RÉSUMÉ
Anti-oestrogen-based therapies, often combined with a CDK4/6 inhibitor, are the current standard-of-care first-line therapy for patients with advanced-stage hormone receptor-positive (HR+) breast cancer. Resistance to anti-oestrogen agents inevitably occurs, mediated by oestrogen receptor (ER)-dependent or ER-independent mechanisms that drive tumour progression. Emerging endocrine therapies include, but are not limited to, next-generation oral ER degraders and proteolysis targeting chimeras, which might be particularly effective in patients with ESR1-mutant breast cancer. Furthermore, cancers harbouring driver alterations in oncogenic signalling pathways, including AKT and PI3K, might be susceptible to novel combination strategies involving targeted inhibitors. Next-generation CDK2/4 inhibitors are an area of active clinical investigation, and efforts are ongoing to evaluate the role of sequential CDK inhibition. Approved and emerging antibody-drug conjugates exploiting novel target antigens have also demonstrated promising clinical activity. These novel agents, as well as further identification and characterization of predictive biomarkers, will hopefully continue to improve clinical outcomes, reduce the incidence of toxicities, and limit the extent of overtreatment in this population. In this Review, we describe the evolving treatment paradigm for patients with metastatic HR+ breast cancer in light of the growing armamentarium of drugs and biomarkers that will help to shape the future therapeutic landscape. These strategies are expected to involve tumour molecular profiling to enable the delivery of precision medicine.
RÉSUMÉ
PURPOSE: Elacestrant significantly prolonged progression-free survival (PFS) with manageable safety versus standard-of-care (SOC) endocrine therapy (ET) in patients with ER+, HER2- mBC and tumors harboring ESR1 mutation following ET plus a cyclin-dependent kinase 4/6 inhibitor (ET+CDK4/6i). In patients with ESR1-mutated tumors, we evaluated the efficacy and safety of elacestrant versus SOC based on prior ET+CDK4/6i duration, and in clinical subgroups with prior ET+CDK4/6i ≥12 months. METHODS: EMERALD, an open-label phase III trial, randomized patients with ER+, HER2- mBC, 1-2 prior lines of ET, mandatory CDK4/6i, and ≤1 chemotherapy to elacestrant (345 mg daily) or SOC (aromatase inhibitor or fulvestrant). PFS was assessed across subgroups in post-hoc exploratory analyses without adjustment for multiple testing. RESULTS: In patients with ESR1-mutated tumors and prior ET+CDK4/6i ≥12 months, median PFS (mPFS) for elacestrant versus SOC was 8.6 versus 1.9 months (HR, 0.41; 95% CI, 0.26-0.63). In this population, mPFS (in months) for elacestrant versus SOC was 9.1 versus 1.9 (bone metastases), 7.3 versus 1.9 (liver and/or lung metastases), 9.0 versus 1.9 (<3 metastatic sites), 10.8 versus 1.8 (≥3 metastatic sites), 5.5 versus 1.9 (PIK3CA mutation), 8.6 versus 1.9 (TP53 mutation), 9.0 versus 1.9 (HER2-low), 9.0 versus 1.9 (ESR1 D538G-mutated tumors), and 9.0 versus 1.9 (ESR1 Y537S/N-mutated tumors). Subgroup safety was consistent with the overall population. CONCLUSIONS: Duration of prior ET+CDK4/6i ≥12 months in mBC was associated with a clinically meaningful improvement in PFS for elacestrant compared to SOC and was consistent across all subgroups evaluated in patients with ER+, HER2-, ESR1-mutated tumors.
Sujet(s)
Anticorps monoclonaux humanisés , Tumeurs du sein , Humains , Anticorps monoclonaux humanisés/usage thérapeutique , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/anatomopathologie , Femelle , Camptothécine/analogues et dérivés , Camptothécine/usage thérapeutique , Camptothécine/administration et posologie , Métastase tumorale , Antinéoplasiques immunologiques/usage thérapeutique , ImmunoconjuguésRÉSUMÉ
Cell cycle dysregulation is a hallmark of cancer that promotes eccessive cell division. Cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6) are key molecules in the G1-to-S phase cell cycle transition and are crucial for the onset, survival, and progression of breast cancer (BC). Small-molecule CDK4/CDK6 inhibitors (CDK4/6i) block phosphorylation of tumor suppressor Rb and thus restrain susceptible BC cells in G1 phase. Three CDK4/6i are approved for the first-line treatment of patients with advanced/metastatic hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) BC in combination with endocrine therapy (ET). Though this has improved the clinical outcomes for survival of BC patients, there is no established standard next-line treatment to tackle drug resistance. Recent studies suggest that CDK4/6i can modulate other distinct effects in both BC and breast stromal compartments, which may provide new insights into aspects of their clinical activity. This review describes the biochemistry of the CDK4/6-Rb-E2F pathway in HR+ BC, then discusses how CDK4/6i can trigger other effects in BC/breast stromal compartments, and finally outlines the mechanisms of CDK4/6i resistance that have emerged in recent preclinical studies and clinical cohorts, emphasizing the impact of these findings on novel therapeutic opportunities in BC.
Sujet(s)
Tumeurs du sein , Kinase-4 cycline-dépendante , Kinase-6 cycline-dépendante , Résistance aux médicaments antinéoplasiques , Inhibiteurs de protéines kinases , Humains , Kinase-4 cycline-dépendante/antagonistes et inhibiteurs , Kinase-4 cycline-dépendante/métabolisme , Kinase-6 cycline-dépendante/antagonistes et inhibiteurs , Kinase-6 cycline-dépendante/métabolisme , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/anatomopathologie , Tumeurs du sein/métabolisme , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Femelle , Inhibiteurs de protéines kinases/pharmacologie , Inhibiteurs de protéines kinases/usage thérapeutique , Antinéoplasiques/pharmacologie , Antinéoplasiques/usage thérapeutique , Animaux , Cycle cellulaire/effets des médicaments et des substances chimiques , Récepteurs des oestrogènes/métabolismeRÉSUMÉ
PURPOSE: AMEERA-5 investigated amcenestrant (oral selective estrogen receptor [ER] degrader) plus palbociclib versus letrozole plus palbociclib as first-line treatment for ER-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced/metastatic breast cancer (aBC). MATERIALS AND METHODS: In AMEERA-5 (ClinicalTrials.gov identifier: NCT04478266), a double-blind, double-dummy, international phase III trial, adult pre-/post-menopausal women and men without previous systemic therapy for ER+/HER2- aBC were randomly assigned 1:1 to amcenestrant 200 mg once daily + standard palbociclib dosage (125 mg once daily, 21 days on/7 days off) or letrozole 2.5 mg once daily + standard palbociclib dosage, stratified by de novo metastatic disease, postmenopausal women, and visceral metastasis. The primary end point was progression-free survival (PFS), compared using a stratified log-rank test with one-sided type I error rate of 2.5%. Secondary end points included overall survival (key secondary), pharmacokinetics, and safety. RESULTS: Between October 14, 2020, and December 2, 2021, 1,068 patients were randomly assigned to amcenestrant + palbociclib (N = 534) or letrozole + palbociclib (N = 534). At the interim analysis (median follow-up 8.4 months), the stratified hazard ratio for PFS was 1.209 (95% CI, 0.939 to 1.557; one-sided P value = .9304); therefore, the study was stopped for futility. The 6-month PFS rate was 82.7% (95% CI, 79.0 to 85.8) with amcenestrant + palbociclib versus 86.9% (95% CI, 83.5 to 89.6) with letrozole + palbociclib. In the amcenestrant + palbociclib versus letrozole + palbociclib groups, treatment-emergent adverse events (any grade) occurred in 85.6% versus 85.4% of patients and grade ≥3 events in 46.3% versus 60.8%, respectively. CONCLUSION: The AMEERA-5 study was discontinued on the basis of the recommendation of the data monitoring committee at the interim futility analysis. No new safety signals were identified.
Sujet(s)
Protocoles de polychimiothérapie antinéoplasique , Tumeurs du sein , Létrozole , Pipérazines , Pyridines , Récepteur ErbB-2 , Récepteurs des oestrogènes , Humains , Femelle , Létrozole/administration et posologie , Létrozole/usage thérapeutique , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/anatomopathologie , Adulte d'âge moyen , Pyridines/usage thérapeutique , Pyridines/administration et posologie , Pyridines/effets indésirables , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Récepteur ErbB-2/métabolisme , Récepteur ErbB-2/analyse , Récepteurs des oestrogènes/métabolisme , Récepteurs des oestrogènes/analyse , Sujet âgé , Pipérazines/usage thérapeutique , Pipérazines/administration et posologie , Pipérazines/effets indésirables , Méthode en double aveugle , Adulte , Mâle , Tumeur du sein de l'homme/traitement médicamenteux , Tumeur du sein de l'homme/anatomopathologie , Tumeur du sein de l'homme/métabolisme , Sujet âgé de 80 ans ou plusRÉSUMÉ
PURPOSE: The antibody-drug conjugate (ADC) sacituzumab govitecan (SG) comprises the topoisomerase 1 (TOP1) inhibitor (TOP1i) SN-38, coupled to a monoclonal antibody targeting trophoblast cell surface antigen 2 (TROP-2). Poly(ADP-ribose) polymerase (PARP) inhibition may synergize with TOP1i and SG, but previous studies combining systemic PARP and TOP1 inhibitors failed due to dose-limiting myelosuppression. Here, we assess the proof-of-mechanism and clinical feasibility for SG and talazoparib (TZP) employing an innovative sequential dosing schedule. PATIENTS AND METHODS: In vitro models tested pharmacodynamic endpoints, and in a phase 1b clinical trial (NCT04039230), 30 patients with metastatic triple-negative breast cancer (mTNBC) received SG and TZP in a concurrent (N = 7) or sequential (N = 23) schedule. Outcome measures included safety, tolerability, preliminary efficacy, and establishment of a recommended phase 2 dose. RESULTS: We hypothesized that tumor-selective delivery of TOP1i via SG would reduce nontumor toxicity and create a temporal window, enabling sequential dosing of SG and PARP inhibition. In vitro, sequential SG followed by TZP delayed TOP1 cleavage complex clearance, increased DNA damage, and promoted apoptosis. In the clinical trial, sequential SG/TZP successfully met primary objectives and demonstrated median progression-free survival (PFS) of 7.6 months without dose-limiting toxicities (DLT), while concurrent dosing yielded 2.3 months PFS and multiple DLTs including severe myelosuppression. CONCLUSIONS: While SG dosed concurrently with TZP is not tolerated clinically due to an insufficient therapeutic window, sequential dosing of SG followed by TZP proved a viable strategy. These findings support further clinical development of the combination and suggest that ADC-based therapy may facilitate novel, mechanism-based dosing strategies.
Sujet(s)
Anticorps monoclonaux humanisés , Protocoles de polychimiothérapie antinéoplasique , Camptothécine , Immunoconjugués , Inhibiteurs de poly(ADP-ribose) polymérases , Inhibiteurs de la topoisomérase-I , Humains , Femelle , Immunoconjugués/administration et posologie , Immunoconjugués/usage thérapeutique , Immunoconjugués/pharmacologie , Inhibiteurs de poly(ADP-ribose) polymérases/administration et posologie , Adulte d'âge moyen , Anticorps monoclonaux humanisés/administration et posologie , Camptothécine/analogues et dérivés , Camptothécine/administration et posologie , Camptothécine/usage thérapeutique , Sujet âgé , Inhibiteurs de la topoisomérase-I/administration et posologie , Inhibiteurs de la topoisomérase-I/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/pharmacologie , Adulte , Tumeurs du sein triple-négatives/traitement médicamenteux , Tumeurs du sein triple-négatives/anatomopathologie , Phtalazines/administration et posologie , Lignée cellulaire tumorale , ADN topoisomérases de type I/métabolisme , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/anatomopathologie , Antigènes néoplasiques/immunologie , Molécules d'adhérence cellulaireRÉSUMÉ
BACKGROUND: Trastuzumab deruxtecan is a HER2-directed antibody-drug conjugate approved by the US Food and Drug Administration and the European Medicines Agency for HER2-mutant non-small-cell lung cancer. Few treatment options exist for patients with HER2-mutant solid tumours beyond lung cancers. We investigated trastuzumab deruxtecan in metastatic solid tumours with specific activating HER2 mutations. METHODS: In this open-label, phase 2, basket study done in 29 centres in Asia, Europe, and North America, we investigated trastuzumab deruxtecan (5·4 mg/kg every 3 weeks by intravenous infusion) in patients aged 18 years or older with unresectable or metastatic solid tumours with specific activating HER2 mutations, an Eastern Cooperative Oncology Group performance status of 0 or 1, and disease progression following previous treatment (previous HER2-targeted therapy was permitted) or with no satisfactory alternative treatment options. The primary endpoint was confirmed objective response rate by independent central review. Anti-tumour activity and safety were analysed in all patients who received at least one dose of trastuzumab deruxtecan. This trial is registered with ClinicalTrials.gov, NCT04639219, and is active but no longer recruiting. FINDINGS: Between Dec 30, 2020, and Jan 25, 2023, 102 patients (62 [61%] female and 40 [39%] male; median age 66·5 years [IQR 58-72]; 51 [50%] White, two [2%] Black or African American, 38 [37%] Asian, and 11 [11%] did not have race information reported) with solid tumours with activating HER2 mutations received trastuzumab deruxtecan and were included in the anti-tumour activity and safety analyses sets. Patients had a median of three (IQR 2-4) previous treatment regimens. The median duration of follow-up was 8·61 months (IQR 3·71-12·68). The objective response rate by independent central review was 29·4% (95% CI 20·8-39·3; 30 of 102 patients). 52 (51%) patients had a treatment-emergent adverse event of grade 3 or worse; the most common events (in ≥5% of patients) were anaemia (16 [16%]) and neutrophil count decreased (eight [8%]). Drug-related treatment-emergent serious adverse events occurred in ten (10%) patients. Adjudicated drug-related interstitial lung disease or pneumonitis of any grade occurred in 11 patients (11%; three grade 1, five grade 2, one grade 3, and two grade 5); there were two (2%) cases of fatal adjudicated drug-related interstitial lung disease or pneumonitis. INTERPRETATION: Trastuzumab deruxtecan showed anti-tumour activity and durable responses in heavily pretreated patients across multiple tumour types with activating HER2 mutations, with no new safety signals. Prespecified HER2 mutations might be targeted by HER2-directed antibody-drug conjugates and our findings support further investigation of trastuzumab deruxtecan in the pan-tumour setting. FUNDING: AstraZeneca and Daiichi Sankyo.
Sujet(s)
Immunoconjugués , Mutation , Tumeurs , Récepteur ErbB-2 , Trastuzumab , Humains , Femelle , Trastuzumab/usage thérapeutique , Trastuzumab/effets indésirables , Mâle , Récepteur ErbB-2/génétique , Adulte d'âge moyen , Sujet âgé , Immunoconjugués/usage thérapeutique , Immunoconjugués/effets indésirables , Tumeurs/traitement médicamenteux , Tumeurs/génétique , Tumeurs/anatomopathologie , Camptothécine/analogues et dérivés , Camptothécine/usage thérapeutique , Camptothécine/effets indésirables , Antinéoplasiques immunologiques/usage thérapeutique , Antinéoplasiques immunologiques/effets indésirables , AdulteRÉSUMÉ
BACKGROUND: In estrogen receptor-positive metastatic breast cancer, ESR1 mutations (ESR1m) are a common mechanism of acquired resistance to aromatase inhibitors (ArIh). However, the impact ESR1 alterations have on CDK4/6 inhibitor (CDK4/6i) sensitivity has not been established. Analyses of CDK4/6i trials suggest that the endocrine therapy partner and specific ESR1 allele may affect susceptibility. We analyzed a real-world data set to investigate CDK4/6i efficacy in ESR1m metastatic breast cancer and associated clinical factors. METHODS: ESR1m were identified by analysis of circulating-tumor deoxyribonucleic acid. The GuardantINFORM database contains genomic information from tumors linked with claims data. Patients who started a CDK4/6i within 30 days of sequencing were categorized as having ESR1m or non-ESR1-mutant (non-ESR1m) breast cancer. Data were analyzed to determine the real-world time-to-next-treatment, defined as the start of a breast cancer treatment to initiation of the subsequent treatment. RESULTS: One hundred forty-five patients with ESR1m and 612 with non-ESR1m metastatic breast cancer were analyzed. ESR1m and non-ESR1m tumors had similar real-world time-to-next-treatment on CDK4/6i regimens (hazard ratio, 1.02; 95% confidence interval, 0.82 to 1.23). Duration on therapy in the first-line and second-line plus treatment settings were comparable regardless of ESR1 status. We stratified treatment duration by concurrent endocrine therapy, and patients with ESR1m had worse outcomes on ArIh but comparable real-world time-to-next-treatment on fulvestrant. CONCLUSIONS: These data suggest ESR1 variants are not associated with pan-CDK4/6i resistance and are consistent with the hypothesis that CDK4/6 blockade combined with a selective estrogen receptor degrader is potentially an effective option for ESR1m metastatic breast cancer.
Sujet(s)
Tumeurs du sein , Kinase-4 cycline-dépendante , Kinase-6 cycline-dépendante , Récepteur alpha des oestrogènes , Mutation , Humains , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/génétique , Tumeurs du sein/anatomopathologie , Femelle , Récepteur alpha des oestrogènes/génétique , Adulte d'âge moyen , Kinase-4 cycline-dépendante/antagonistes et inhibiteurs , Kinase-4 cycline-dépendante/génétique , Kinase-6 cycline-dépendante/antagonistes et inhibiteurs , Kinase-6 cycline-dépendante/génétique , Sujet âgé , Adulte , Inhibiteurs de l'aromatase/usage thérapeutique , Pipérazines/usage thérapeutique , Métastase tumorale , Fulvestrant/usage thérapeutique , Inhibiteurs de protéines kinases/usage thérapeutiqueRÉSUMÉ
BACKGROUND: The TROPiCS-02 study (NCT03901339) demonstrated that sacituzumab govitecan (SG) has superior clinical outcomes over treatment of physician's choice (TPC) chemotherapy in patients with hormone receptor-positive, human epidermal growth factor 2 receptor-negative (HR+/HER2-) metastatic breast cancer (mBC). Here, we present health-related quality of life (HRQoL) patient-reported outcome (PRO) findings from this study. PATIENTS AND METHODS: Eligible adults with HR+/HER2- mBC who previously received a taxane, endocrine-based therapy, a CDK4/6 inhibitor, and 2-4 lines of chemotherapy were randomized 1:1 to receive SG or TPC until progression or unacceptable toxicity. PROs were assessed at baseline and on day 1 of each cycle, using the European Organization for Research and Treatment of Cancer Quality-of-Life Core 30 (EORTC QLQ-C30), EQ-5D-5L, and PRO Common Terminology Criteria for Adverse Events (PRO-CTCAE). RESULTS: Compared to TPC, overall least square mean change from baseline was significantly better for SG for physical functioning and dyspnea, but worse for diarrhea. Time to first clinically meaningful worsening or death was significantly longer for SG in global health status/quality of life, physical functioning, fatigue, emotional functioning, dyspnea, insomnia, and financial difficulties of the EORTC QLQ-C30 and the EQ-VAS, but longer for TPC in diarrhea. Few patients in both arms reported experiencing any worsening to level 3 or 4 treatment-related symptomatic events during treatment, as assessed by 16 PRO-CTCAE items, except for diarrhea frequency and amount of hair loss, which favored TPC. CONCLUSIONS: SG was associated with an HRQoL benefit in most symptoms and functioning, compared with TPC. This supports the favorable profile of SG as a treatment option for patients with pretreated HR+/HER2- mBC.
RÉSUMÉ
PURPOSE: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of a humanized antitrophoblast cell-surface antigen 2 (TROP2) monoclonal antibody linked to a potent, exatecan-derived topoisomerase I inhibitor payload via a plasma-stable, selectively cleavable linker. PATIENTS AND METHODS: TROPION-PanTumor01 (ClinicalTrials.gov identifier: NCT03401385) is a phase I, dose-escalation, and dose-expansion study evaluating Dato-DXd in patients with previously treated solid tumors. The primary study objective was to assess the safety and tolerability of Dato-DXd. Secondary objectives included evaluation of antitumor activity and pharmacokinetics. Results from patients with advanced/metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC) or triple-negative BC (TNBC) are reported. RESULTS: At data cutoff (July 22, 2022), 85 patients (HR+/HER2- BC = 41, and TNBC = 44) had received Dato-DXd. The objective response rate by blinded independent central review was 26.8% (95% CI, 14.2 to 42.9) and 31.8% (95% CI, 18.6 to 47.6) for patients with HR+/HER2- BC and TNBC, respectively. The median duration of response was not evaluable in the HR+/HER2- BC cohort and 16.8 months in the TNBC cohort. The median progression-free survival in patients with HR+/HER2- BC and TNBC was 8.3 and 4.4 months, respectively. All-cause treatment-emergent adverse events (TEAEs; any grade, grade ≥3) were observed in 100% and 41.5% of patients with HR+/HER2- BC and 100% and 52.3% of patients with TNBC. Stomatitis was the most common TEAE (any grade, grade ≥3) in both HR+/HER2- BC (82.9%, 9.8%) and TNBC (72.7%, 11.4%) cohorts. CONCLUSION: In patients with heavily pretreated advanced HR+/HER2- BC and TNBC, Dato-DXd demonstrated promising clinical activity and a manageable safety profile. Dato-DXd is currently being evaluated in phase III studies.
Sujet(s)
Immunoconjugués , Récepteur ErbB-2 , Tumeurs du sein triple-négatives , Humains , Femelle , Tumeurs du sein triple-négatives/traitement médicamenteux , Tumeurs du sein triple-négatives/anatomopathologie , Adulte d'âge moyen , Sujet âgé , Immunoconjugués/usage thérapeutique , Immunoconjugués/effets indésirables , Immunoconjugués/pharmacocinétique , Adulte , Récepteur ErbB-2/métabolisme , Camptothécine/analogues et dérivés , Camptothécine/usage thérapeutique , Récepteurs des oestrogènes/métabolisme , Anticorps monoclonaux humanisés/usage thérapeutique , Anticorps monoclonaux humanisés/effets indésirables , Anticorps monoclonaux humanisés/pharmacocinétique , Récepteurs à la progestérone/métabolisme , Antigènes néoplasiques , Molécules d'adhérence cellulaire/métabolisme , TrastuzumabRÉSUMÉ
In this post hoc analysis of the ASCENT study, we compared outcomes with sacituzumab govitecan (SG) vs single-agent chemotherapy in clinically important subgroups of patients with metastatic triple-negative breast cancer (mTNBC). Patients with mTNBC refractory to/relapsing after ≥2 prior chemotherapies (≥1 in the metastatic setting) were randomized 1:1 to receive SG or treatment of physician's choice (TPC) until unacceptable toxicity/progression. The primary endpoint was progression-free survival (PFS) per RECIST 1.1 by central review in patients without brain metastases. Patients with brain metastases were allowed if metastases were stable ≥4 weeks. In the intention-to-treat (ITT) population, 19% of patients were age ≥65 years; 12% were Black, and 12% had brain metastases. SG improved PFS and overall survival (OS), respectively, vs TPC in patients age ≥65 years (7.1 vs 2.4 months and 14.7 vs 8.9 months), or of Black race (5.4 vs 2.2 months and 13.8 vs 8.5 months), consistent with outcomes in the ITT population. Patients with brain metastases had numerically higher median PFS with SG vs TPC, but median OS was similar between treatment groups. SG was well tolerated and had a manageable safety profile consistent with the full safety population across all subgroups; neutropenia and diarrhea were the most common treatment-emergent adverse events. These findings confirm the meaningful clinical benefit of SG vs standard chemotherapy in patient subgroups with high unmet needs. SG should be considered an effective and safe treatment option for patients with mTNBC eligible for second-line or later therapy. ClinicalTrials.gov Number: NCT02574455.
RÉSUMÉ
INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.
Sujet(s)
Tumeurs du sein , Humains , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/anatomopathologie , Femelle , Administration par voie orale , Inhibiteurs de l'aromatase/pharmacologie , Inhibiteurs de l'aromatase/administration et posologie , Récepteur alpha des oestrogènes/métabolisme , Récepteur alpha des oestrogènes/génétique , Animaux , Mutation , Fulvestrant/administration et posologie , Fulvestrant/pharmacologie , Résistance aux médicaments antinéoplasiques , Récepteurs des oestrogènes/métabolisme , Modulateurs sélectifs des récepteurs des oestrogènes/pharmacologie , Modulateurs sélectifs des récepteurs des oestrogènes/administration et posologie , Thérapie moléculaire ciblée , Transduction du signal/effets des médicaments et des substances chimiquesRÉSUMÉ
Background: Despite advances in the treatment of early triple-negative breast cancer (TNBC), patients with residual invasive disease after neoadjuvant therapy have a high risk of disease recurrence and worse survival outcomes than those who have pathological complete response (pCR). Improving outcomes in early TNBC remains an unmet need requiring new adjuvant treatment approaches. Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate comprising a humanized anti-trophoblast cell-surface antigen 2 immunoglobulin G1 (IgG1) monoclonal antibody attached via a plasma-stable, cleavable linker to a potent topoisomerase I inhibitor payload, with activity observed in advanced TNBC. Objectives: TROPION-Breast03 is an ongoing phase III study evaluating the efficacy and safety of Dato-DXd alone or combined with durvalumab versus standard-of-care therapy as adjuvant treatment in patients with stage I-III TNBC with residual invasive disease at surgical resection following neoadjuvant treatment. Methods and design: Eligible patients, aged ⩾18 years, will be randomized in a 2:1:2 ratio to receive Dato-DXd [6 mg/kg intravenously (IV) every 3 weeks (Q3W); eight cycles] and durvalumab (1120 mg IV Q3W; nine cycles), Dato-DXd monotherapy (6 mg/kg IV Q3W), or investigator's choice of therapy (ICT; capecitabine, pembrolizumab, or capecitabine and pembrolizumab). The primary endpoint is invasive disease-free survival (iDFS) for Dato-DXd and durvalumab versus ICT. Key secondary endpoints include safety, distant disease-free survival, and overall survival for Dato-DXd and durvalumab versus ICT and iDFS for Dato-DXd monotherapy versus ICT. Ethics: TROPION-Breast03 will be approved by the independent ethics committees or institutional review boards at each study site. All study participants will provide written informed consent. Discussion: TROPION-Breast03 will help define the potential role of Dato-DXd in the treatment of patients with early-stage TNBC who do not have pCR after neoadjuvant therapy. Trial registration: ClinicalTrials.gov identifier: NCT05629585 (registration date: 29 November 2022).
TROPION-Breast03: a clinical trial designed to assess the effectiveness and safety of Dato-DXd, alone or in combination with durvalumab, in patients with triple-negative breast cancer who have cancer cells remaining at the time of surgery after initial systemic therapy Triple-negative breast cancer (TNBC), in which cells do not have estrogen or progesterone receptors or high levels of human epidermal growth factor receptor 2, is the most aggressive breast cancer subtype. TNBC is difficult to treat and associated with high risk of recurrence despite standard systemic therapy (treatment targeting the entire body), which can include chemotherapy alone or in combination with immunotherapy (treatment targeting the immune system). To reduce the risk of recurrence, standard systemic treatment is often followed by surgical removal of the patient's tumors and additional systemic treatment. Dato-DXd is an antibody-drug conjugate, which is an anticancer drug (DXd) connected to an antibody (datopotamab) by a stable linker. Datopotamab binds to TROP2, a protein found on breast cancer cells, and is taken into the tumor cell where the linker breaks, releasing DXd to kill the cell. By delivering DXd directly to cancer cells, Dato-DXd reduces exposure in the rest of the body, reducing the risk of side effects. Since Dato-DXd can recruit immune cells to cancer sites, it may work better combined with durvalumab, a drug that blocks the activity of a protein called PD-L1, making cancer cells more susceptible to being killed by immune cells. The TROPION-Breast03 study will compare Dato-DXd, alone or combined with durvalumab, with standard-of-care therapy in patients with TNBC that has not spread to parts of the body away from the original tumor site(s), but with cancer cells remaining at the time of surgery after initial systemic therapy. It will assess how well each treatment works and describe any side effects. We plan to recruit 1,075 eligible adults who will be randomly assigned in a 2:1:2 ratio to: ⢠Dato-DXd + durvalumab ⢠Dato-DXd alone ⢠Standard-of-care therapy ⢠Patients will receive treatment until they complete the planned course of therapy (8 or 9 cycles), their cancer returns, side effects become unacceptable, or they choose to stop.
RÉSUMÉ
Circulating Tumor Cells (CTCs), interrogated by sampling blood from patients with cancer, contain multiple analytes, including intact RNA, high molecular weight DNA, proteins, and metabolic markers. However, the clinical utility of tumor cell-based liquid biopsy has been limited since CTCs are very rare, and current technologies cannot process the blood volumes required to isolate a sufficient number of tumor cells for in-depth assays. We previously described a high-throughput microfluidic prototype utilizing high-flow channels and amplification of cell sorting forces through magnetic lenses. Here, we apply this technology to analyze patient-derived leukapheresis products, interrogating a mean blood volume of 5.83 liters from patients with metastatic cancer, with a median of 2,799 CTCs purified per patient. Isolation of many CTCs from individual patients enables characterization of their morphological and molecular heterogeneity, including cell and nuclear size and RNA expression. It also allows robust detection of gene copy number variation, a definitive cancer marker with potential diagnostic applications. High-volume microfluidic enrichment of CTCs constitutes a new dimension in liquid biopsies.
RÉSUMÉ
We aimed to study the incidence and genomic spectrum of actionable alterations (AA) detected in serial cfDNA collections from patients with metastatic breast cancer (MBC). Patients with MBC who underwent plasma-based cfDNA testing (Guardant360®) between 2015 and 2021 at an academic institution were included. For patients with serial draws, new pathogenic alterations in each draw were classified as actionable alterations (AA) if they met ESCAT I or II criteria of the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT). A total of 344 patients with hormone receptor-positive (HR+)/HER2-negative (HER2-) MBC, 95 patients with triple-negative (TN) MBC and 42 patients with HER2-positive (HER2 + ) MBC had a baseline (BL) cfDNA draw. Of these, 139 HR+/HER2-, 33 TN and 13 HER2+ patients underwent subsequent cfDNA draws. In the HR+/HER2- cohort, the proportion of patients with new AA decreased from 63% at BL to 27-33% in the 2nd-4th draws (p < 0.0001). While some of the new AA in subsequent draws from patients with HR+/HER2- MBC were new actionable variants in the same genes that were known to be altered in previous draws, 10-24% of patients had new AA in previously unaltered genes. The incidence of new AA also decreased with subsequent draws in the TN and HER2+ cohorts (TN: 25% to 0-9%, HER2 + : 38% to 14-15%). While the incidence of new AA in serial cfDNA decreased with subsequent draws across all MBC subtypes, new alterations with a potential impact on treatment selection continued to emerge, particularly for patients with HR+/HER2- MBC.
RÉSUMÉ
PURPOSE: To compare giredestrant and physician's choice of endocrine monotherapy (PCET) for estrogen receptor-positive, HER2-negative, advanced breast cancer (BC) in the phase II acelERA BC study (ClinicalTrials.gov identifier: NCT04576455). METHODS: Post-/pre-/perimenopausal women, or men, age 18 years or older with measurable disease/evaluable bone lesions, whose disease progressed after 1-2 lines of systemic therapy (≤1 targeted, ≤1 chemotherapy regimen, prior fulvestrant allowed) were randomly assigned 1:1 to giredestrant (30 mg oral once daily) or fulvestrant/aromatase inhibitor per local guidelines (+luteinizing hormone-releasing hormone agonist in pre-/perimenopausal women, and men) until disease progression/unacceptable toxicity. Stratification was by visceral versus nonvisceral disease, prior cyclin-dependent kinase 4/6 inhibitor, and prior fulvestrant. The primary end point was investigator-assessed progression-free survival (INV-PFS). RESULTS: At clinical cutoff (February 18, 2022; median follow-up: 7.9 months; N = 303), the INV-PFS hazard ratio (HR) was 0.81 (95% CI, 0.60 to 1.10; P = .1757). In the prespecified secondary end point analysis of INV-PFS by ESR1 mutation (m) status in circulating tumor DNA-evaluable patients (n = 232), the HR in patients with a detectable ESR1m (n = 90) was 0.60 (95% CI, 0.35 to 1.03) versus 0.88 (95% CI, 0.54 to 1.42) in patients with no ESR1m detected (n = 142). Related grade 3-4 adverse events (AEs), serious AEs, and discontinuations due to AEs were balanced across arms. CONCLUSION: Although the acelERA BC study did not reach statistical significance for its primary INV-PFS end point, there was a consistent treatment effect with giredestrant across most key subgroups and a trend toward favorable benefit among patients with ESR1-mutated tumors. Giredestrant was well tolerated, with a safety profile comparable to PCET and consistent with known endocrine therapy risks. Overall, these data support the continued investigation of giredestrant in other studies.
Sujet(s)
Tumeurs du sein , Fulvestrant , Récepteur ErbB-2 , Récepteurs des oestrogènes , Humains , Femelle , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/génétique , Tumeurs du sein/anatomopathologie , Tumeurs du sein/mortalité , Adulte d'âge moyen , Récepteur ErbB-2/métabolisme , Récepteurs des oestrogènes/métabolisme , Récepteurs des oestrogènes/analyse , Sujet âgé , Adulte , Fulvestrant/usage thérapeutique , Mâle , Inhibiteurs de l'aromatase/usage thérapeutique , Inhibiteurs de l'aromatase/effets indésirables , Antinéoplasiques hormonaux/usage thérapeutique , Survie sans progression , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/effets indésirablesRÉSUMÉ
PURPOSE: Although patients with metastatic breast cancer (MBC) have been living longer with the advent of more effective treatments such as targeted therapy and immunotherapy, the disease remains incurable, and most patients will undergo therapy indefinitely. When beginning therapy, patients are typically prescribed dose often based upon the maximum tolerated dose identified in phase I clinical trials. However, patients' perspectives about tolerability and willingness to discuss individualized dosing of drugs upon initiation of a new regimen and throughout the course of treatment have not been comprehensively evaluated. METHODS: Patient advocates and medical oncologists from the Patient-Centered Dosing Initiative (PCDI) developed a survey to ascertain the prevalence and severity of MBC patients' treatment-related side effects, the level of patient-physician communication, mitigation strategies, perception about the relative efficacy of higher versus lower doses, and willingness to discuss alternative dosing. The PCDI distributed the anonymous confidential online survey in August 2020 to individuals with self-reported MBC. RESULTS: One thousand and two hundred twenty-one patients with MBC completed the survey. 86.1% (n = 1,051) reported experiencing at least one significant treatment-related side effect, and of these, 20.3% (n = 213) visited the emergency room/hospital and 43.2% (n = 454) missed at least one treatment. Nearly all patients with side effects (97.6%, n = 1,026) informed their doctor and 81.7% (n = 838) received assistance. Of the 556 patients given a dose reduction for side-effect mitigation, 82.6% (n = 459) reported relief. Notably, majority of patients (53.3%, n = 651) do not believe that higher dose is always more effective than lower dose, and 92.3% (n = 1,127) would be willing to discuss flexible dosing options with their physicians based upon personal characteristics to optimize quality of life. CONCLUSION: Given that the majority of patients with MBC experienced at least one substantial treatment-related side effect and most patients given a dose reduction reported improvement, innovative dosage-related strategies are warranted to sustain and improve patients' well-being. Patient-physician discussions in which the patient's unique attributes and circumstances are assessed upon initiation of new treatment and throughout the course of therapy may facilitate the identification of the most favorable dose for each patient, and the majority of patients would be receptive to this approach.
Sujet(s)
Tumeurs du sein , Qualité de vie , Humains , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/anatomopathologie , Femelle , Adulte d'âge moyen , Enquêtes et questionnaires , Sujet âgé , Adulte , Défense du patient , Métastase tumorale , Effets secondaires indésirables des médicaments , Sujet âgé de 80 ans ou plusRÉSUMÉ
BACKGROUND: Ribociclib has been shown to have a significant overall survival benefit in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Whether this benefit in advanced breast cancer extends to early breast cancer is unclear. METHODS: In this international, open-label, randomized, phase 3 trial, we randomly assigned patients with HR-positive, HER2-negative early breast cancer in a 1:1 ratio to receive ribociclib (at a dose of 400 mg per day for 3 weeks, followed by 1 week off, for 3 years) plus a nonsteroidal aromatase inhibitor (NSAI; letrozole at a dose of 2.5 mg per day or anastrozole at a dose of 1 mg per day for ≥5 years) or an NSAI alone. Premenopausal women and men also received goserelin every 28 days. Eligible patients had anatomical stage II or III breast cancer. Here we report the results of a prespecified interim analysis of invasive disease-free survival, the primary end point; other efficacy and safety results are also reported. Invasive disease-free survival was evaluated with the use of the Kaplan-Meier method. The statistical comparison was made with the use of a stratified log-rank test, with a protocol-specified stopping boundary of a one-sided P-value threshold of 0.0128 for superior efficacy. RESULTS: As of the data-cutoff date for this prespecified interim analysis (January 11, 2023), a total of 426 patients had had invasive disease, recurrence, or death. A significant invasive disease-free survival benefit was seen with ribociclib plus an NSAI as compared with an NSAI alone. At 3 years, invasive disease-free survival was 90.4% with ribociclib plus an NSAI and 87.1% with an NSAI alone (hazard ratio for invasive disease, recurrence, or death, 0.75; 95% confidence interval, 0.62 to 0.91; P = 0.003). Secondary end points - distant disease-free survival and recurrence-free survival - also favored ribociclib plus an NSAI. The 3-year regimen of ribociclib at a 400-mg starting dose plus an NSAI was not associated with any new safety signals. CONCLUSIONS: Ribociclib plus an NSAI significantly improved invasive disease-free survival among patients with HR-positive, HER2-negative stage II or III early breast cancer. (Funded by Novartis; NATALEE ClinicalTrials.gov number, NCT03701334.).