addition to the previously observed PFS benefit over exemestane alone in patients with pre-treated, ET-resistant ABC. These findings further support entinostat as an effective and safe treatment option for the specific patient population. Clinical trial information: NCT03538171 .

Symptom management through electronic patient-reported outcome (ePRO)-based intervention in patients with breast cancer treated with abemaciclib: Primary results from the LIBRA study, a phase II randomized controlled trial.

11110 Background: We have developed a system using LINE, a widely-used social network service in Japan, for rapid collection of ePROs based on the PRO-CTCAE criteria. To evaluate the effectiveness of intervention through this system in reducing diarrhea frequency and enhancing quality of life (QOL) in patients treated with abemaciclib, we conducted a randomized controlled trial. Methods: Patients with hormone receptor-positive advanced breast cancer scheduled to begin abemaciclib treatment were randomized to the intervention and control arms with 1:1 ratio. The LINE-ePRO system was used to monitor symptoms daily in both arms. In the intervention arm, expert medical staffs contacted patients via phone when symptoms met certain criteria, whereas patients in the control arm received standard care. The primary endpoint was the increase in the number of defecations from baseline during 28 days. The secondary endpoints included the increase in the number of defecations from baseline during 56 days, other symptoms monitored via the LINE-ePRO system, QOL evaluated by EORTC QLQ C-30 and EQ-5D-5L, relative dose intensity (RDI), treatment interruption rate, progression-free survival (PFS), and overall survival (OS). This study (LIBRA, UMIN000045432) is funded by Eli Lilly. Results: Between Jan 2022 and Apr 2023, 60 women were enrolled and 58 (29 in each arm) were analyzed in this study. Median age was 57.5 years (range 43-80), 93% of patients were post-menopausal, 71% received abemaciclib as first-line treatment, and 74% were treated in combination with aromatase inhibitors. The increase in the number of defecations from baseline was significantly lower in the intervention arm compared to the control arm both during 28 days (0.64 vs. 1.21 per day, p=0.003) and during 56 days (0.55 vs. 1.18 per day, p=0.0004). No significant difference was observed in other symptoms between the arms. In the EORTC QLQ C-30 scales, global health status/QOL (mean score change from baseline to after one cycle of abemaciclib treatment: 0 vs. -13.5, p=0.038) and diarrhea (20.7 vs. 32.2, p=0.049) were better in the intervention arm. The treatment interruption and dose reduction rates were 41.4 and 31.0% in the intervention arm, and 31.0 and 27.6% in the control arm, respectively. The mean RDI of abemaciclib was numerically lower in the intervention arm (73.5% vs. 84.8%). Conclusions: This study is the first randomized trial to demonstrate that the intervention based on daily ePROs reduces the frequency of diarrhea in patients with advanced breast cancer treated with abemaciclib. Clinical trial information: UMIN000045432.

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)