First-round deep research: mapping literature and clinical evidence. How does the treatment strategy for hormone receptor-positive, HER2-negative advanced or metastatic breast cancer change according to disease biological characteristics, endocrine resistance, prior therapies, and molecular alterations such as ESR1, PIK3CA, AKT1, or PTEN alterations?

Extracted mechanistic / response-determinant data (in detail, not a HR dump): In the CAPItello-291 trial, capivasertib plus fulvestrant demonstrated a statistically significant progression-free survival benefit in pretreated HR+/HER2- advanced breast cancer; the benefit was driven by tumours harbouring PIK3CA, AKT1, or PTEN alterations. FDA Approval Summary: Capivasertib in combination with fulvestrant for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer with PIK3CA/AKT1/PTEN alterations. Purpose The US Food and Drug Administration (FDA) approved capivasertib in combination with fulvestrant for adult patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer (MBC) who have received at least one prior endocrine therapy and whose tumours harbour one or more phosphatidylinositol-3-kinase (PIK3CA)/AKT serine/threonine kinase 1 (AKT1)/phosphatase and tensin homolog (PTEN) alterations as detected by an FDA-approved test. Patients and Methods Approval was based on the CAPItello-291 trial, a randomised, double-blind, multicentre trial that enrolled 708 patients with hormone receptor-positive, HER2-negative advanced or MBC, including 289 patients whose tumours had a PIK3CA/AKT1/PTEN alteration. Randomisation was stratified by the presence of liver metastases, prior CDK4/6i (cyclin-dependent kinase 4 and 6 [CDK4/6] inhibitor) therapy, and geographic region. Results A statistically significant progression-free survival (PFS) benefit was demonstrated in the overall population (hazard ratio [HR], 0.6 [95% CI, 0.51–0.71]); this result was driven by the 289 patients in the biomarker-positive population (HR, 0.5 [95% CI, 0.37–0.68]). Primary concerns included hyperglycaemia (18% all-grade, 2.8% grade ≥3), cutaneous toxicity (58% all-grade, 17% grade ≥3), and diarrhoea (72% all-grade, 9% grade ≥3). Conclusion Capivasertib in combination with fulvestrant was approved for patients whose tumours harbour PIK3CA/AKT1/PTEN alterations. (pmid:39159418) In the phase III postMONARCH trial, abemaciclib plus fulvestrant significantly improved progression-free survival compared with placebo plus fulvestrant in HR+/HER2- advanced breast cancer that had progressed on prior CDK4/6 inhibitor plus endocrine therapy. Purpose Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) are the standard first-line treatment for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC); however, disease progression occurs in nearly all patients, and additional treatment options are needed. A consistent treatment effect was observed across key clinical and genomic subgroups, including patients with and without ESR1 or PIK3CA mutations. (pmid:39693591) In the randomised phase IV PADMA trial, first-line palbociclib plus endocrine therapy significantly improved time to treatment failure and progression-free survival compared with monochemotherapy in high-risk HR+/HER2- metastatic breast cancer. Background PADMA is a prospective, randomised, open-label, multicentre phase IV trial comparing the combination of palbociclib and endocrine therapy (ET) with monochemotherapy (CT) +/- maintenance ET (at physician discretion) as first-line therapy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR-positive/HER2-negative) metastatic breast cancer (m BC). Patients and Methods Patients were randomised 1:1 to receive first-line palbociclib + ET or investigator's choice of CT (capecitabine, epirubicin, paclitaxel, or vinorelbine) +/- maintenance ET. The primary endpoint was time to treatment failure (TTF). Secondary endpoints were progression-free survival (PFS), overall survival (OS), safety, and treatment compliance. Results One hundred and twenty patients were randomised and initiated treatment (palbociclib + ET, n = 61; CT, n = 59), of whom 106 (88.3%) were postmenopausal. The TTF benefit across subgroups—including AKT pathway alterations or g/t BRCA1/2 mutations—was consistent with that observed in the overall population. Haematological toxicity was significantly higher in the palbociclib + ET arm than in the CT-based arm (96.8% versus 70.7%; P < 0.001), although non-haematological toxicity was similar in both arms. Conclusion PADMA is the first randomised, multicentre trial to demonstrate that first-line palbociclib + ET compared to CT leads to improvements in both TTF and PFS in predominantly postmenopausal patients with HR-positive/HER2-negative m BC. (pmid:42275799) Broader literature (case report / preclinical / other cohort / indirect comparison) — not automatically the head-to-head result of the named trial: In real-world comprehensive genomic profiling of HR+/HER2- metastatic breast cancer, ESR1 mutations were detected in 8.1% of first-line tissue biopsies, increasing to 59% in third-line liquid biopsy at a tumour fraction of at least 1%, whereas PTEN loss was detected more frequently in tissue than in liquid biopsy. Comprehensive Genomic Profiling of ESR1, PIK3CA, AKT1, and PTEN in HR(+)HER2(-) Metastatic Breast Cancer: Prevalence across Lines of Therapy and Predictive Value for Endocrine Therapy Resistance in Real-World Practice. Background: The treatment landscape for HR(+)HER2(-) metastatic breast cancer (MBC) is continuously evolving for patients with ESR1 mutations (mut) and genomic alterations (GA) in the PI3K/AKT pathway. (pmid:38872062) In patients with HR+/HER2- metastatic breast cancer progressing on CDK4/6 inhibitors, ctDNA profiling revealed frequent alterations in ESR1 (46.2%) and PIK3CA (37.6%), while PTEN alterations were independently associated with significantly shorter progression-free survival and overall survival. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) constitute the foundation of treatment for hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer (MBC). However, disease progression is inevitable, and elucidating resistance mechanisms is crucial to guide therapeutic strategies following CDK4/6i. In this study, we retrospectively analysed a real-world multi-institutional cohort of patients with HR+/HER2- MBC who underwent circulating tumour DNA (ctDNA) next-generation sequencing (NGS) prior to initiating second-line therapy. In multivariable analyses, PTEN alterations were independently associated with shorter progression-free survival (PFS) (p = 0.008) and overall survival (OS) (p = 0.006), whereas TP53 (p = 0.031), CCDN1 (p = 0.003), and clinician's choice of second-line ET (p = 0.011) affected OS. These findings highlight the prognostic significance of specific molecular alterations and support the role of genomic profiling in guiding second-line therapeutic decisions following CDK4/6i therapy. (pmid:40819062) In a real-world cohort of HR+/HER2- metastatic breast cancer assessed by serial ctDNA testing prior to second-line therapy following CDK4/6i, the most frequent alterations were PIK3CA (37.6%), ESR1 (46.2%), and TP53 (31.2%); PTEN alterations independently predicted shorter PFS (p=0.008) and OS (p=0.006). (pmid:40819062) In a large clinicogenomic database of patients with HR+/HER2- metastatic breast cancer, ESR1 mutations emerged as acquired resistance during first-line aromatase inhibitor plus CDK4/6i therapy, with ESR1 mutation prevalence increasing from 8.1% in first-line tissue specimens to 59% in third-line ctDNA. (pmid:38872062) Following first-line CDK4/6 inhibitor therapy, choice of second-line chemotherapy did not significantly affect progression-free survival or overall survival in HR-positive HER2-negative metastatic breast cancer. Introduction While CDK4/6 inhibitors (CDK4/6i) represent standard first-line therapy for patients with hormone receptor-positive (HRpos), HER2-negative (HER2neg) metastatic breast cancer, guidelines for treatment options following progression on CDK4/6i are more diverse. Chemotherapy is recommended when patients develop endocrine resistance or experience visceral crisis. (pmid:40780076) In the prospective PRAEGNANT registry, patients with PIK3CA-mutated HR+/HER2- advanced breast cancer receiving alpelisib plus fulvestrant following CDK4/6 inhibitor therapy achieved a median PFS of 5.0 months and a median OS of 20.1 months. Purpose PIK3CA mutations are among actionable targets in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. The lack of evidence regarding the use of alpelisib in the context of current treatment options, such as cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), highlights the importance of this analysis. Progression-free survival (PFS) and overall survival (OS) were calculated for all patients and stratified according to prior CDK4/6i therapy using the Kaplan–Meier method. Subgroups (including age, line of therapy, comorbidity), somatic PIK3CA mutations, reasons for treatment discontinuation, and adverse events (AEs) were analysed. Results Median PFS was 5.0 (95% confidence interval [CI], 3.1-9.4) months, and median OS was 20.1 (95% CI, 14.6-30.8) months. (pmid:41925922) Short answer to queried points (derived solely from extracted text): — treatment strategy: gap in retrieved abstracts. — endocrine resistance: A consistent treatment effect was observed across key clinical and genomic subgroups, including patients with and without ESR1 or PIK3CA mutations. — molecular alterations: These findings highlight the prognostic significance of specific molecular alterations and support the role of genomic profiling in guiding second-line therapeutic decisions following CDK4/6i therapy.

Lead

Extracted mechanistic / response-determinant data (in detail, not a HR dump): In the CAPItello-291 trial, capivasertib plus fulvestrant demonstrated a statistically significant progression-free survival benefit in previously treated HR+/HER2- advanced breast cancer; the benefit was driven by tumours harbouring PIK3CA, AKT1, or PTEN alterations. FDA Approval Summary: Capivasertib in combination with fulvestrant for hormone receptor-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer with PIK3CA/AKT1/PTEN alterations. Purpose The US Food and Drug Administration (FDA) approved capivasertib in combination with fulvestrant for the treatment of adult patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer (MBC) who have received at least one prior endocrine therapy and whose tumours harbour one or more phosphatidylinositol-3-kinase (PIK3CA) / AKT serine/threonine kinase 1 (AKT1) / phosphatase and tensin homolog (PTEN) alterations as detected by an FDA-approved test. Patients and Methods Approval was based on the CAPItello-291 trial, a randomised, double-blind, multicentre trial enrolling 708 patients with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer, including 289 patients whose tumours harboured a PIK3CA/AKT1/PTEN alteration. Randomisation was stratified by the presence of liver metastases, prior CDK4/6i (cyclin-dependent kinase 4 and 6 [CDK4/6] inhibitor) therapy, and geographic region. Results A statistically significant progression-free survival (PFS) benefit was demonstrated in the overall population (hazard ratio [HR], 0.6 [95% CI, 0.51–0.71]); this result was driven by the 289 patients in the biomarker-positive population (HR, 0.5 [95% CI, 0.37–0.68]). Primary concerns included hyperglycaemia (18% all-grade, 2.8% grade ≥3), cutaneous toxicity (58% all-grade, 17% grade ≥3), and diarrhoea (72% all-grade, 9% grade ≥3). Conclusion Capivasertib in combination with fulvestrant was approved for patients whose tumours harboured PIK3CA/AKT1/PTEN alterations. (pmid:39159418) In the phase III postMONARCH trial, abemaciclib plus fulvestrant significantly improved progression-free survival compared with placebo plus fulvestrant in HR+/HER2- advanced breast cancer progressing on prior CDK4/6 inhibitor plus endocrine therapy. Purpose Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) represent the standard first-line treatment in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC); however, disease progression occurs in nearly all patients, and additional treatment options are needed. A consistent treatment effect was observed across key clinical and genomic subgroups, including patients with and without ESR1 or PIK3CA mutations. (pmid:39693591) In the randomised phase IV PADMA trial, first-line palbociclib plus endocrine therapy significantly improved time to treatment failure and progression-free survival compared with monochemotherapy in high-risk HR+/HER2- metastatic breast cancer. Background PADMA is a prospective, randomised, open-label, multicentre phase IV trial comparing palbociclib and endocrine therapy (ET) with monochemotherapy (CT) +/- maintenance ET (at physician discretion) as first-line therapy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR-positive/HER2-negative) metastatic breast cancer (m BC). Patients and Methods Patients were randomised 1:1 to receive first-line palbociclib + ET or investigator's choice chemotherapy (capecitabine, epirubicin, paclitaxel, or vinorelbine) +/- maintenance ET. The primary endpoint was time to treatment failure (TTF). Secondary endpoints were progression-free survival (PFS), overall survival (OS), safety, and treatment compliance. Results One hundred and twenty patients were randomised and initiated treatment (palbociclib + ET, n = 61; CT, n = 59), of whom 106 (88.3%) were postmenopausal. The TTF benefit across subgroups—including AKT signalling alterations or g/t BRCA1/2 mutations—was consistent with that observed in the overall population. Haematological toxicity was significantly higher in the palbociclib + ET arm than in the CT-based arm (96.8% vs. 70.7%; P < 0.001), although non-haematological toxicity was similar in both arms. Conclusion PADMA is the first randomised, multicentre trial demonstrating that palbociclib + ET as first-line therapy leads to improvements in both TTF and PFS compared with CT in predominantly postmenopausal patients with HR-positive/HER2-negative m BC. (pmid:42275799) Broader literature (case report / preclinical / other cohort / indirect comparison) — not automatically the head-to-head result of the named trial: In real-world comprehensive genomic profiling of HR+/HER2- metastatic breast cancer, ESR1 mutations were detected in 8.1% of first-line tissue biopsies, increasing to 59% in third-line liquid biopsies with >=1% tumour fraction, whereas PTEN loss was observed more frequently in tissue than in liquid biopsy. Comprehensive Genomic Profiling of ESR1, PIK3CA, AKT1, and PTEN in HR(+)HER2(-) Metastatic Breast Cancer: Prevalence across Lines of Therapy and Predictive Value for Endocrine Therapy Resistance in Real-World Clinical Practice. Background The treatment landscape of HR(+)HER2(-) metastatic breast cancer (MBC) is continuously evolving for patients with ESR1 mutations (mut) and PI3K/AKT pathway genomic alterations (GA). (pmid:38872062) In patients with HR+/HER2- metastatic breast cancer progressing on CDK4/6 inhibitors, ctDNA profiling revealed frequent alterations in the ESR1 (46.2%) and PIK3CA (37.6%) genes, while PTEN alterations were independently associated with significantly shorter progression-free survival and overall survival. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) plus endocrine therapy (ET) constitute the foundation of treatment for hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer (MBC). However, disease progression is inevitable, and identifying resistance mechanisms is essential to defining therapeutic strategies following CDK4/6i. In this study, we retrospectively analysed a real-world, multi-institutional cohort of patients with HR+/HER2- MBC characterized by next-generation sequencing (NGS) of circulating tumour DNA (ctDNA) prior to second-line treatment initiation. In multivariable analyses, PTEN alterations were independently associated with shorter progression-free survival (PFS) (p = 0.008) and overall survival (OS) (p = 0.006), whereas TP53 (p = 0.031), CCDN1 (p = 0.003), and clinician's choice of second-line ET (p = 0.011) influenced OS. These results highlight the prognostic significance of specific molecular alterations and support the role of genomic profiling in guiding second-line therapeutic decisions following CDK4/6i therapy. (pmid:40819062) In a real-world cohort of HR+/HER2- metastatic breast cancer assessed by serial ctDNA testing prior to second-line therapy following CDK4/6i, PIK3CA (37.6%), ESR1 (46.2%), and TP53 (31.2%) were the most frequent alterations; PTEN alterations independently predicted shorter PFS (p=0.008) and OS (p=0.006). (pmid:40819062) In a large clinicogenomic database of HR+/HER2- metastatic breast cancer, ESR1 mutations emerged as acquired resistance during first-line aromatase inhibitor plus CDK4/6i therapy; ESR1 mutation prevalence rose from 8.1% in first-line tissue to 59% in third-line ctDNA. (pmid:38872062) Following first-line CDK4/6 inhibitor therapy, choice of second-line chemotherapy did not significantly affect progression-free survival or overall survival in HR-positive, HER2-negative metastatic breast cancer. Introduction While CDK4/6 inhibitors (CDK4/6i) represent standard first-line therapy for patients with hormone receptor-positive (HRpos), HER2-negative (HER2neg) metastatic breast cancer, guidelines for treatment options following progression on CDK4/6i are much more diverse. Chemotherapy is recommended when patients develop endocrine resistance or experience visceral crisis. (pmid:40780076) In the prospective PRAEGNANT registry, patients with PIK3CA-mutated HR+/HER2- advanced breast cancer treated with alpelisib plus fulvestrant following CDK4/6 inhibitor therapy achieved a median PFS of 5.0 months and a median OS of 20.1 months. Purpose PIK3CA mutations are among numerous actionable targets in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. The lack of evidence regarding the use of alpelisib in the context of current treatment options—such as cyclin-dependent kinase 4/6 inhibitors (CDK4/6i)—underscores the importance of this analysis. Progression-free survival (PFS) and overall survival (OS) were calculated for all patients and stratified according to prior CDK4/6i therapy using the Kaplan–Meier method. Subgroups (including age, line of therapy, comorbidity), somatic PIK3CA mutations, reasons for treatment discontinuation, and adverse events (AEs) were analysed. Results Median PFS was 5.0 (95% confidence interval [CI], 3.1–9.4) months, and median OS was 20.1 (95% CI, 14.6–30.8) months. (pmid:41925922) Short answer to queried points (derived solely from extracted text): — treatment strategy: gap in retrieved abstracts. — endocrine resistance: A consistent treatment effect was observed across key clinical and genomic subgroups, including patients with and without ESR1 or PIK3CA mutations. — molecular alterations: These results highlight the prognostic significance of specific molecular alterations and support the role of genomic profiling in guiding second-line therapeutic decisions following CDK4/6i therapy. ^{1, 2, 3, 4, 5, 6, 7}

Poszthoc / alcsoport / mechanizmus

PFS HR 0.41 · first-line ribociclib + letrozole ctDNA cohort · first_line · pmid:41587113 PFS HR 0.44 · first-line ribociclib + letrozole ctDNA cohort · first_line · pmid:41587113 PFS HR 0.51 · first-line ribociclib + letrozole ctDNA cohort · first_line · pmid:41587113 PFS median 23.4 months · first-line ribociclib + letrozole ctDNA cohort · first_line · pmid:41587113 ESR1 mutation frequency 54.0% · PACE trial baseline ctDNA cohort after CDK4/6i · pretreated · pmid:40714513 GATA3 mutation frequency 18.5% · PACE trial baseline ctDNA cohort after CDK4/6i · pretreated · pmid:40714513 PIK3CA mutation frequency 22.1% · first-line ribociclib + letrozole ctDNA cohort · first_line · pmid:41587113 PIK3CA mutation frequency 34.0% · PACE trial baseline ctDNA cohort after CDK4/6i · pretreated · pmid:40714513 RB1 mutation frequency 10.0% · PACE trial baseline ctDNA cohort after CDK4/6i · pretreated · pmid:40714513 TP53 mutation frequency 15.5% · first-line ribociclib + letrozole ctDNA cohort · first_line · pmid:41587113 TP53 mutation frequency 35.5% · PACE trial baseline ctDNA cohort after CDK4/6i · pretreated · pmid:40714513 Resistance to endocrine therapy following CDK4/6 inhibitors is mediated by distinct alterations, including ESR1 mutations and activation of the PI3K/AKT/mTOR pathway, guiding the use of precision targeted options such as oral SERDs (elacestrant, imlunestrant) and pathway inhibitors (alpelisib, capivasertib). · pmid:42445743 In ctDNA analysis of metastatic breast cancer, ESR1 and PIK3CA mutations represent distinct evolutionary events, and the presence or absence of mutations—rather than variant allele fraction—serves as the primary evidence-based criterion for therapy selection. · pmid:42437171 Oral selective oestrogen receptor degraders (SERDs) such as elacestrant and imlunestrant, together with PI3K and AKT pathway inhibitors such as alpelisib and capivasertib, demonstrate clinical efficacy in overcoming resistance mechanisms following progression on CDK4/6 inhibitors. · pmid:42445743 Circulating tumour DNA (ctDNA) testing enables real-time detection of resistance mutations and allows guided, adaptive endocrine-based combination therapy to delay chemotherapy. · pmid:42445743 Activating ESR1 mutations emerge under aromatase inhibitor pressure and drive ligand-independent ER activation; randomised trials (PADA-1, SERENA-6) demonstrate that early molecular detection via ctDNA can guide endocrine therapy switching to improve progression-free survival. · pmid:42222274 In metastatic breast cancer, PIK3CA mutations are early, clonal, and stable alterations, whereas ESR1 mutations are acquired under endocrine pressure; pivotal trials support mutation detection as the evidence-based criterion for selecting targeted therapy, independent of variant allele fraction. · pmid:42437171 In patients with PIK3CA-mutant tumours progressing during or within 12 months of completing adjuvant endocrine therapy, superior outcomes were achieved with the combination of inavolisib, palbociclib, and fulvestrant. · pmid:42505223 Following progression on a CDK4/6 inhibitor, second-line strategies include oral SERDs for ESR1-mutated disease, and alpelisib or capivasertib combinations for PIK3CA-AKT-PTEN pathway alterations. · pmid:41999452 Capivasertib in combination with fulvestrant significantly prolongs progression-free survival in patients with HR+/HER2- advanced breast cancer harbouring PIK3CA, AKT1, or PTEN alterations. · pmid:42194764 Alpelisib and capivasertib are FDA-approved agents in combination with fulvestrant for the treatment of PIK3CA-mutated, endocrine-resistant HR+/HER2- metastatic breast cancer; capivasertib is additionally approved for tumours harbouring PTEN or AKT alterations. · pmid:39674130 Based on ctDNA analyses from the PACE trial following progression on a CDK4/6 inhibitor, baseline TP53, PIK3CA, and RB1 mutations, as well as the ESR1 Y537S alteration, were significantly associated with shorter progression-free survival. · pmid:40714513 ^{8, 9, 10, 11, 12, 13, 14, 15, 16}

Egykarú

PFS median 10.7 months · PF-07248144 plus fulvestrant combination (n=43) · pretreated · pmid:38824244 ORR 25.8% · pretreated HR+/HER2- ABC · pretreated · pmid:41651834 ORR 25.8% · pretreated with CDK4/6i · pretreated · pmid:41651834 ORR 25.8% · pretreated cohort (20/31 with prior CDK4/6i) · pretreated · pmid:41651834 ORR objective response rate 25.8% · pretreated HR-positive, HER2-negative advanced breast cancer · pretreated · pmid:41651834 ORR 30.2% · PF-07248144 plus fulvestrant combination (n=43) · pretreated · pmid:38824244 ^{17, 18}

RWE

PFS HR 0.53 (0.29–0.97) · Second-line chemotherapy after CDK4/6i (N=215) · pretreated · pmid:40780076 PFS HR 0.64 (0.35–1.15) · Second-line chemotherapy after CDK4/6i (N=215) · pretreated · pmid:40780076 PFS HR 1.25 (0.94–1.65) · First-line cohort (N=508) · first_line · pmid:39952220 PFS HR 1.75 (1.31–2.34) · First-line cohort (N=508) · first_line · pmid:39952220 OS median 20.1 months (14.6–30.8) · PIK3CA-mutated HR+/HER2- ABC after CDK4/6i · pretreated · pmid:41925922 OS median 20.1 months (14.6–30.8) · PRAEGNANT registry, pretreated after CDK4/6i · pretreated · pmid:41925922 OS median 20.1 months (14.6–30.8) · PIK3CA-mutated, CDK4/6i-pretreated cohort · pretreated · pmid:41925922 PFS median 5.0 months (3.1–9.4) · PIK3CA-mutated HR+/HER2- ABC after CDK4/6i · pretreated · pmid:41925922 PFS median 5.0 months (3.1–9.4) · PRAEGNANT registry, pretreated after CDK4/6i · pretreated · pmid:41925922 PFS median 5.0 months (3.1–9.4) · PIK3CA-mutated, CDK4/6i-pretreated cohort · pretreated · pmid:41925922 ESR1 alteration frequency 46.2% · pre-second-line ctDNA NGS after CDK4/6i · pretreated · pmid:40819062 ESR1 mutation prevalence 46.2% · HR+/HER2- MBC ctDNA after CDK4/6i · pretreated · pmid:40819062 ESR1 mutation prevalence in 1L tissue 8.1% · HR+/HER2- MBC across treatment lines · pretreated · pmid:38872062 ESR1 mutation rate ESR1 mutation rate in first-line liquid biopsy TF >= 1% 17.5% · stratified by treatment line and biopsy type · pretreated · pmid:38872062 ESR1 mutation rate ESR1 mutation rate in third-line liquid biopsy TF >= 1% 59% · stratified by treatment line and biopsy type · pretreated · pmid:38872062 ESR1 mutation rate ESR1 mutation rate in first-line tissue biopsy 8.1% · stratified by treatment line and biopsy type · pretreated · pmid:38872062 PIK3CA alteration frequency 37.6% · pre-second-line ctDNA NGS after CDK4/6i · pretreated · pmid:40819062 PIK3CA mutation prevalence 37.6% · HR+/HER2- MBC ctDNA after CDK4/6i · pretreated · pmid:40819062 PTEN homozygous loss rate PTEN homozygous loss in tissue biopsy 4.3% · stratified by treatment line and biopsy type · pretreated · pmid:38872062 TP53 alteration frequency 31.2% · pre-second-line ctDNA NGS after CDK4/6i · pretreated · pmid:40819062 treatment discontinuation treatment discontinuation due to tumour progression 56.1% · PIK3CA-mutated, CDK4/6i-pretreated cohort · pretreated · pmid:41925922 proportion ESR1 mutation prevalence in 1st-line LBx TF >=1% 17.5% · liquid biopsy vs. tissue biopsy over course of therapy · pretreated · pmid:38872062 proportion ESR1 mutation prevalence in 3rd-line LBx TF >=1% 59% · liquid biopsy vs. tissue biopsy over course of therapy · pretreated · pmid:38872062 proportion ESR1 mutation prevalence in 1st-line TBx 8.1% · liquid biopsy vs. tissue biopsy over course of therapy · pretreated · pmid:38872062 ^{6, 19, 7, 5, 4}

Biztonság

Grade 3 or higher adverse events 29.0% · pretreated with CDK4/6i · pretreated · pmid:41651834 Grade 3 or higher adverse events 29.0% · pretreated cohort (20/31 with prior CDK4/6i) · pretreated · pmid:41651834 Grade 3–4 anaemia 13.1% · PF-07248144 plus fulvestrant combination (n=43) · pretreated · pmid:38824244 Grade >=3 cutaneous toxicity 17% · biomarker-positive (PIK3CA/AKT1/PTEN-altered) and overall population · pretreated · pmid:39159418 All-grade cutaneous toxicity 58% · biomarker-positive (PIK3CA/AKT1/PTEN-altered) and overall population · pretreated · pmid:39159418 All-grade diarrhoea 72% · biomarker-positive (PIK3CA/AKT1/PTEN-altered) and overall population · pretreated · pmid:39159418 Grade >=3 diarrhoea 9% · biomarker-positive (PIK3CA/AKT1/PTEN-altered) and overall population · pretreated · pmid:39159418 All-grade dysgeusia 83.2% · PF-07248144 plus fulvestrant combination (n=43) · pretreated · pmid:38824244 Grade >=3 adverse events 29.0% · pretreated HR+/HER2- ABC · pretreated · pmid:41651834 Haematological toxicity 70.7% · predominantly postmenopausal, high-risk HR+/HER2- mBC · first-line · pmid:42275799 Haematological toxicity 96.8% · predominantly postmenopausal, high-risk HR+/HER2- mBC · first-line · pmid:42275799 All-grade hyperglycaemia 18% · biomarker-positive (PIK3CA/AKT1/PTEN-altered) and overall population · pretreated · pmid:39159418 Grade >=3 hyperglycaemia 2.8% · biomarker-positive (PIK3CA/AKT1/PTEN-altered) and overall population · pretreated · pmid:39159418 Hyperglycaemia 2.8% · pretreated HR+/HER2- ABC/MBC · pretreated · pmid:39159418 Grade 3–4 neutropenia 35.5% · PF-07248144 plus fulvestrant combination (n=43) · pretreated · pmid:38824244 Grade >=3 cutaneous toxicity 17% · PIK3CA/AKT1/PTEN altered vs. overall · pretreated · pmid:39159418 Grade >=3 hyperglycaemia 2.8% · PIK3CA/AKT1/PTEN altered vs. overall · pretreated · pmid:39159418 Haematological toxicity in CT arm 70.7% · chemotherapy indicated, high-risk HR+/HER2- mBC · first-line · pmid:42275799 Grade >=3 diarrhoea 9% · PIK3CA/AKT1/PTEN altered vs. overall · pretreated · pmid:39159418 Haematological toxicity in palbociclib + ET arm 96.8% · chemotherapy indicated, high-risk HR+/HER2- mBC · first-line · pmid:42275799 Grade 3 or higher adverse events 29.0% · pretreated HR-positive, HER2-negative advanced breast cancer · pretreated · pmid:41651834 ^{18, 17, 1, 3}

Osztály / másik szer

BICR-assessed PFS HR 0.55 (0.39–0.77) · HR+/HER2- ABC after CDK4/6i · pretreated · pmid:39693591 BICR-assessed PFS HR 0.55 (0.39–0.77) · ITT progression after CDK4/6 inhibitor · pretreated · pmid:39693591 PFS progression or death HR 0.34 (0.14–0.82) · progression after CDK4/6 inhibitor · pretreated · pmid:41079023 PFS HR 0.34 (0.14–0.82) · network meta-analysis of 28 randomised trials (n=6544) · pretreated · pmid:41079023 PFS HR 0.45 (0.29–0.7) · 1L HR+/HER2- mBC · first-line · pmid:42275799 PFS progression or death HR 0.45 (0.29–0.7) · chemotherapy indicated, high-risk HR+/HER2- mBC · first-line · pmid:42275799 PFS HR 0.45 (0.29–0.7) · predominantly postmenopausal, high-risk HR+/HER2- mBC · first-line · pmid:42275799 PFS progression or death HR 0.49 (0.32–0.76) · network meta-analysis after CDK4/6 inhibitor · pretreated · pmid:41654790 PFS HR 0.5 (0.37–0.68) · pretreated HR+/HER2- ABC/MBC · pretreated · pmid:39159418 PFS progression or death HR 0.5 (0.37–0.68) · PIK3CA/AKT1/PTEN altered vs. overall · pretreated · pmid:39159418 PFS HR 0.5 (0.37–0.68) · biomarker-positive (PIK3CA/AKT1/PTEN-altered) and overall population · pretreated · pmid:39159418 PFS progression or death HR 0.57 (0.39–0.84) · network meta-analysis after CDK4/6 inhibitor · pretreated · pmid:41654790 PFS progression or death HR 0.57 (0.39–0.84) · progression after CDK4/6 inhibitor · pretreated · pmid:41079023 PFS HR 0.57 (0.39–0.84) · network meta-analysis of 28 randomised trials (n=6544) · pretreated · pmid:41079023 PFS HR 0.59 (0.48–0.72) · HR+/HER2- ABC after CDK4/6i · pretreated · pmid:41654790 PFS progression or death HR 0.59 (0.48–0.72) · network meta-analysis after CDK4/6 inhibitor · pretreated · pmid:41654790 PFS HR 0.6 (0.51–0.71) · pretreated HR+/HER2- ABC/MBC · pretreated · pmid:39159418 PFS progression or death HR 0.6 (0.51–0.71) · PIK3CA/AKT1/PTEN altered vs. overall · pretreated · pmid:39159418 PFS HR 0.6 (0.51–0.71) · biomarker-positive (PIK3CA/AKT1/PTEN-altered) and overall population · pretreated · pmid:39159418 PFS HR 0.61 (0.48–0.77) · 2L HR+/HER2- ABC after CDK4/6i · pretreated · pmid:41037898 PFS progression or death HR 0.61 (0.48–0.77) · switched CDK4/6i, PIK3CA-mutant and ESR1-mutant subgroups · pretreated · pmid:41037898 PFS HR 0.61 (0.48–0.77) · overall, CDK4/6i-switch, PIK3CA-mutant and ESR1-mutant subgroups · pretreated · pmid:41037898 PFS HR 0.62 (0.51–0.75) · HR+/HER2- mBC after CDK4/6i · pretreated · pmid:41079023 PFS progression or death HR 0.62 (0.51–0.75) · progression after CDK4/6 inhibitor · pretreated · pmid:41079023 PFS HR 0.62 (0.51–0.75) · network meta-analysis of 28 randomised trials (n=6544) · pretreated · pmid:41079023 PFS HR 0.66 (0.49–0.89) · 2L HR+/HER2- ABC after CDK4/6i · pretreated · pmid:41037898 PFS progression or death HR 0.66 (0.49–0.89) · switched CDK4/6i, PIK3CA-mutant and ESR1-mutant subgroups · pretreated · pmid:41037898 PFS HR 0.66 (0.49–0.89) · overall, CDK4/6i-switch, PIK3CA-mutant and ESR1-mutant subgroups · pretreated · pmid:41037898 PFS HR 0.7 (0.55–0.89) · HR+/HER2- ABC after CDK4/6i · pretreated · pmid:41654790 PFS HR 0.7 (0.55–0.89) · HR+/HER2- mBC after CDK4/6i · pretreated · pmid:41079023 PFS progression or death HR 0.7 (0.55–0.89) · network meta-analysis after CDK4/6 inhibitor · pretreated · pmid:41654790 PFS progression or death HR 0.7 (0.55–0.89) · progression after CDK4/6 inhibitor · pretreated · pmid:41079023 PFS HR 0.7 (0.55–0.89) · network meta-analysis of 28 randomised trials (n=6544) · pretreated · pmid:41079023 PFS HR 0.71 (0.52–0.98) · 2L HR+/HER2- ABC after CDK4/6i · pretreated · pmid:41037898 PFS progression or death HR 0.71 (0.52–0.98) · switched CDK4/6i, PIK3CA-mutant and ESR1-mutant subgroups · pretreated · pmid:41037898 PFS HR 0.71 (0.52–0.98) · overall, CDK4/6i-switch, PIK3CA-mutant and ESR1-mutant subgroups · pretreated · pmid:41037898 PFS HR 0.73 (0.57–0.95) · HR+/HER2- ABC after CDK4/6i · pretreated · pmid:39693591 PFS HR 0.73 (0.56–0.94) · 2L HR+/HER2- ABC after CDK4/6i · pretreated · pmid:41037898 PFS progression or death HR 0.73 (0.57–0.95) · progression after CDK4/6 inhibitor · pretreated · pmid:39693591 PFS progression or death HR 0.73 (0.56–0.94) · switched CDK4/6i, PIK3CA-mutant and ESR1-mutant subgroups · pretreated · pmid:41037898 PFS progression or death HR 0.73 (0.57–0.94) · network meta-analysis after CDK4/6 inhibitor · pretreated · pmid:41654790 PFS HR 0.73 (0.56–0.94) · overall, CDK4/6i-switch, PIK3CA-mutant and ESR1-mutant subgroups · pretreated · pmid:41037898 PFS HR 0.78 (0.6–1.01) · pretreated HR+/HER2- ABC/MBC · pretreated · pmid:39159418 PFS progression or death HR 0.78 (0.6–1.01) · PIK3CA/AKT1/PTEN altered vs. overall · pretreated · pmid:39159418 PFS HR 0.78 (0.6–1.01) · biomarker-positive (PIK3CA/AKT1/PTEN-altered) and overall population · pretreated · pmid:39159418 BICR-assessed PFS progression or death HR 0.55 (0.39–0.77) · progression after CDK4/6 inhibitor · pretreated · pmid:39693591 TTF HR 0.46 (0.31–0.69) · 1L HR+/HER2- mBC · first-line · pmid:42275799 TTF treatment failure HR 0.46 (0.31–0.69) · chemotherapy indicated, high-risk HR+/HER2- mBC · first-line · pmid:42275799 TTF HR 0.46 (0.31–0.69) · predominantly postmenopausal, high-risk HR+/HER2- mBC · first-line · pmid:42275799 investigator-assessed PFS HR 0.73 (0.57–0.95) · ITT progression after CDK4/6 inhibitor · pretreated · pmid:39693591 PFS HR 0.44 · ctDNA clearance at C2D1 · first-line · pmid:41587113 PFS median 5.3 months (3.7–5.6) · HR+/HER2- ABC after CDK4/6i · pretreated · pmid:39693591 PFS median 5.3 months (3.7–5.6) · progression after CDK4/6 inhibitor · pretreated · pmid:39693591 PFS median 6.0 months (5.6–8.6) · HR+/HER2- ABC after CDK4/6i · pretreated · pmid:39693591 PFS median 6.0 months (5.6–8.6) · progression after CDK4/6 inhibitor · pretreated · pmid:39693591 investigator-assessed PFS median 5.3 months (3.7–5.6) · ITT progression after CDK4/6 inhibitor · pretreated · pmid:39693591 investigator-assessed PFS median 6.0 months (5.6–8.6) · ITT progression after CDK4/6 inhibitor · pretreated · pmid:39693591 PFS median 18.7 months · 1L HR+/HER2- mBC · first-line · pmid:42275799 PFS median 18.7 months · chemotherapy indicated, high-risk HR+/HER2- mBC · first-line · pmid:42275799 PFS median 18.7 months · predominantly postmenopausal, high-risk HR+/HER2- mBC · first-line · pmid:42275799 PFS median 23.4 months · ctDNA clearance at C2D1 · first-line · pmid:41587113 PFS median 7.8 months · 1L HR+/HER2- mBC · first-line · pmid:42275799 PFS median 7.8 months · chemotherapy indicated, high-risk HR+/HER2- mBC · first-line · pmid:42275799 PFS median 7.8 months · predominantly postmenopausal, high-risk HR+/HER2- mBC · first-line · pmid:42275799 TTF median 17.2 months · 1L HR+/HER2- mBC · first-line · pmid:42275799 TTF median 17.2 months · chemotherapy indicated, high-risk HR+/HER2- mBC · first-line · pmid:42275799 TTF median 17.2 months · predominantly postmenopausal, high-risk HR+/HER2- mBC · first-line · pmid:42275799 TTF median 6.1 months · 1L HR+/HER2- mBC · first-line · pmid:42275799 TTF median 6.1 months · chemotherapy indicated, high-risk HR+/HER2- mBC · first-line · pmid:42275799 TTF median 6.1 months · predominantly postmenopausal, high-risk HR+/HER2- mBC · first-line · pmid:42275799 6-month PFS rate 37% · progression after CDK4/6 inhibitor · pretreated · pmid:39693591 6-month PFS rate 37% · ITT progression after CDK4/6 inhibitor · pretreated · pmid:39693591 6-month PFS rate 50% · progression after CDK4/6 inhibitor · pretreated · pmid:39693591 6-month PFS rate 50% · ITT progression after CDK4/6 inhibitor · pretreated · pmid:39693591 ORR 17% · progression after CDK4/6 inhibitor · pretreated · pmid:39693591 ORR 17% · ITT progression after CDK4/6 inhibitor · pretreated · pmid:39693591 ORR 7% · progression after CDK4/6 inhibitor · pretreated · pmid:39693591 ORR 7% · ITT progression after CDK4/6 inhibitor · pretreated · pmid:39693591 ^{2, 20, 3, 21, 1, 22, 8}

Fejlesztési fázis (Pipeline)

ctDNA-tested cohort (N=49) · pretreated · pmid:39839709 pretreated · NCT04606446 ^{23, 24}