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AbstractBackgroundMethodsResultsConclusion\nPLAIN LANGUAGE SUMMARYCyclin-dependent kinase 4/6 (CDK 4/6) inhibitors have emerged as a significant advancement in the treatment of HR+/HER2− metastatic breast cancer (MBC). Despite the clinical efficacy of CDK 4/6 inhibitors in HR+/HER2− metastatic breast cancer, there remains a significant gap in understanding their cost-effectiveness, particularly regarding the long-term economic impact and the key drivers of costs, when used in combination with endocrine therapy. This study aims to systematically review and conduct a meta-analysis of cost-effectiveness studies evaluating CDK4/6 inhibitors in treatment of HR+/HER2− advanced breast cancer and identify key drivers of costs of CDK4/6 inhibitors in combination with endocrine therapy.A comprehensive search of PubMed and Embase was conducted to identify peer-reviewed studies from February 2015 to March 2022 reporting cost-effectiveness of CDK4/6 inhibitors in MBC treatment. Incremental net benefits (INBs) were estimated, and meta-analysis was conducted. This review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.We identified 120 articles, of which 18 were eligible for systematic review and 16 for meta-analysis. None of the three CDK4/6 inhibitors had positive INB compared to endocrine/aromatase inhibitors therapy alone. The pooled INB was estimated at −$149,266.87 (95% Confidence Interval (CI) = −$196,961.54, −$101,572.20).The combination of CDK4/6 inhibitors and letrozole/endocrine therapy for the treatment of postmenopausal patients with advanced HR+/HER2 − MBC was not cost-effective.Breast cancer, a significant health concern worldwide, represents around 30% of new cancer diagnoses and 25% of cancer related fatalities. Among these cases, approximately two-thirds are characterized by hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) tumors. In the metastatic stage, up to half of patients exhibit inherent resistance to endocrine therapy, leading to poorer survival rates, while others, initially responsive, eventually develop resistance, leading to disease progression and eventual mortality. Nevertheless, recent advancements in CDK4/6 inhibitors have shown efficacy in overcoming both inherent and acquired endocrine resistance, representing a substantial breakthrough in HR+/HER2− metastatic breast cancer treatment. This study conducts a review of literature focusing on comparative cost-effectiveness and economic evaluations of the three CDK4/6 inhibitors, evaluating the pooled incremental net benefit (INB) reported in these studies. It marks the first attempt to compare all three CDK4/6 inhibitors and employs a meta-analysis approach to ascertain the option demonstrating the most positive INB. Our findings indicate that CDK4/6 inhibitors fail to provide an economic advantage over letrozole or endocrine therapy alone. The aim of this study is to offer insights for clinical and reimbursement decision-making in the treatment of postmenopausal patients with advanced HR+/HER2− breast cancer, providing valuable guidance for policymakers, payers, and clinicians. [ABSTRACT FROM AUTHOR]

Background: Absolute lymphocyte count (ALC) is a predictive and prognostic factor for various tumor types, including breast cancer. Palbociclib is a CDK4/6 inhibitor widely used for the treatment of metastatic estrogen receptor (ER)-positive, HER2-negative breast cancer. However, predictive biomarkers of the efficacy of palbociclib remain unelucidated. We conducted a retrospective study to examine the predictive value of the baseline ALC in patients treated with palbociclib. Methods: The medical records of patients with ER-positive, HER2-negative breast cancer treated with palbociclib plus hormonal therapy between December 2017 and December 2021 were analyzed retrospectively. The cutoff value of ALC was set at 1800 cells/μL at the initiation of palbociclib treatment. The clinical benefit rate (CBR) was defined as the rate of complete or partial response or stable disease for at least 6 months. Progression-free survival (PFS) rates were estimated using the Kaplan–Meier method and compared using the log-rank test. Univariate and multivariate analyses were performed using Cox proportional hazards regression. Results: All of the 202 patients were women, with a median age of 59 years and a performance status (PS) of ≤ 2. The median numbers of lines of chemotherapy and endocrine therapy before palbociclib treatment were 0 (range, 0–9) and 1 (range, 0–7), respectively. Fifty-one patients had liver metastases. Forty-six patients tested negative for progesterone receptor (PgR) expression. The median follow-up time was 9.1 months. The CBR was significantly higher in the ALC-high group than in the ALC-low group (79% vs. 60%; P = 0.018). The median PFS was significantly longer in the ALC-high group than in the ALC-low group (26.8 months vs. 8.4 moths, respectively; P = 0.000013). ALC, age, PS, PgR status, prior chemotherapy, prior endocrine therapy, and liver metastasis were entered into the multivariate analysis. ALC was identified as an independent factor for PFS (P = 0.00085), along with liver metastasis (P = 0.0020), PS (P = 0.026), and prior endocrine therapy (P = 0.019). Conclusion: ALC can serve as a predictor of palbociclib efficacy in patients with metastatic ER-positive, HER2-negative breast cancer. [ABSTRACT FROM AUTHOR]

Background: The combination of CDK4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) is currently the standard first-line treatment for patients with metastatic hormone receptor positive (HR+), and HER2-negative (HER2-) breast cancer. However, the impact of HER2 status on the prognosis of patients receiving CDK4/6i and ET remains unclear. The meta-analysis was conducted to evaluate different outcomes between HER2-low and HER2-zero patients in advanced HR+ breast cancer receiving CDK4/6i and ET. Methods: A systematic search was performed in PubMed and EMBASE databases for relevant published literature. Objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) were pooled by fixed or random effects models. Results: Overall, 12 studies with 3567 patients were eligible for analysis. The pooled analysis suggested that no significant differences were observed in terms of ORR and OS between HER2-low and HER2-zero patients who underwent CDK4/6i and ET. Similarly, no significant difference in PFS was found between HER2-low and HER2-zero patients who underwent post-line CDK4/6i and ET or first-line Palbociclib and ET. However, in patients who received mixed-line (not a single treatment line) or first-line CDK4/6i and ET, the PFS was significantly shorter in the HER2-low subgroup than in the HER2-zero subgroup (mixed-line: HR = 1.36; 95% CI = 1.11–1.65; P = 0.002; first-line: HR = 1.14; 95% CI = 1.01– 1.28; P = 0.04). A similar phenomenon was observed in patients who received mixed-line or post-line Palbociclib and ET (mixed-line: HR = 1.60; 95% CI = 1.09–2.34; P = 0.02; post-line: HR = 1.43; 95% CI = 1.03–2.00; P = 0.03). Conclusion: These results indicated that HER2-low status did not have a significant association with ORR and OS, but it may have a worse impact on PFS in patients who received mixed-line or first-line CDK4/6i and ET, as well as mixed-line or post-line palbociclib plus ET. [ABSTRACT FROM AUTHOR]

Introduction: Hotspots (HS) mutations in the PIK3CA gene may lead to poorer oncological outcomes and endocrine resistance in advanced breast cancer (BC), but their prognostic role in early‐stage disease remains controversial. The overall agreement within plasma and tissue methods has not been well explored. Our aim was to correlate tissue and plasma approaches and to analyze the prognostic impact of PIK3CA mutations (PIK3CAm) in HR+/HER2− BC. Methods: A retrospective and unicentric analysis of PIK3CA mutational status in tissue and plasma samples by Cobas®PIK3CA Mutation Kit in patients with HR+/HER2− BC. Results: We analyzed 225 samples from 161 patients with luminal BC. PIK3CA mutations were identified in 62 patients (38.5%), of which 39.6% were found in tissue and 11.8% in plasma. In advanced disease, plasma and tissue correlation rate was performed in 64 cases, with an overall agreement of 70.3%. Eighty patients were treated with CDK4/6 inhibitors + endocrine therapy. We observed a moderately worse progression‐free survival (PFS) in PIK3CAm versus wild‐type (WT) (24 m vs. 30 m; HR = 1.39, p = 0.26). A subanalysis was carried out based on exons 9 and 20, which showed a statistically poorer PFS in PIK3CAm exon 9 versus 20 population (9.7 m vs. 30.3 m; HR = 2.84; p = 0.024). Furthermore, detection of PIK3CAm in plasma was linked to a worse PFS vs PIK3CAm detection just in tissue (12.4 vs. 29.3; HR = 2.4; p = 0.08). Conclusions: Our findings suggest the PIK3CA evaluation in tissue as the diagnostic method of choice, however, additional investigations are required to improve the role of liquid biopsy in the PIK3CA assessment. PIK3CAm show worse outcomes in advanced luminal BC, especially in exon 9 mutation carriers, despite visceral involvement, prior exposure to endocrine therapy or detection of PIK3CAm in plasma, with an unclear prognosis in early‐stage disease. Nonetheless, this should be validated in a prospective cohort study. [ABSTRACT FROM AUTHOR]

CAPItello-291 is an ongoing phase 3 trial in which capivasertib–fulvestrant significantly improved progression-free survival versus placebo–fulvestrant in patients with hormone receptor-positive, HER2-negative advanced breast cancer who had relapse or disease progression during or after aromatase inhibitor treatment, in both the overall population and in patients with PIK3CA , AKT1 , or PTEN -altered tumours. This study further explored patient-reported health-related quality of life (HRQOL), functioning, symptoms, and symptom tolerability in CAPItello-291. This phase 3, randomised, double-blind, placebo-controlled trial, which was conducted across 193 hospitals and cancer centres in 19 countries, enrolled women with any menopausal status or men, aged ≥18 years (≥20 years in Japan), with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer who had relapse or disease progression during or after treatment with an aromatase inhibitor, with or without previous cyclin-dependent kinase (CDK) 4 or 6 inhibitor therapy. Patients had an Eastern Cooperative Oncology Group/WHO performance score of 0 or 1 and could have received up to two previous lines of endocrine therapy and up to one previous line of chemotherapy for advanced disease. Patients were randomly assigned (1:1) using block randomisation (stratified according to the presence or absence of liver metastases, previous use of a CDK4/6 inhibitor [yes vs no], and geographical region) to receive oral capivasertib 400 mg (twice daily for 4 days, followed by 3 days off) plus intramuscular fulvestrant 500 mg (every 14 days for the first three injections, then every 28 days) or placebo with matching fulvestrant dosing. The dual primary endpoint of the trial was investigator-assessed progression-free survival assessed both in the overall population and among patients with PIK3CA , AKT1 , or PTEN -altered tumours. The EORTC Quality of Life Questionnaire 30-item core module (QLQ-C30) and breast module (QLQ-BR23), Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and Patient Global Impression of Treatment Tolerability (PGI-TT) questionnaires were used to assess patient-reported outcomes. Evaluation of EORTC QLQ-C30 and EORTC QLQ-BR23 were secondary endpoints and evaluation of PRO-CTCAE and PGI-TT were pre-defined exploratory endpoints, and these endpoints are the subject of analysis in this Article. Data were collected at baseline and prespecified timepoints. Patient-reported outcomes were analysed in all randomly assigned patients with an evaluable baseline assessment and at least one evaluable post-baseline assessment. Change from baseline was assessed using mixed model with repeated measures for EORTC QLQ-C30 and summarised for QLQ-BR23. Time to deterioration was described using the Kaplan–Meier method. PGI-TT and PRO-CTCAE responses were summarised at each treatment cycle. Patient-reported outcomes were not prospectively powered for statistical comparison. The trial is registered with ClinicalTrials.gov , NCT04305496. Between June 2, 2020, and Oct 13, 2021, 901 patients were enrolled, of whom 708 patients were randomly assigned to receive capivasertib–fulvestrant (n=355) or placebo–fulvestrant (n=353). The median age of the patients was 59 years (IQR 51–67) in the capivasertib–fulvestrant group and 58 years (IQR 49–66) in the placebo–fulvestrant group. At data cutoff (Aug 15, 2022), the median duration of follow-up for progression-free survival in censored patients was 13·0 months (IQR 9·1–16·7) for capivasertib–fulvestrant and 12·7 months (IQR 2·0–16·4) for placebo–fulvestrant in the overall population. EORTC QLQ-C30 global health status/quality of life (GHS/QOL) scores were maintained from baseline and were similar between treatment groups throughout the study period (difference in mean change from baseline of −2·5 [95% CI −4·5 to −0·6] with capivasertib–fulvestrant vs −5·6 [−7·9 to −3·4] with placebo–fulvestrant; treatment difference 3·1 [95% CI 0·2 to 6·0]). Median time to deterioration in EORTC QLQ-C30 GHS/QOL was 24·9 months (95% CI 13·8 to not reached) in the capivasertib–fulvestrant group and 12·0 months (10·2 to 15·7) in the placebo–fulvestrant group (hazard ratio [HR] 0·70, 95% CI 0·53 to 0·92). Time to deterioration HRs for all EORTC QLQ-C30 and QLQ-BR23 subscale scores showed little difference between the treatment groups, except for diarrhoea, which was worse in the capivasertib–fulvestrant group than in the placebo–fulvestrant group (HR 2·75, 95% CI 2·01–3·81). In PRO-CTCAE symptom assessment, the proportion of patients reporting loose and watery stools "frequently" or "almost constantly" was 29% higher at cycle 1, day 15 in the capivasertib–fulvestrant group than in the placebo–fulvestrant group, decreasing at subsequent cycles. Other PRO-CTCAE-reported symptoms (rash, mouth or throat sores, itchy skin, and numbness or tingling in hands or feet) were absent or mild in most patients in both groups throughout treatment. According to the PGI-TT, most patients in both groups reported "not at all" or "a little bit" of bother from treatment side-effects. Patient-reported outcomes from CAPItello-291 demonstrated that capivasertib–fulvestrant delayed time to deterioration of GHS/QOL and maintained other dimensions of HRQOL (except symptoms of diarrhoea) similarly to fulvestrant. With the clinical efficacy and manageable safety profile, these exploratory results further support the positive benefit–risk profile of capivasertib–fulvestrant in this population. AstraZeneca. [ABSTRACT FROM AUTHOR]

Purpose: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy have demonstrated significant clinical benefits in progression-free and overall survival. This study investigates the outcomes associated with two kinds of CDK4/6i in patients with hormone receptor (HR)-positive metastatic and relapsed breast cancer to inform real-world evidence of treatment strategies. Methods: This retrospective study included 340 Taiwanese patients with HR-positive advanced breast cancer from the Taipei Veterans General Hospital, between 2018 and 2023. We analyzed patient characteristics, treatment strategies and outcomes associated with two CDK4/6i. The efficacy of patients who experienced economic burden and interrupted CDK4/6i treatment after 2 years of National Health Insurance (NHI) reimbursement was also investigated. Results: Patients receiving ribociclib and palbociclib showed no significant differences in age, histology, body mass index(BMI), or pathologic status. The distribution of disease status and endocrine therapy partners was comparable between the two groups. Dose reduction was similar, while patients with palbociclib tended to discontinue CDK4/6i usage, and those with ribociclib tended to switch to the other CDK4/6i or endocrine partners. There was no significant difference in progression-free survival (PFS) between the two CDK4/6i in the first-line setting. Adverse prognostic factors were increasing HER2 IHC score, higher Ki-67 levels, visceral and liver metastasis, prior chemotherapy, and endocrine therapy resistance, while higher BMI, bone-only metastasis, and letrozole treatment were associated with a lower risk of progression. The limited follow-up time in our study was insufficient to assess the outcomes of patients treated with interrupted CDK4/6i for up to two years under the NHI reimbursement policy. Conclusion: Treatment outcomes between the two types of CDK4/6i did not differ significantly, indicating the safety and efficacy of CDK4/6i for the Asian population. Ribociclib and palbociclib showed similar efficacy in PFS in the real-world setting. [ABSTRACT FROM AUTHOR]

SERENA-1 (NCT03616587) is a phase I, multi-part, open-label study of camizestrant in pre- and post-menopausal women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer. Parts A and B aim to determine the safety and tolerability of camizestrant monotherapy and define doses for clinical evaluation. Women aged ≥18 years with metastatic or recurrent ER+, HER2− breast cancer, refractory (or intolerant) to therapy, were assigned 25 mg up to 450 mg once daily (QD; escalation) or 75, 150, or 300 mg QD (expansion). Safety and tolerability, antitumor efficacy, pharmacokinetics, and impact on mutations in the estrogen receptor gene (ESR1 m) circulating tumor (ct)DNA levels were assessed. By 9 March 2021, 108 patients received camizestrant monotherapy at 25-450 mg doses. Of these, 93 (86.1%) experienced treatment-related adverse events (TRAEs), 82.4% of which were grade 1 or 2. The most common TRAEs were visual effects (56%), (sinus) bradycardia (44%), fatigue (26%), and nausea (15%). There were no TRAEs grade 3 or higher, or treatment-related serious adverse events at doses ≤150 mg. Median t max was achieved ∼2-4 h post-dose at all doses investigated, with an estimated half-life of 20-23 h. Efficacy was observed at all doses investigated, including in patients with prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and/or fulvestrant treatment, with and without baseline ESR1 mutations, and with visceral disease, including liver metastases. Camizestrant is a next-generation oral selective ER antagonist and degrader (SERD) and pure ER antagonist with a tolerable safety profile. The pharmacokinetics profile supports once-daily dosing, with evidence of pharmacodynamic and clinical efficacy in heavily pre-treated patients, regardless of ESR1 m. This study established 75-, 150-, and 300-mg QD doses for phase II testing (SERENA-2, NCT04214288 and SERENA-3, NCT04588298). • SERENA-1 (A/B): safety and efficacy of camizestrant monotherapy (25-450 mg) in women with ER+ HER2- advanced breast cancer. • Efficacy was observed at all doses, regardless of prior treatment with CDK4/6i or fulvestrant, or of ESR1 mutation status. • At all doses investigated, median t max was achieved ∼2-4 h post-dose, with an estimated half-life of 20-23 h. • In total, 86.1% of patients experienced TRAEs, with none beyond grade 2 at ≤150 mg camizestrant. • Camizestrant is a next-generation oral SERD and pure ER antagonist with a tolerable safety profile, suitable for QD dosing. [ABSTRACT FROM AUTHOR]

Background: This study was designed to evaluate the effect of progesterone receptor (PR) status on the prognosis of advanced estrogen receptor (ER)-high human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients receiving CDK4/6 inhibitor combined with endocrine as first-line therapy. Methods: Advanced ER-high HER2-negative breast cancer patients who were admitted to Harbin Medical University Cancer Hospital and received cyclin-dependent kinase (CDK)4/6 inhibitor combined with endocrine as first-line therapy were included for analysis. Patients were divided into PR-high group (11-100%), PR-low group (1-10%), and PR-negative group (< 1%) according to the expression of PR. Chi-square test was used to analyze the correlation of variables between groups. COX regression analysis were used to analyze the risk factors of survival. Kaplan-Meier survival curve was used to analyze the differences of progression-free survival (PFS) and overall survival (OS) between groups. Results: Among the 152 patients, 72 were PR-high, 32 were PR-low, and 48 were PR-negative. Compared with PR-negative group, the proportions of disease-free survival (DFS) ≥ 5 years and Ki-67 index ≤ 30% in PR-low group and PR-high group were significant higher. PR-negative patients were more likely to occur first-line progression of disease within 24 months (POD24) than PR-high(P = 0.026). Univariate and multivariate analysis showed that PR-negative and first-line POD24 occurrence were risk factors for survival. Survival curve analysis showed that compared with PR-high group, the PFS and OS were significantly lower in PR-negative group (P = 0.001, P = 0.036, respectively). Patients with first-line POD24 had shorter OS in the overall population as well as in subgroups stratified by PR status. Conclusions: PR-negative and first-line POD24 occurrence were risk factors of advanced ER-high HER2-negative breast cancer patients receiving CDK4/6 inhibitor combined with endocrine as first-line therapy. PR-negative patients had shortest PFS and OS. Regardless of PR status, first-line POD24 occurrence predicted shorter OS. [ABSTRACT FROM AUTHOR]

Aims and objectives: Human epidermal growth factor receptor 2 (HER2)-low breast cancer (BC) is a new entity considered a biologically distinct subtype from HER2-zero BC. However, the importance of HER2 low expression on the activity of cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) remains unclear. Methods/materials: We conducted a single-center retrospective study including hormone receptor-positive (HR +) /HER2- metastatic BC (mBC) patients treated with CDK4/6i plus endocrine treatment (ET) as first-line therapy. Clinical outcomes were analyzed according to HER2 expression. Results: 258 women were analyzed with a median follow-up of 25.4 months; 39.9% had HER2 low, and 60.1% had HER2 zero BC. Median progression-free survival (mPFS) in the HER2-low group was 27.6 months compared with 44.3 months in the HER2-zero group (p = 0.341). In patients receiving ribociclib, the mPFS in the HER2-low group was 24.2 months compared with 53.1 months in the HER2-zero group (multivariate-adjusted HR: 1.981, 95 Cl 1.094–3.586; p = 0.024). The survival probabilities at 24, 36 and 48 months for the HER2 low and HER2 zero groups were 82%, 69%, 69% and 83%, 75% and 69%, respectively (p = 0.336). Objective response rate (p = 0.179) and disease control rate (p = 0.338) did not significantly differ between HER-2-low and HER-2-zero groups. Conclusions: The mPFS in the Her2-zero group was almost twice that of the Her2-low group, but the difference was not statistically significant. mPFS was significantly longer in the HER2-zero group compared to the HER2-low group in patients receiving ribociclib. More prospective studies are needed to understand the actual consequences of this biomarker. [ABSTRACT FROM AUTHOR]

Key Clinical Message: There is no consensus regarding the therapeutic approach of breast neuroendocrine carcinomas (NECs). As most NECs are hormone receptor positive and HER‐2 negative, we suggest that endocrine‐based strategies may play a leading role. Here, we report a new treatment strategy by incorporating CDK4/6 inhibitors in the therapeutic armamentarium. Primary neuroendocrine neoplasms of the breast constitute a rare entity. They are characterized by predominant neuroendocrine differentiation and are further divided into well‐differentiated neuroendocrine tumors and poorly differentiated (high‐grade) neuroendocrine carcinomas (NECs). Regarding their therapeutic approach, there are no standardized guidelines. Herein, we present the first case ever reported, concerning a female patient with de novo metastatic breast NEC who received hormonal therapy, a combination of a CDK4/6 inhibitor palbociclib with letrozole and triptorelin, as first‐line treatment with significant clinical and radiological response. As most NECs are estrogen receptor and/or progesterone receptor positive and HER‐2 negative, we suggest that hormonal therapy may play a leading role even in the first‐line setting. The present report provides a new treatment strategy by incorporating CDK4/6 inhibitors in the therapeutic armamentarium of breast NECs. [ABSTRACT FROM AUTHOR]

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) represent the gold standard of the hormone receptor positive human epidermal growth factor receptor 2 (HER-2) negative advanced breast cancer. However, optimal treatment after disease progression is a matter of debate. We aimed to assess predictive and prognostic factors associated with the treatment outcome following CDK4/6i progression. Methods: We retrospectively analyzed patients who progressed on CDK4/6i treatment between 2018 and 2024. Treatment based on molecular findings (PIK3CA mutation), genetic findings (BRCA1/2 germline mutation), or adapted to the change in the tumor phenotype in rebiopsy (anti-HER2 therapy in the transformation to HER-2-positive disease) was grouped into tailored treatment and compared to the endocrine-based therapy and chemotherapy alone. Results: Five hundred twelve patients were treated with CDK4/6i. Two hundred patients with disease progression were enrolled in the study. Duration of response to CDK4/6i was not predictive of the response to subsequent treatment, whereas the progression in the central nervous system was the worst prognostic factor. Thirty patients were ineligible for subsequent treatment. Survival after CDK4/6i progression was significantly longer in patients eligible for tailored treatment. The median PFS in patients with tailored treatment (n=19) was 13.5 months vs. 4.9 months in patients with non-tailored therapy (n=151; p=0.045). 12-month PFS was 54.1% with tailored treatment [95% CI 24.1–76.7%] compared to 18.5% with non-tailored therapy [95% CI 11.6– 26.6%]. The median OS for patients treated with a tailored approach was not reached compared to 11.5 months with non-tailored treatment (p=0.016). The 24-month OS for patients treated with a tailored approach was 80.2% [95% CI 40.3–94.8%] compared to 21.1% [95% CI 12.2–31.7%] for patients with nontailored treatment. Conclusions: Tailoring of subsequent treatment strategy seems to be essential for achieving long-term benefit. Further studies are required, as the prognosis after CDK4/6i progression remains dismal, especially in cases affecting the central nervous system. [ABSTRACT FROM AUTHOR]

Estrogen receptor (ER)-positive breast cancer (BC) is the most common BC subtype. Endocrine therapy (ET) targeting ER signaling still remains the mainstay treatment option for hormone receptor (HR)-positive BC either in the early or in advanced setting, including different strategies, such as the suppression of estrogen production or directly blocking the ER pathway through SERMs—selective estrogen receptor modulators—or SERDs—selective estrogen receptor degraders. Nevertheless, the development of de novo or acquired endocrine resistance still remains challenging for oncologists. The use of novel ET combined with targeted drugs, such as cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, has significantly improved long-term outcome rates, thus changing the therapeutic algorithm for metastatic BC (MBC) and recently the therapeutic strategy in the adjuvant setting for early high-risk BC. Eluding the resistance to CDK4/6 inhibitors combined with ET is currently an unmet medical need, and there is disagreement concerning the best course of action for patients who continue to progress after this combination approach. Genetic changes in the tumor along its growth uncovered by genomic profiling of recurrent and/or metastatic lesions through tumor and/or liquid biopsies may predict the response or resistance to specific agents, suggesting the best therapeutic strategy for each patient by targeting the altered ER-dependent pathway (novel oral SERDs and a new generation of anti-estrogen agents) or alternative ER-independent signaling pathways such as PI3K/AKT/mTOR or tyrosine kinase receptors (HER2 mutations or HER2 low status) or by inhibiting pathways weakened through germline BRCA1/2 mutations. These agents are being investigated as single molecules and in combination with other target therapies, offering promising weapons to overcome or avoid treatment failure and propose increasingly more personalized treatment approaches. This review presents novel insights into ET and other targeted therapies for managing metastatic HR+/HER2− BC by exploring potential strategies based on clinical evidence and genomic profiling following the failure of the CDK4/6i and ET combination. [ABSTRACT FROM AUTHOR]

Estrogen receptor positive (ER+) breast cancer is the most common breast cancer subtype, and therapeutic management relies primarily on inhibiting ER signaling. In the metastatic setting, ER signaling is typically targeted by selective estrogen receptor degraders (SERDs) or aromatase inhibitors (AIs), the latter of which prevent estrogen production. Activating ESR1 mutations are among the most common emergent breast cancer mutations and confer resistance to AIs. Until 2023, fulvestrant was the only approved SERD; fulvestrant is administered intramuscularly, and in some cases may also have limited efficacy in the setting of certain ESR1 mutations. In 2023, the first oral SERD, elacestrant, was approved for use in ESR1-mutated, ER+/HER2- advanced breast cancer and represents a new class of therapeutic options. While the initial approval was as monotherapy, ongoing studies are evaluating elacestrant (as well as other oral SERDs) in combination with other therapies including CDK4/6 inhibitors and PI3K inhibitors, which parallels the current combination uses of fulvestrant. Elacestrant's recent approval sheds light on the use of biomarkers such as ESR1 to gauge a tumor's endocrine sensitivity. Ongoing therapeutic and correlative biomarker studies will offer new insight and expanding treatment options for patients with advanced breast cancer. [ABSTRACT FROM AUTHOR]

Background: Cyclin‐dependent kinase (CDK) 4/6 inhibitor plus endocrine therapy (ET) become standard‐of‐care for patients with hormone receptor‐positive, human epidermal growth factor receptor‐2 negative (HR+/HER2−) metastatic breast cancer (MBC). However, the optimal therapeutic paradigm after progression on CDK4/6 inhibitor remains unclear. This study aimed to evaluate the efficacy and safety of abemaciclib with switching ET versus chemotherapy after progression on prior palbociclib‐based ET in Chinese patients with HR+/HER2− MBC. Methods: From 414 consecutive patients with HR+/HER2− MBC who had been treated with palbociclib plus ET from September 2018 to May 2022 in Peking University Cancer Hospital, we identified 80 patients who received abemaciclib plus switching ET or chemotherapy after progression on palbociclib, matched for age, original stage at diagnosis, disease‐free interval, and tumor burden at 1:1 ratio. The primary endpoint was progression‐free survival (PFS) compared using the Kaplan–Meier method. A Cox proportional hazard model was performed to identify clinical factors associated with PFS in the abemaciclib group. Results: The median PFS was 6.0 months (95% confidence interval [CI]: 3.94–8.06) in abemaciclib group and 4.0 months (95% CI, 2.52–5.49) in chemotherapy group (p = 0.667). And, there was no difference in median PFS between the sequential and nonsequential arm (6.0 vs. 6.0 months) in the abemaciclib group though fewer lines of prior systemic therapy and longer PFS from prior palbociclib in the sequential arm. However, patients with prior palbociclib as the first‐line therapy had a significantly longer median PFS versus prior palbociclib as ≥2nd‐line therapy (11.0 vs. 5.0 months, p = 0.043). Based on multivariable analysis, ER+/PR+ was an independent factor associated with longer PFS. There was no significant difference in overall survival between the abemaciclib and chemotherapy groups (p = 0.069). Conclusion: Our findings indicate that abemaciclib plus switching ET might be one of feasible treatment options for Chinese patients with HR+/HER2− MBC after progression on prior palbociclib‐based therapy in addition to chemotherapy. [ABSTRACT FROM AUTHOR]

Locally advanced breast cancer poses significant challenges to the multidisciplinary team, in particular with hormone receptor (HR) positive, HER2- negative tumors that classically yield lower pathological complete responses with chemotherapy. The increasingly significant use of CDK 4/6 inhibitors (CDK4/6i) plus endocrine therapy (ET) in different breast cancer settings has led to clinical trials focusing on this strategy as a primary treatment, with promising results. The impact of the microbiota on cancer, and vice-versa, is an emerging topic in oncology. The authors report a clinical case of a postmenopausal female patient with an invasive breast carcinoma of the right breast, Luminal B-like, staged as cT4cN3M0 (IIIB). Since the lesion was considered primarily inoperable, the patient started letrozole and ribociclib. Following 6 months of systemic therapy, the clinical response was significant, and surgery with curative intent was performed. The final staging was ypT3ypN2aM0, R1, and the patient started adjuvant letrozole and radiotherapy. This case provides important insights on primary CDK4/6i plus ET in locally advanced unresectable HR+/HER2- breast cancer and its potential implications in disease management further ahead. The patient's gut microbiota was analyzed throughout the disease course and therapeutic approach, evidencing a shift in gut microbial dominance from Firmicutes to Bacteroidetes and a loss of microbial diversity following 6 months of systemic therapy. The analysis of the intratumoral microbiota from the surgical specimen revealed high microbial dissimilarity between the residual tumor and respective margins. [ABSTRACT FROM AUTHOR]

Endocrine therapy (ET) with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is currently the first-line standard treatment for most patients with hormone receptor-positive (HR+) and human epidermal growth receptor 2-negative (HER2-) metastatic or advanced breast cancer. However, the majority of tumors response to and eventually develop resistance to CDK4/6is. The mechanisms of resistance are poorly understood, and the optimal postprogression treatment regimens and their sequences continue to evolve in the rapidly changing treatment landscape. In this review, we generally summarize the mechanisms of resistance to CDK4/6is and ET, and describe the findings from clinical trials using small molecule inhibitors, antibody-drug conjugates and immunotherapy, providing insights into how these novel strategies may reverse treatment resistance, and discussing how some have not translated into clinical benefit. Finally, we provide rational treatment strategies based on the current emerging evidence. [ABSTRACT FROM AUTHOR]

Background: Cyclin-dependent kinase 4 and 6 (CDK4 and CDK6) inhibitors have changed the therapeutic management of hormone receptor-positive (HR+) metastatic breast cancer (mBC) by targeting the cell cycle machinery and overcoming endocrine resistance. However, a large number of patients present disease progression due to cancer cells resisting CDK4/6 inhibitors. Our research considers which clinicopathological characteristics could be useful in identifying patients who might respond to CDK4/6 inhibitors by analyzing a retrospective case series of patients with HR+ mBC who were treated with hormone therapy plus CDK4/6 inhibitors. Methods: Approximately 177 mBC patients were enrolled, of whom 66 were treated with CD4/6 inhibitors plus letrozole and 111 were treated with CDK4/6 inhibitors and fulvestrant. A multistate model was used. Results: A low body surface area and older age were associated with an increased risk of developing neutropenia. A high Ki67 index, the presence of visceral metastases, and not having previously undergone adjuvant chemotherapy were prognostic factors of disease progression/death. As expected, some of the neutropenic patients who had previously undergone multiple lines of treatment were at a higher risk of disease progression/death. Furthermore, neutropenia status was associated with a more than doubled risk of progression/death compared to patients without neutropenia (HR = 2.311; p = 0.025). Conclusions: Having identified certain factors that could be associated with the development of neutropenia and considering that neutropenia itself is associated with an increased risk of progression, we believe that the baseline characteristics should be taken into account to reduce cases of neutropenia and disease progression. [ABSTRACT FROM AUTHOR]

Background: Chidamide is a selective histone deacetylase inhibitor approved for patients with hormone receptor (HoR)‐positive and HER2‐negative metastatic breast cancer (MBC). We aimed to investigate the efficacy, safety, and treatment patterns of chidamide and identify clinicopathological factors that predict the efficacy of chidamide in real‐world scenarios. Methods: Consecutive MBC patients treated with chidamide from January 2020 to August 2021 across 11 institutions were enrolled in this multicenter, retrospective study. Eligible patients were pre‐ and postmenopausal women who had clinically or histologically confirmed ER‐positive, HER2‐negative MBC, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients with multiple primary malignancies or missing baseline characteristics were excluded. Patients received 30 mg chidamide orally twice a week, combined with aromatase inhibitors (AIs) or non‐AIs. Efficacy analyses included progression‐free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR). Univariate and multivariate Cox regression analyses were performed to identify the potential efficacy predictors. Results: A total of 157 patients were finally included for analysis. The median number of lines prior to chidamide was four. In the whole cohort, the median PFS was 4.2 months (95% confidence interval [CI] 3.8–4.5). The ORR was 7.5% and the CBR was 31.3%. The efficacy of chidamide was consistent in patients pretreated with CDK4/6 inhibitors and patients treated with different endocrine combinations. Multivariate analysis indicated that patients who had liver metastases (adjusted HR = 1.66, 95% CI 1.14–2.43, adjusted p = 0.008) or ≥3 prior lines of treatment (adjusted HR = 1.80, 95% CI 1.17–2.77, adjusted p = 0.008) had significantly worse PFS. The most common AEs with chidamide were thrombocytopenia, leucopenia, neutropenia, and anemia. Conclusion: This study provided real‐world data for the use of chidamide in patients with HoR‐positive and HER2‐negative MBC. Our data endorsed the use of chidamide in patients pretreated with CDK4/6 inhibitors and patients treated with different endocrine combinations. [ABSTRACT FROM AUTHOR]

Background: Intratumour heterogeneity is a hallmark of most solid tumours, including breast cancers. We applied spatial transcriptomics and single‐cell RNA‐sequencing on patient‐derived xenografts (PDXs) to profile spatially resolved cell populations within oestrogen receptor‐positive (ER+) breast cancer and to elucidate their importance in oestrogen‐dependent tumour growth. Methods: Two PDXs of 'ER‐high' breast cancers with opposite oestrogen‐mediated growth responses were investigated: oestrogen‐suppressed GS3 (80–100% ER) and oestrogen‐dependent SC31 (40–90% ER) models. The observation was validated via single‐cell analyses on an 'ER‐low' PDX, GS1 (5% ER). The results from our spatial and single‐cell analyses were further supported by a public ER+ breast cancer single‐cell dataset and protein‐based dual immunohistochemistry (IHC) of SC31 examining important luminal cancer markers (i.e., ER, progesterone receptor and Ki67). The translational implication of our findings was assessed by clinical outcome analyses on publicly available cohorts. Results: Our space‐gene‐function study revealed four spatially distinct compartments within ER+ breast cancers. These compartments showed functional diversity (oestrogen‐responsive, proliferative, hypoxia‐induced and inflammation‐related). The 'proliferative' population, rather than the 'oestrogen‐responsive' compartment, was crucial for oestrogen‐dependent tumour growth, leading to the acquisition of luminal B‐like features. The cells expressing typical oestrogen‐responsive genes like PGR were not directly linked to oestrogen‐dependent proliferation. Dual IHC analyses demonstrated the distinct contribution of the Ki67+ proliferative cells toward oestrogen‐mediated growth and their response to a CDK4/6 inhibitor. The gene signatures derived from the proliferative, hypoxia‐induced and inflammation‐related compartments were significantly correlated with worse clinical outcomes, while patients with the oestrogen‐responsive signature showed better prognoses, suggesting that this compartment would not be directly associated with oestrogen‐dependent tumour progression. Conclusions: Our study identified the gene signature in our 'proliferative' compartment as an important determinant of luminal cancer subtypes. This 'proliferative' cell population is a causative feature of luminal B breast cancer, contributing toward its aggressive behaviours. [ABSTRACT FROM AUTHOR]

Acquired estrogen receptor alpha (ER/ ESR1) mutations commonly cause endocrine resistance in ER+ metastatic breast cancer (mBC). Lasofoxifene, a novel selective ER modulator, stabilizes an antagonist conformation of wild-type and ESR1 -mutated ER-ligand binding domains, and has antitumor activity in ESR1 -mutated xenografts. In this open-label, randomized, phase II, multicenter, ELAINE 1 study (NCT03781063), we randomized women with ESR1 -mutated, ER+/human epidermal growth factor receptor 2 negative (HER2−) mBC that had progressed on an aromatase inhibitor (AI) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) to oral lasofoxifene 5 mg daily or IM fulvestrant 500 mg (days 1, 15, and 29, and then every 4 weeks) until disease progression/toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were safety/tolerability. A total of 103 patients received lasofoxifene (n = 52) or fulvestrant (n = 51). The most current efficacy analysis showed that lasofoxifene did not significantly prolong median PFS compared with fulvestrant: 24.2 weeks (∼5.6 months) versus 16.2 weeks (∼3.7 months; P = 0.138); hazard ratio 0.699 (95% confidence interval 0.434-1.125). However, PFS and other clinical endpoints numerically favored lasofoxifene: clinical benefit rate (36.5% versus 21.6%; P = 0.117), objective response rate [13.2% (including a complete response in one lasofoxifene-treated patient) versus 2.9%; P = 0.124], and 6-month (53.4% versus 37.9%) and 12-month (30.7% versus 14.1%) PFS rates. Most common treatment-emergent adverse events with lasofoxifene were nausea, fatigue, arthralgia, and hot flushes. One death occurred in the fulvestrant arm. Circulating tumor DNA ESR1 mutant allele fraction (MAF) decreased from baseline to week 8 in 82.9% of evaluable lasofoxifene-treated versus 61.5% of fulvestrant-treated patients. Lasofoxifene demonstrated encouraging antitumor activity versus fulvestrant and was well tolerated in patients with ESR1 -mutated, endocrine-resistant mBC following progression on AI plus CDK4/6i. Consistent with target engagement, lasofoxifene reduced ESR1 MAF, and to a greater extent than fulvestrant. Lasofoxifene may be a promising targeted treatment for patients with ESR1 -mutated mBC and warrants further investigation. • Lasofoxifene showed antitumor activity in patients with ESR1 -mutated mBC that progressed on an AI plus a CDK4/6i. • Lasofoxifene numerically improved PFS (5.6 versus 3.7 months) and clinical benefit rate (37% versus 22%) versus fulvestrant. • Lasofoxifene was well-tolerated with no unexpected safety signals. • Lasofoxifene reduced ESR1 MAF, including Y537S MAF, in more patients than fulvestrant, exhibiting target engagement. • Lasofoxifene may be a promising endocrine therapy backbone for ESR1 -mutated mBC in a post-CDK4/6i setting. [ABSTRACT FROM AUTHOR]

Acquired ESR1 mutations in estrogen receptor-positive (ER+) metastatic breast cancer (mBC) drive treatment resistance and tumor progression; new treatment strategies are needed. Lasofoxifene, a next-generation, oral, endocrine therapy and tissue-specific ER antagonist, provided preclinical antitumor activity, alone or combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) in ESR1 -mutated mBC. In the open-label, phase II, ELAINE 2 trial (NCT04432454), women with ESR1 -mutated, ER+/human epidermal growth factor receptor 2-negative (HER2−) mBC who progressed on prior therapies (including CDK4/6i) received lasofoxifene 5 mg/day and abemaciclib 150 mg b.i.d until disease progression/toxicity. The primary endpoint was safety/tolerability. Secondary endpoints included progression-free survival (PFS), clinical benefit rate (CBR), and objective response rate (ORR). Twenty-nine women (median age 60 years) participated; all but one were previously treated with a CDK4/6i (median duration 2 years). The lasofoxifene–abemaciclib combination was well tolerated with primarily grade 1/2 treatment-emergent adverse events (TEAEs), most commonly diarrhea, nausea, fatigue, and vomiting. One patient (with no prior CDK4/6i) discontinued treatment due to grade 2 diarrhea. No deaths occurred during the study. Median PFS was 56.0 weeks [95% confidence interval (CI) 31.9 weeks-not estimable; ∼13 months]; PFS rates at 6, 12, and 18 months were 76.1%, 56.1%, and 38.8%, respectively. CBR at 24 weeks was 65.5% (95% CI 47.3% to 80.1%). In 18 patients with measurable lesions, ORR was 55.6% (95% CI 33.7% to 75.4%). ESR1 -mutant circulating tumor DNA (ctDNA) allele fraction decreased from baseline to week 4 in 21/26 (80.8%) patients. Lasofoxifene plus abemaciclib had an acceptable safety profile, was well tolerated, and exhibited meaningful antitumor activity in women with ESR1 -mutated, ER+/HER2− mBC after disease progression on prior CDK4/6i. Observed decreases in ESR1 -mutant ctDNA with lasofoxifene concordant with clinical response suggest target engagement. If the ELAINE 2 findings are confirmed in the initiated, phase III, ELAINE 3 trial, these data could be practice-changing and help address a critical unmet need. • Lasofoxifene–abemaciclib led to meaningful PFS (∼13 months), ORR (56%), and CBR (66%) in ESR1 -mutant mBC. • Lasofoxifene–abemaciclib was active for ESR1 -mutated breast tumors that progressed with endocrine therapy and CDK4/6is. • Lasofoxifene–abemaciclib was well tolerated with a manageable safety profile. • ESR1 mutant allele fractions were reduced/undetected with lasofoxifene–abemaciclib, consistent with target engagement. • Lasofoxifene–abemaciclib may become a promising therapy for ESR1 -mutant mBC after CDK4/6i treatment. [ABSTRACT FROM AUTHOR]

Purpose: Inhibition of the cyclin-dependent kinase (CDK) 4/6-retinoblastoma (RB) pathway exerts a considerable inhibitory effect, preventing the spread and metastasis of breast cancer cells and promoting tumor regression. In this study, we examined the antitumor activity of TQB3616, a novel inhibitor of CDK4/6 activity, which showed a greater efficacy improvement in antitumor effects.Methods: TQB3616 group, abemaciclib group and endocrine or HER-2 targeted combination therapy group were set up respectively. The effects of drugs on cell proliferation activity, cell cycle, apoptosis, downstream protein expression and gene expression of HR positive (T47D, MCF-7) and HER-2 positive (BT474, MDA-MB-361) breast cancer cell lines were studied. The antiproliferative effect of TQB3616 was also measured in vivo.Results: TQB3616 showed a remarkable inhibitory effect on the proliferation of hormone receptor-positive breast cancer cells in vitro. In addition, TQB3616 combined with endocrine therapy or Human Epidermal Growth Factor Receptor 2 (HER2) targeted therapy showed significant synergistic antitumor activity in estrogen receptor (ER)-positive/HER2-negative or HER2-positive breast cancer. In contrast to abemaciclib, which targets the CDK4/6 pathway with proven efficacy, the oral agent TQB3616 not only induced G1 stalling, leading to a profound reduction in the level of RB protein phosphorylated at Ser807/811, but also showed enhanced tumor killing effects by promoting cell apoptosis. Oral administration of TQB3616 showed more potent antitumor activity than abemaciclib in an in vitro breast cancer xenograft model, causing significant tumor regression associated with sustained target inhibition in tumor tissue and manageable in vivo toxicity.Conclusion: The results of this study indicate that TQB3616 is a novel CDK4/6 inhibitor, and its highly effective antitumor activity against breast cancer is expected to yield promising therapeutic effects in clinical studies. [ABSTRACT FROM AUTHOR]

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare but known and potentially severe side effect of drugs. The recent development of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, such as ribociclib, has considerably improved the management of hormone receptor positive (HR+) and HER2 negative (HER2-) advanced breast cancer. Here, we present the case of an 83-year-old patient who developed a probable DRESS syndrome induced by ribociclib, presenting with fever, eosinophilia, rash, and hepatic cytolysis. The RegiSCAR score was 4. The symptomatology evolved favorably with topical and systemic corticosteroids, without any sequel. Another CDK4/6 inhibitor, palbociclib, was introduced later without any cross-toxicity and with an excellent therapeutic response for more than 3 years. [ABSTRACT FROM AUTHOR]

Background: The combination of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and standard endocrine therapy (ET) in the adjuvant treatment of hormone receptor (HR)-positive/HER2-negative breast cancer (BC) has yielded conflicting results. We performed a pooled analysis of the adjuvant efficacy of CDK4/6 inhibitors by including data from the NATALEE trial, the most recent trial on this topic. Methods: We searched major databases and congress proceedings until 7 June 2023 to identify randomized controlled trials (RCT) comparing adjuvant CDK4/6 inhibitor plus ET combination versus ET in HR-positive/HER2-negative early-stage BC. Results: Four RCTs involving a total of 17,749 patients were included. According to the pooled analysis of these four studies, significant improvement in invasive disease-free survival (iDFS) was observed with the addition of CDK4/6 inhibitors to standard ET (HzR: 0.81, 95% CI 0.67-0.97). IDFS benefit was irrespective from menopausal status, Ki-67 index, tumor grade, and previous chemotherapy. CDK4/6 inhibitors plus ET had a significant improvement in iDFS in stage 3 whereas there was a trend toward better iDFS in stage 2 (HzR for stage 3: 0.67, 95% CI 0.58-0.78; HzR for stage 2: 0.74, 95% CI 0.55-1.01). Conclusions: Addition of CDK4/6 inhibitors to standard ET in the adjuvant treatment of HR-positive /HER2-negative early-stage BC improves iDFS. [ABSTRACT FROM AUTHOR]

The personalization of therapies in breast cancer has favoured the introduction of new molecular-targeted therapies into clinical practice. Among them, cyclindependent kinases 4 and 6 (CDK4/6) inhibitors have acquired increasing importance, with the approval in recent years of palbociclib, ribociclib, and abemaciclib in combination with endocrine therapy. Currently, no guidelines are available to monitor and manage potential long-term toxicities associated with the use of these drugs. A multidisciplinary panel of European oncologists, was supported by a pharmacologist, a hematologist, a hepatologist and a pulmonologist to discuss the management of long-term toxicities, based on the literature review and their clinical experience. The panel provided detailed roadmaps to manage long-term toxicities associated with the use of CDK4/6 inhibitors in clinical practice. Knowing the frequency and characteristics of the toxicity profile associated with each CDK4/6 inhibitor is important in the decision-making process to match the right drug to the right patient. [ABSTRACT FROM AUTHOR]

Sacituzumab govitecan demonstrated significant progression-free survival benefit over chemotherapy in the phase 3 TROPiCS-02 trial in patients with pretreated, endocrine-resistant hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+ and HER2–) metastatic breast cancer with limited treatment options. Here, we report the protocol-specified final analysis of overall survival and endpoints by trophoblast cell-surface antigen 2 (Trop-2) expression and other variables. In this randomised, open-label, multicentre, phase 3 trial, which took place in 91 centres across North America (the USA and Canada) and Europe (Belgium, France, Germany, Italy, the Netherlands, Spain, and the UK), patients were randomly assigned (1:1) to receive sacituzumab govitecan or chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine). Patients had confirmed HR+ and HER2– locally recurrent inoperable or metastatic breast cancer and had received at least one previous endocrine therapy, a taxane, and a CDK4/6 inhibitor in any setting and two to four previous chemotherapy regimens for metastatic disease. The primary endpoint was progression-free survival (previously reported and not included in this analysis), and secondary endpoints included overall survival, objective response rate (ORR), and patient-reported outcomes. Overall survival was assessed using stratified log-rank tests and Cox regression. Trop-2 expression was assessed in tumour tissue by immunohistochemistry. In the statistical testing hierarchy, ORR and patient-reported outcomes were tested sequentially if overall survival was significant. This study is registered with ClinicalTrials.gov , NCT03901339. At the data cutoff date of July 1, 2022, 543 of 776 screened patients were randomly assigned between May 30, 2019, and April 5, 2021, with 272 patients in the sacituzumab govitecan group and 271 patients in the chemotherapy group. With a 12·5-month (IQR 6·4–18·8) median follow-up, 390 deaths occurred among 543 patients. Overall survival was significantly improved with sacituzumab govitecan versus chemotherapy (median 14·4 months [95% CI 13·0–15·7] vs 11·2 months [10·1–12·7]; hazard ratio [HR] 0·79, 95% CI 0·65–0·96; p=0·020); survival benefit was consistent across Trop-2 expression-level subgroups. ORR was significantly improved with sacituzumab govitecan compared with chemotherapy (57 [21%] patients vs 38 [14%]; odds ratio 1·63 [95% CI 1·03–2·56]; p=0·035), as was time to deterioration of global health status and quality of life (median 4·3 months vs 3·0 months; HR 0·75 [0·61–0·92]; p=0·0059) and fatigue (median 2·2 months vs 1·4 months; HR 0·73 [0·60–0·89]; p=0·0021). The safety profile of sacituzumab govitecan was consistent with previous studies (including the TROPiCS-02 primary analysis and the ASCENT trial). One fatal adverse event (septic shock caused by neutropenic colitis) was determined to be related to sacituzumab govitecan treatment. Sacituzumab govitecan demonstrated statistically significant and clinically meaningful benefit over chemotherapy, with a 3·2-month median overall survival improvement and a manageable safety profile. These data support sacituzumab govitecan as a new treatment option for patients with pretreated, endocrine-resistant HR+ and HER2– metastatic breast cancer. Gilead Sciences. [ABSTRACT FROM AUTHOR]

Breast cancer is the most commonly diagnosed cancer in women worldwide. Over the past decade, the treatment paradigm for patients with metastatic breast cancer (MBC) has taken an important shift towards better survival and improved quality of life (QOL), especially for those with hormone receptor (HR)-positive diseases which represent the majority of breast cancer subtypes. The introduction of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in the upfront therapy of such patients has resulted in dramatic improvement in progressionfree survival (PFS) and overall survival (OS), too. However, almost all patients would, sooner or later, develop disease progression and necessitate transition to different lines of treatment that may include chemotherapy. The idea of maintaining CDK4/6 inhibitors beyond disease progression seems attractive, as this approach has the potential to improve outcome in this setting despite the fact that the true benefit, in terms of survival, might not carry the same weight as it initially does. Researchers have been investigating potential mechanisms of resistance and identify possible biological markers for response after disease progression. Much of the available data is retrospective; however, few randomized clinical trials were recently published and few more are ongoing, addressing this point. In this paper, we intend to review the available published studies investigating the potential role for keeping CDK4/6 inhibitors in play beyond disease progression. [ABSTRACT FROM AUTHOR]

Hormone receptor--positive (HR+) disease is the most frequently diagnosed subtype of breast cancer. Among tumor subtypes, natural course of HR+ breast cancer is indolent with favorable prognosis compared to other subtypes such as human epidermal growth factor protein 2--positive disease and triple-negative disease. HR+ tumors are dependent on steroid hormone signaling and endocrine therapy is the main treatment option. Recently, the discovery of cyclin-dependent kinase 4/6 inhibitors and their synergistic effects with endocrine therapy has dramatically improved treatment outcome of advanced HR+ breast cancer. The demonstrated efficacy of additional nonhormonal agents, such as targeted therapy against mammalian target of rapamycin and phosphatidylinositol 3-kinase signaling, poly(ADP-ribose) polymerase inhibitors, antibody-drug conjugates, and immunotherapeutic agents have further expanded the available therapeutic options. This article reviews the latest advancements in the treatment of HR+ breast cancer, and in doing so discusses not only the development of currently available treatment regimens but also emerging therapies that invite future research opportunities in the field. [ABSTRACT FROM AUTHOR]

HER2 mutations are targetable alterations in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). In the SUMMIT basket study, patients with HER2 -mutant MBC received neratinib monotherapy, neratinib + fulvestrant, or neratinib + fulvestrant + trastuzumab (N + F + T). We report results from 71 patients with HR+, HER2 -mutant MBC, including 21 (seven in each arm) from a randomized substudy of fulvestrant versus fulvestrant + trastuzumab (F + T) versus N + F + T. Patients with HR+ HER2-negative MBC with activating HER2 mutation(s) and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy received N + F + T (oral neratinib 240 mg/day with loperamide prophylaxis, intramuscular fulvestrant 500 mg on days 1, 15, and 29 of cycle 1 then q4w, intravenous trastuzumab 8 mg/kg then 6 mg/kg q3w) or F + T or fulvestrant alone. Those whose disease progressed on F + T or fulvestrant could cross-over to N + F + T. Efficacy endpoints included investigator-assessed objective response rate (ORR), clinical benefit rate (RECIST v1.1), duration of response, and progression-free survival (PFS). Plasma and/or formalin-fixed paraffin-embedded tissue samples were collected at baseline; plasma was collected during and at end of treatment. Extracted DNA was analyzed by next-generation sequencing. ORR for 57 N + F + T-treated patients was 39% [95% confidence interval (CI) 26% to 52%); median PFS was 8.3 months (95% CI 6.0-15.1 months). No responses occurred in fulvestrant- or F + T-treated patients; responses in patients crossing over to N + F + T supported the requirement for neratinib in the triplet. Responses were observed in patients with ductal and lobular histology, 1 or ≥1 HER2 mutations, and co-occurring HER3 mutations. Longitudinal circulating tumor DNA sequencing revealed acquisition of additional HER2 alterations, and mutations in genes including PIK3CA, enabling further precision targeting and possible re-response. The benefit of N + F + T for HR+ HER2 -mutant MBC after progression on CDK4/6is is clinically meaningful and, based on this study, N + F + T has been included in the National Comprehensive Cancer Network treatment guidelines. SUMMIT has improved our understanding of the translational implications of targeting HER2 mutations with neratinib-based therapy. • The phase II SUMMIT basket study evaluated neratinib-based therapy in patients with solid tumors harboring HER2 mutations. • 57 MBC patients received N + F + T, including 7 of 21 randomized 1:1:1 to F, F + T, or N + F + T. • The ORR for patients who received N + F + T was 39% (95% CI 26% to 52%); this included 1 complete and 21 partial responses. • Responses were seen in ductal (ORR 39%) and lobular (ORR 41%) MBC, one or more HER2 mutations, or co-occurring HER3 mutation. • Responses after cross-over from F or F + T to N + F + T support the requirement of neratinib for efficacy of the triplet. [ABSTRACT FROM AUTHOR]

The objective of the present study was to assess the outcomes and toxicity of patients treated with concurrent administration of CDK4/6 inhibitors (CDK4/6i) and locoregional radiation therapy (RT), including the breast with a boost or the thoracic wall after mastectomy and the regional lymph node areas. We retrospectively analyzed data from 27 patients with hormone receptor‐positive, HER2‐negative de novo metastatic breast cancer treated with CDK4/6i and concomitant locoregional RT in 2017/2022. Survival rates were calculated by Kaplan‐Meier method. Prognostic factors were tested with log‐rank test. CDK4/6i was used as the first systemic metastatic treatment for all the patients, and the median overall treatment time was 26 months. The median time from initiation of CDK4/6i to the start of RT was 10 months (IQR: 7‐14 months). The median duration of concomitant CDK4/6i and RT administration was 21 days (IQR: 14.5‐23 days). After a median follow‐up of 19 months (IQR: 14‐36 months), 1 patient died, 11/27 had distant metastases and 1 patient had local recurrence, respectively. The 1‐ and 3‐years progression‐free survival (PFS) were 61.4% (95% CI: 45.1%‐83.7%) and 53.7% (35.8%‐80.5%), respectively. The acute toxicities most observed during RT were neutropenia (44%) and dermatitis (37%). Dermatitis was significantly more frequent in patients with large target volumes (CTV > 911 cc and PTV > 1285 cc). CDK4/6i had to be discontinued in five patients during RT (due to toxicity in three cases and disease progression in two cases). One patient has developed grade 2 late pulmonary fibrosis. Finally, our study demonstrated that concurrent administration of locoregional RT and CDK4/6i did not induce severe late toxicity for most patients. [ABSTRACT FROM AUTHOR]

Background: MBC is a lethal form of breast cancer that arises when cancer cells invade other organs or tissues. The treatment of MBC needs personalized approaches based on the tumor and patient characteristics. The purpose of this paper is to analyze MBC studies from 2002 to 2022 using bibliometrics and to investigate its current situation, main contributors, core journals, highly cited papers, and topic evolution. Materials and methods: We retrieved data from Web of Science Core Collection (WOSCC). Bibliometric analysis of the included literatures mainly used the following tools: the function of "analyze results" and "citation report" in WoS, Microsoft excel 2021, CiteSpace v.6.1. R6, VOSviewer v.1.6.18, BICOMB v.2.04 and gCLUTO v.1.0. Results: We found 12,653 articles on MBC research published in 1, 802 journals by 69, 753 authors from 118 countries. The annual output and citation of MBC articles showed a rising trend over time. The United States was the most influential country in MBC research. The most cited journal in this field was The Journal of Clinical Oncology. And the most cited article was by Slamon DJ. The co-word analysis of keywords divides MBC into six research clusters. The hormone receptor-positive MBC and liquid biopsy of MBC are the frontiers research trends. "CDK4/6 inhibitor" had the highest burst strength. Conclusion: Our bibliometric analysis offers a comprehensive overview of MBC research in the past two decades. It shows the current situation, main contributors, core journals, highly cited papers, and topic evolution of this field. Our study can assist researchers and practitioners to comprehend the development and trends of MBC research and to discover potential directions for future research. [ABSTRACT FROM AUTHOR]

Hormone receptor (HR)‐positive and human epidermal growth factor receptor 2 (HER2)‐negative breast cancer is defined by the presence of the estrogen receptor and/or the progesterone receptor and the absence of HER2 gene amplification. HR‐positive/HER2‐negative breast cancer accounts for 65%–70% of all breast cancers, and incidence increases with increasing age. Treatment varies by stage, and endocrine therapy is the mainstay of treatment in both early stage and late‐stage disease. Combinations with cyclin‐dependent kinase 4/6 inhibitors have reduced distant recurrence in the early stage setting and improved overall survival in the metastatic setting. Chemotherapy is used based on stage and tumor biology in the early stage setting and after endocrine resistance for advanced disease. New therapies, including novel endocrine agents and antibody‐drug conjugates, are now changing the treatment landscape. With the availability of new treatment options, it is important to define the optimal sequence of treatment to maximize clinical benefit while minimizing toxicity. In this review, the authors first discuss the pathologic and molecular features of HR‐positive/HER2‐negative breast cancer and mechanisms of endocrine resistance. Then, they discuss current and emerging therapies for both early stage and metastatic HR‐positive/HER2‐negative breast cancer, including treatment algorithms based on current data. [ABSTRACT FROM AUTHOR]

CDK4/6 inhibitors combined with endocrine therapy have significantly improved treatment outcomes for metastatic hormone receptor-positive (HR+) breast cancer patients. However, the impact of low HER2 expression on treatment response and progression-free survival (PFS) remains unclear. This multicenter retrospective study included 204 HR+ breast cancer patients treated with a combination of CDK4/6 inhibitor and endocrine therapy. HER2-zero disease was detected in 138 (68%) and HER2-low disease in 66 (32%) patients. Treatment-related characteristics and clinical outcomes were analyzed, with a median follow-up of 22 months. The objective response rate (ORR) was 72.7% in the HER2 low group and 66.6% in the HER2 zero group (p = 0.54). Median PFS was not significantly different between the HER2-low and HER2 zero groups (19 months vs.18 months, p = 0.89), although there was a trend toward longer PFS in the HER2-low group for first-line treatment (24 months progression-free survival rate 63% vs 49%). In recurrent disease, the median PFS was 25 months in the HER2-low group and 12 months in the HER2-zero group (p = 0.08), while in de novo metastatic disease, the median PFS was 18 months in the HER2-low group and 27 months in the HER2-zero group (p = 0.16). The order of CDK4/6 inhibitor use and the presence of visceral metastasis were identified as independent variables affecting PFS. Low HER2 expression did not significantly impact treatment response or PFS in HR+ breast cancer patients treated with a CDK4/6 inhibitor and endocrine therapy. Because of the conflicting results in the literature, further prospective studies are needed to evaluate the clinical significance of HER2 expression in HR+ breast cancer. • Combination therapy with CDK4/6 inhibitors and endocrine therapy achieves impressive objective response rates in metastatic hormone-positive breast cancer patients regardless of HER2 status. • Low HER2 expression did not significantly affect survival in hormone-positive metastatic breast cancer patients receiving CDK4/6 inhibitors and endocrine therapy. • The order of CDK4/6 inhibitor use and the presence of visceral metastasis were identified as independent factors influencing progression-free survival. [ABSTRACT FROM AUTHOR]

This is a prospective observational cohort study to evaluate dynamics of circulating tumor cells (CTCs) with adjuvant breast radiotherapy (RT). We present a per-protocol planned interim analysis triggered at 12 months following study activation. Eligible patients with clinical or pathologic T3-4 or node-positive non-metastatic Her2-negative breast cancer dispositioned to receive RT were prospectively enrolled. All patients received RT to the breast/chest wall and regional (axillary, infraclavicular, supraclavicular, and internal mammary) lymph nodes with a boost to unresected involved nodes. CTCs were enumerated using the CellSearch® assay at up to 3 timepoints: immediately prior to RT (Pre-RT), within 1 week of completing RT (End of RT), and at follow-up 3-6 months after RT (Post-RT). Rates of CTC detection and clearance with RT were calculated. Associations between clinicopathologic variables and Pre-RT CTC status were determined using the Chi-square or Fisher exact test. As of March 2024, 100 patients had a Pre-RT assessment. Seventy-three (73%) of patients had estrogen receptor-positive disease, 61 (61%) received neoadjuvant chemotherapy (NAC), 68 (68%) underwent mastectomy, and 63 (63%) had axillary lymph node dissection. Prior to RT, 22 (22%) patients had ≥1 detectable CTC (median=1 cell [1-2]), of which 16 (72%) had received NAC. Of the 19 CTC-positive patients with completed subsequent blood draws, 17 (89%) and 19 (100%) were CTC-negative at the "End of RT" and "Post-RT" timepoints, respectively. CTC-positive status was significantly associated with more advanced clinical tumor stage (p=0.05) and nodal stage (p=0.05) but not with pathologic complete response (pCR). Patients with detectable CTCs Pre-RT were significantly more likely to have disease in the supraclavicular or infraclavicular nodal basins or internal mammary chain (cN3) (36% vs 12%, p=0.02) or a diagnosis of inflammatory breast cancer (IBC) (22% vs 4%, p=0.02). Of the 4 CTC-positive patients with pCR, 3 had cN3 disease and 1 had IBC. IBC and cN3 disease were significantly associated with detection of CTCs immediately prior to RT, including patients with pCR. Following comprehensive RT, 100% of CTC-positive patients experienced CTC clearance. While delayed clearance of CTCs without RT cannot be assessed on this single arm study, particularly in the setting of additional systemic therapy (endocrine therapy; CDK4/6 inhibitors), these results support the hypothesis that CTC status may represent a real-time biomarker for residual locoregional disease prior to RT, even among patients with pCR, as well as a potential surrogate for radiotherapeutic efficacy. Future studies will assess banked circulating tumor DNA and association of circulating tumor material with clinical outcomes. [ABSTRACT FROM AUTHOR]

Resistance to endocrine treatments and CDK4/6 inhibitors is considered a near-inevitability in most patients with estrogen receptor positive breast cancers (ER + BC). By genomic and metabolomics analyses of patients' tumours, metastasis-derived patient-derived xenografts (PDX) and isogenic cell lines we demonstrate that a fraction of metastatic ER + BC is highly reliant on oxidative phosphorylation (OXPHOS). Treatment by the OXPHOS inhibitor IACS-010759 strongly inhibits tumour growth in multiple endocrine and palbociclib resistant PDX. Mutations in the PIK3CA/AKT1 genes are significantly associated with response to IACS-010759. At the metabolic level, in vivo response to IACS-010759 is associated with decreased levels of metabolites of the glutathione, glycogen and pentose phosphate pathways in treated tumours. In vitro, endocrine and palbociclib resistant cells show increased OXPHOS dependency and increased ROS levels upon IACS-010759 treatment. Finally, in ER + BC patients, high expression of OXPHOS associated genes predict poor prognosis. In conclusion, these results identify OXPHOS as a promising target for treatment resistant ER + BC patients. Patients with estrogen receptor positive breast cancer (ER + BC) treated with palbociclib (CDK4/6 inhibitor) frequently develop resistance. Here, the authors identify a reliance of palbociclib resistance on oxidative phosphorylation (OXPHOS) and therapeutically target this vulnerability using an OXPHOS inhibitor, restoring sensitivity in ER + BC preclinical models. [ABSTRACT FROM AUTHOR]

Stereotactic body radiotherapy (SBRT) has emerged as a technique to treat oligoprogressive sites among patients with breast cancer who are otherwise doing well on systemic therapy. This study systematically reviewed the efficacy and safety of SBRT in the setting of oligoprogressive breast cancer. A literature search was conducted in the MEDLINE database. Studies regarding SBRT and oligoprogressive breast cancer were included. Key outcomes of interest were toxicity, local control, progression, and overall survival. From 863 references, five retrospective single-center cohort studies were identified. All studies included patients with both oligometastatic and oligoprogressive disease; 112 patients with oligoprogressive breast cancer were identified across these studies. Patient age ranged from 22 to 84, with a median of 55 years of age. Most patients had hormone-receptor-positive and HER2-negative disease. SBRT doses varied from 24 to 60 Gy in 1–10 fractions based on the location/size of the lesion. Forty toxicity events were reported, of which the majority (n = 25, 62.5%) were grade 1–2 events. Among 15 patients who received SBRT concurrently with a CDK4/6 inhibitor, 37.5% of patients experienced grade 3–5 toxicities. Progression-free and overall survival ranged from 17 to 57% and 62 to 91%, respectively. There are limited data on the role of SBRT in oligoprogressive breast cancer, and prospective evaluation of this strategy is awaited to inform its safety and efficacy. [ABSTRACT FROM AUTHOR]

Background: Metastatic breast cancers (MBC) with no expression of human epidermal growth factor receptor-2 (HER2) are recently classified into two groups; HER2-zero [HER2-immunohistochemistry (IHC) score of 0 (IHC-0)] and HER2-low, defined as those with IHC score of 1+ or 2+ with negative in situ hybridization (ISH) assay. We investigate differences in treatment outcomes between both groups treated with endocrine therapy (ET) and the CDK4/6 inhibitor ribociclib.Methods: Data were retrospectively collected for patients with HR-positive+/HER2−negative MBC who received ribociclib with an aromatase inhibitor (AI) or fulvestrant and were divided into two groups: HER2-zero and HER2-low.Results: A total of 257 patients, median age 48 (22– 87) years, all with MBC who were treated with ET and ribociclib were enrolled. One hundred and thirty-seven (53.3%) patients had de novo MBC, and majority (n = 162, 63.0%) received ribociclib as a first-line therapy. In total, 114 (44.4%) patients had HER2-zero (IHC-0), while 143 (55.6%) others had HER2-low disease. The overall response rate (ORR) was 52.0% for the HER2-zero group compared to 39.4% for the HER2-low group, p = 0.005. The median PFS was 22.2 (95% confidence interval [CI], 19.4-NR) months for HER2-zero versus 17.3 (95% CI, 14.1– 20.6) months for HER2-low, P = 0.0039. In multivariable analysis, HER2-low expression remained significant determinant of inferior PFS after adjusting for other factors, including the site of metastasis, prior chemotherapy, and the line of treatment.Conclusion: In patients with MBC treated with ET and ribociclib, level of HER2 negativity may affect treatment outcomes; patients with HER2-zero had better response rate and PFS compared to those with HER2-low disease. These findings, if confirmed in larger studies, may help oncologists select patients with HER2-low for better treatment options. [ABSTRACT FROM AUTHOR]

Background: Xentuzumab is a humanised monoclonal antibody that binds to IGF-1 and IGF-2, neutralising their proliferative activity and restoring inhibition of AKT by everolimus. This study evaluated the addition of xentuzumab to everolimus and exemestane in patients with advanced breast cancer with non-visceral disease. Methods: This double-blind, randomised, Phase II study was undertaken in female patients with hormone-receptor (HR)-positive/human epidermal growth factor 2 (HER2)-negative advanced breast cancer with non-visceral disease who had received prior endocrine therapy with or without CDK4/6 inhibitors. Patients received a weekly intravenous infusion of xentuzumab (1000 mg) or placebo in combination with everolimus (10 mg/day orally) and exemestane (25 mg/day orally). The primary endpoint was progression-free survival (PFS) per independent review. Results: A total of 103 patients were randomised and 101 were treated (n = 50 in the xentuzumab arm and n = 51 in the placebo arm). The trial was unblinded early due to high rates of discordance between independent and investigator assessment of PFS. Per independent assessment, median PFS was 12.7 (95% CI 6.8–29.3) months with xentuzumab and 11.0 (7.7–19.5) months with placebo (hazard ratio 1.19; 95% CI 0.55–2.59; p = 0.6534). Per investigator assessment, median PFS was 7.4 (6.8–9.7) months with xentuzumab and 9.2 (5.6–14.4) months with placebo (hazard ratio 1.23; 95% CI 0.69–2.20; p = 0.4800). Tolerability was similar between the arms, with diarrhoea (33.3–56.0%), fatigue (33.3–44.0%) and headache (21.6–40.0%) being the most common treatment-emergent adverse events. The incidence of grade ≥ 3 hyperglycaemia was similar between the xentuzumab (2.0%) and placebo (5.9%) arms. Conclusions: While this study demonstrated that xentuzumab could be safely combined with everolimus and exemestane in patients with HR-positive/HER2-negative advanced breast cancer with non-visceral disease, there was no PFS benefit with the addition of xentuzumab. Trial registration ClinicalTrials.gov, NCT03659136. Prospectively registered, September 6, 2018. [ABSTRACT FROM AUTHOR]

Adding CDK4/6 inhibitor dalpiciclib to fulvestrant significantly prolonged progression-free survival in patients with hormone receptor-positive, HER2-negative advanced breast cancer progressing after endocrine therapy. We aimed to assess the efficacy and safety of dalpiciclib plus letrozole or anastrozole in patients with hormone receptor-positive, HER2-negative advanced breast cancer who had no previous systemic therapy in the advanced setting. DAWNA-2 is a randomised, double-blind, placebo-controlled, phase 3 trial done at 42 hospitals in China. Eligible patients were aged 18–75 years, of any menopausal status, had an ECOG performance status of 0–1, and had pathologically confirmed hormone receptor-positive, HER2-negative untreated advanced breast cancer. Patients were randomly assigned (2:1) to receive oral dalpiciclib (150 mg per day for 3 weeks, followed by 1 week off) or matching placebo. Both groups also received endocrine therapy: either 2·5 mg letrozole or 1 mg anastrozole orally once daily continuously. Randomisation was using an interactive web response system (block size of six) and stratified according to visceral metastasis, previous endocrine therapy in the adjuvant or neoadjuvant setting, and endocrine therapy partner. All investigators, patients, and the funders of the study were masked to group allocation. We present the results of the preplanned interim analyses for the primary endpoint of investigator-assessed progression-free survival, which was assessed in all randomly assigned patients who met the eligibility criteria by intention-to treat. Safety was analysed in all randomly assigned patients who received at least one dose of study treatment. The superiority boundary was calculated as a one-sided p value of 0·0076 or less. This trial is registered with ClinicalTrials.gov , NCT03966898 , and is ongoing but closed to recruitment. Between July 19, 2019, and Dec 25, 2020, 580 patients were screened and 456 were eligible and randomly assigned to the dalpiciclib group (n=303) or placebo group (n=153). At data cutoff (June 1, 2022), median follow-up was 21·6 months (IQR 18·3–25·9), and 103 (34%) of 303 patients in the dalpiciclib group and 83 (54%) of 153 patients in the placebo group had disease progression or died. Median progression-free survival was significantly longer in the dalpiciclib group than in the placebo group (30·6 months [95% CI 30·6–not reached] vs 18·2 months [16·5–22·5]; stratified hazard ratio 0·51 [95% CI 0·38–0·69]; one-sided log-rank p<0·0001). Adverse events of grade 3 or 4 were reported in 271 (90%) of 302 patients in the dalpiciclib group and 18 (12%) of 153 patients in the placebo group. The most common adverse events of grade 3 or 4 were neutropenia (259 [86%] in the dalpiciclib group vs none in the placebo group) and leukopenia (201 [67%] vs none). Serious adverse events were reported for 36 (12%) patients in the dalpiciclib group and ten (7%) patients in the placebo group. Two treatment-related deaths occurred, both in the dalpiciclib group (deaths from unknown causes). Our findings suggest that dalpiciclib plus letrozole or anastrozole could be a novel standard first-line treatment for patients with hormone receptor-positive, HER2-negative advanced breast cancer, and is an alternative option to the current treatment landscape. Jiangsu Hengrui Pharmaceuticals and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences. For the Chinese translation of the abstract see Supplementary Materials section. [ABSTRACT FROM AUTHOR]

Background: Evidence on overall survival (OS) with cyclin‐dependent kinase 4 and 6 (CDK4/6) inhibitors is generally limited to data from clinical trials or a few observational studies with limited generalizability to Medicare population. The aim of this study was to determine OS benefits associated with CDK4/6 inhibitors in older Medicare patients with hormone receptor (HR)–positive and human epidermal growth factor receptor‐2 overexpressing (HER2–) metastatic breast cancer (MBC). Methods: In a retrospective cohort design, female patients aged ≥65 years with diagnosis of HR+/HER2– MBC from 2015 to 2017 who initiated first‐line systemic therapy within 12 months of MBC diagnosis were selected from the Survey Epidemiology and End Results‐Medicare database. The effect of treatment type (endocrine therapy [ET]+CDK4/6 inhibitor vs. ET alone) on OS was analyzed using Kaplan–Meier methods and multivariable Cox regression models. Adjusted hazard ratio (aHR) and 95% CIs were estimated. Results: A total of 630 eligible patients were identified (169 patients treated with ET+CDK4/6 inhibitor and 461 patients treated with ET alone). In the Kaplan–Meier analysis, OS rate at 3 years after first‐line treatment initiation was 73.0% for ET+CDK4/6 inhibitor versus 49.1% for ET alone (log‐rank p <.0001). In Cox regression analysis, first‐line ET+CDK4/6 inhibitor therapy was associated with 41% lower rate of mortality versus ET alone (aHR, 0.590; 95% CI, 0.423–0.823). Conclusions: The findings of this real‐world study demonstrate significant OS benefit associated with ET+CDK4/6 inhibitor therapy over ET alone in an older Medicare population of patients with HR+/HER2– MBC, largely consistent with the evidence from clinical trials. In patients with metastatic breast cancer (MBC) receiving treatment with cyclin‐dependent kinase 4 and 6 (CDK4/6) inhibitors, evidence on overall survival is generally limited to data from clinical trials or observational studies not generalizable to patients in the Medicare population. The findings of this real‐world analysis demonstrate that the addition of CDK4/6 inhibitors to endocrine therapy (ET) significantly improved survival among older Medicare beneficiaries, suggesting that treatment with ET alone should have a limited role in early lines of therapy for Medicare patients with HR+/HER2– MBC. [ABSTRACT FROM AUTHOR]

BACKGROUND: Palbociclib is a selective, reversible cyclin-dependent kinase 4/6 inhibitor approved for the treatment of hormone receptor--positive metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant. Although palbociclib is generally well-tolerated, rare cases of hepatotoxicity have occurred in postmarketing studies. DISCUSSION: We present a female patient with metastatic breast cancer and no baseline hepatic involvement or abnormal liver function tests (LFTs) who received palbociclib and anastrozole. After 3 months of therapy, she had asymptomatic grade 3/4 hepatotoxicity, and treatment with anastrozole and palbociclib was held. After aspartate aminotransferase (AST) and alanine aminotransferase (ALT) began to normalize, anastrozole was reintroduced and then palbociclib 125 mg was restarted 3 weeks later. Markedly increased AST and ALT occurred again; treatment with palbociclib was held for 3 weeks until the LFTs resolved to grade 1, and the dose of palbociclib was subsequently reduced to 100 mg while treatment with anastrozole was continued. The 100-mg dose of palbociclib continued to cause elevated LFTs, however, so the dose was held again until the LFTs resolved to grade 1. Palbociclib was reduced to a final dose of 75 mg without further elevations. CONCLUSION: Using the Naranjo scale and timing of the elevated AST and ALT, it is probable that palbociclib was the offending agent for the patient's hepatotoxicity. Further reducing the dose of palbociclib per prescribing information recommendations proved to be an effective strategy for managing the patient's hepatotoxicity and correlated with the dose-dependent severity of AST and ALT elevations. In the future, the periodic monitoring of LFTs beyond the first month of treatment with palbociclib should be considered. [ABSTRACT FROM AUTHOR]

Visceral crisis is a life-threatening clinical condition requiring urgent treatment and accounts for 10–15% of new advanced breast cancer diagnoses, mainly hormone receptor-positive/human epidermal growth factor 2 negative. As its clinical definition is an open topic with nebulous criteria and much room for subjective interpretation, it poses a challenge for daily clinical practice. International guidelines recommend combined chemotherapy as first-line treatment for patients with visceral crisis, but with modest results and a very poor prognosis. Visceral crisis has always been a common exclusion criterion in breast cancer trials, and the available evidence mainly comes from limited retrospective studies which are not sufficient to draw solid conclusions. The outstanding efficacy of innovative drugs, such as CDK4/6 inhibitors, questions the role of chemotherapy in this setting. In the lack of clinical reviews, we aim to critically discuss the management of visceral crisis, advocating future treatment perspectives for this challenging condition. [ABSTRACT FROM AUTHOR]

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors and endocrine therapy are the gold standards for systemic therapy for patients with hormone-positive (HR+)/human epidermal growth factor receptor-2-negative (HER2-) metastatic breast cancer. Following progression, no prospective randomized data exist to help guide second-line treatment. Moreover, there is a scarcity of data on rechallenge treatment strategies with another CDK4/6 inhibitor after prior limiting toxicity. We report a real-world experience of rechallenging with abemaciclib after the prior reaction of grade 4 liver toxicity to ribociclib, with high transaminases values of more than 27 times the upper limit of normal (ULN) and unexpected grade 3 neutropenia and diarrhea after a few months of abemaciclib. After two years of treatment, the patient had stable oncological disease, with normal complete blood count, hepatic enzymes, and a very good performance status. We believe that our clinical case, along with others gathered from all around the world, will help with the consolidation of an unmet clinical need to readjust the treatment after experiencing toxicity to CDK4/6 inhibitors. [ABSTRACT FROM AUTHOR]

Background: The emergence of molecularly targeted agents (MTAs) has altered the treatment landscape for hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2−) advanced breast cancer (ABC)/metastatic breast cancer (MBC). Multiple guidelines recommend molecularly targeted therapy as first-line treatment for HR+/HER2− ABC/MBC. However, optimal treatment for disease progression during MTA therapy remains undetermined. This study evaluated the suitability of different MTA types for this patient subgroup. Methods: In this retrospective study, we analyzed the electronic health records of 56 patients with HR+/HER2− ABC/MBC receiving treatment with palbociclib, abemaciclib, or everolimus in our center between April 2014 and June 2021. Results: Overall, 39, 14, and 35 regimens using palbociclib, abemaciclib, and everolimus, respectively, were identified. Three and 53 patients were premenopausal and postmenopausal, respectively. MTAs were included in the 1st-11th lines of treatment. Time to failure (TTF) was significantly different among the three MTAs. In contrast, TTF did not significantly differ among the 50 regimens that included CDK4/6 inhibitors, with/without prior mTOR inhibitor use, and the 35 regimens that included mTOR inhibitors, with/without prior CDK4/6 inhibitor use. Conclusions: The sequential use of different MTA classes did not affect the TTF of another MTA. mTOR inhibitor + exemestane is a favorable treatment option after CDK4/6 inhibitor + hormone therapy, and CDK4/6 inhibitor + hormone therapy is suitable for patients previously treated with mTOR inhibitor + exemestane. Although this study was retrospective and conducted at a single center, the present findings are useful for treatment selection in clinical practice. [ABSTRACT FROM AUTHOR]

The latest and newest discoveries for advanced and metastatic hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer are the three cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) in association with endocrine therapy (ET). However, even if this treatment revolutionized the world and continued to be the first-line treatment choice for these patients, it also has its limitations, caused by de novo or acquired drug resistance which leads to inevitable progression after some time. Thus, an understanding of the overview of the targeted therapy which represents the gold therapy for this subtype of cancer is essential. The full potential of CDK4/6i is yet to be known, with many trials ongoing to expand their utility to other breast cancer subtypes, such as early breast cancer, and even to other cancers. Our research establishes the important idea that resistance to combined therapy (CDK4/6i + ET) can be due to resistance to endocrine therapy, to treatment with CDK4/6i, or to both. Individuals' responses to treatment are based mostly on genetic features and molecular markers, as well as the tumor's hallmarks; therefore, a future perspective is represented by personalized treatment based on the development of new biomarkers, and strategies to overcome drug resistance to combinations of ET and CDK4/6 inhibitors. The aim of our study was to centralize the mechanisms of resistance, and we believe that our work will have utility for everyone in the medical field who wants to deepen their knowledge about ET + CDK4/6 inhibitors resistance. [ABSTRACT FROM AUTHOR]

Breast cancer remains the second leading cause of cancer mortality in women. Endocrine therapy is the backbone treatment for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, the most common subtype. Although several endocrine therapy agents are available, essentially all HR-positive metastatic breast cancers will become resistant to these drugs. ESR1 mutations represent an important mechanism of resistance to aromatase inhibitors. Elacestrant is a novel oral selective estrogen receptor degrader (SERD) that selectively binds to the estrogen receptor in breast cancer cells, inhibiting tumor growth. Preclinical data suggested greater efficacy of elacestrant in combination with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) or everolimus. In a Phase III clinical trial, elacestrant demonstrated a significant although modest improvement in median progression-free survival (PFS) compared to standard of care endocrine therapy in patients with HR-positive, HER2-negative advanced breast cancer. Importantly, there was also a significant benefit in patients with ESR1 mutations, which led to the FDA approval of elacestrant in this patient group. Elacestrant was generally well tolerated, with main side effects being upper gastrointestinal symptoms. There are several ongoing clinical trials evaluating the efficacy of elacestrant in the early setting as well as in combination with other targeted agents in the treatment of metastatic breast cancer. Other novel oral SERDs are also currently being evaluated in the treatment of HR-positive breast cancer. Results of ongoing clinical trials with these drugs will help clinicians decide the best sequence and combination of endocrine therapy agents. [ABSTRACT FROM AUTHOR]

Patients with hormone-receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer constitute about 70% of the breast cancer population. About 35% of these patients develop distant metastases and their treatment will be palliative. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors were shown to significantly improve the outcomes of these patients. In combination with endocrine therapy, they have become the standard first-line treatment for HR-positive, HER2-negative breast cancer. In Poland, treatment with CDK4/6 inhibitors is reimbursed only for patients participating in the drug program of the Ministry of Health. However, fulfilling the eligibility criteria for the program may be challenging both for patients and for clinicians. This may lead to a delay in treatment with CDK4/6 inhibitors or a decision to use older and less effective drugs that are more widely available. The aim of this review was to compare the efficacy of first-line therapies in patients with HR-positive, HER2-negative metastatic breast cancer depending on the use of CDK4/6 inhibitors. We compared the efficacy of previous standard therapies with that of ribociclib, a CDK4/6 inhibitor, based on the median progression-free survival (PFS) as an outcome. Median PFS is not affected by the efficacy of subsequent treatment lines and is easy to interpret both for clinicians and for patients. The first-line treatment with chemotherapy or endocrine therapy (without CDK4/6 inhibitors) prolongs median PFS by several months and even to over a dozen months. The first-line treatment with endocrine therapy plus CDK4/6 inhibitors provides an opportunity to achieve a median PFS of more than 25 months and to prolong it by about 9 to 14 months. [ABSTRACT FROM AUTHOR]

Anti-estrogens or aromatase inhibitors in combination with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are the current standard of care for estrogen receptor-positive (ER+) Her-2 negative metastatic breast cancer. Although these combination therapies prolong progression-free survival compared to endocrine therapy alone, the growth-arrested state of residual tumor cells is clearly transient. Tumor cells that escape what might be considered a dormant or quiescent state and regain proliferative capacity often acquire resistance to further therapies. Our studies are based upon the observation that breast tumor cells arrested by Fulvestrant + Palbociclib enter into states of both autophagy and senescence from which a subpopulation ultimately escapes, potentially contributing to recurrent disease. Autophagy inhibition utilizing pharmacologic or genetic approaches only moderately enhanced the response to Fulvestrant + Palbociclib in ER+ MCF-7 breast tumor cells, slightly delaying proliferative recovery. In contrast, the BET inhibitor/degrader, ARV-825, prolonged the growth arrested state in both p53 wild type MCF-7 cells and p53 mutant T-47D cells and significantly delayed proliferative recovery. In addition, ARV-825 added after the Fulvestrant + Palbociclib combination promoted apoptosis and demonstrated efficacy in resistant RB deficient cell lines. These studies indicate that administration of BET inhibitors/degraders, which are currently being investigated in multiple clinical trials, may potentially improve standard of care therapy in metastatic ER+ breast cancer patients and may further prolong progression-free survival. [ABSTRACT FROM AUTHOR]

CDK4/6 inhibitors combined with endocrine therapy are standard first- or second-line treatment for patients with HR-positive and HER2-negative advanced breast cancer, however, there is currently no optimal recommendation for therapeutic strategies after progression on CDK4/6i. The aim of this study is to analyze the efficacy and safety of HDAC inhibitor Tucidinostat combined with endocrine therapy in patients after prior CDK4/6 inhibitor progression. The pathological and clinical data of 44 HR-positive and HER2-negative breast cancer patients treated with tucidinostat after progression on CDK4/6i at the Breast Oncology Department of the Fifth Medical Center of the PLA General Hospital from July 2019 to October 2021 were retrospectively analyzed. Observation indexes included progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR), objective response rate (ORR) and adverse events. At the same time, we attempted to identify potential genomic predictors using available next-generation sequencing (NGS). A total of 44 patients were enrolled in this study. Median follow-up was 10 months (1–26 months) by the data cutoff date (February 2022). The CBR was 6.8% (3/44), the median PFS was 2.0 months (95% CI 1.9–2.1), and the median OS was 14 months (95% CI 6.3–21.7). The mPFS was 4.1 months (95%CI: 0–8.2) in patients with 1 metastatic site, and the mPFS was 4.5 months (95%CI: 4.2–4.8) in patients who received sequential tucidinostat after CDK4/6i failure. Multivariate analysis showed that patients with 1 metastatic site or sequential tucidinostat treatment after failure of CDK4/6i were more likely to benefit from tucidinostat combined with endocrine therapy. Preliminary data showed PIK3CA mutation may be associated with resistance of tucidinostat therapy. No grade 4 adverse events and no treatment-related deaths were recorded in the study. Dose reductions because of adverse events occurred in 4 (9.1%) patients. This study preliminarily shows that tucidinostat combined with endocrine therapy may be an optional sequential strategy for patients with HR+/HER2-advanced breast cancer that has progressed on CDK4/6 inhibitor, especially for these with lower tumor burden and fewer prior palliative treatment. • CDK4/6 inhibitor became standard treatment for HR-positive MBC patients. • There is no optimal treatment strategy after progression on CDK4/6i. • Tcucidinostat was the only HDAC inhibitor approved in solid tumors worldwide. • The mPFS of Tcucidinostat was 4.5 months when used sequentially after prior CDK4/6i. • PIK3CA mutation may be associated with resistance of tucidinostat. [ABSTRACT FROM AUTHOR]