32.931 vs. are being progressively used and considered in the metastatic setting. In this review, we summarise the current state-of-the-art therapies; prognostic, predictive, and pharmacodynamic molecular biomarkers; and how these are impacted by emerging therapies for HR+ breast malignancy. mutations (range 12C56%) compared to main Fonadelpar breast cancers (0.4%, The Malignancy Genome Atlas (TCGA), https://www.cancer.gov/tcga (accessed on30 December 2020).) [10,11,12,13,14]. Table 1 Summary of current treatment strategies for hormone receptor-positive (HR+) breast malignancy. 0.00001[24]5 year total therapy (tamoxifen AI)5 year tamoxifen10 year breast cancer mortality RR 0.85 (95% CI 0.75C0.96), = Rabbit polyclonal to ITLN1 0.015[9]5 year AI5 year tamoxifen10 year breast cancer mortality RR 0.85 (95% Fonadelpar CI 0.75C0.96), = 0.009[9]5 year total therapy (AI tamoxifen)5 year AI8 year DFS HR 1.06 (95% CI 0.91C1.23), = 0.48[25]10 Fonadelpar year extended therapy (tamoxifen)5 year tamoxifenBenefit highest after 10 year, e.g., 10C14 12 months breast malignancy mortality RR 0.71 (95% CI 0.58C0.88), = 0.01[6]10 year extended therapy (AI)5 year AI 5 year placebo5 year DFS HR 0.66 (95% CI 0.48C0.91), = 0.01[26]Endocrine Therapy in Premenopausal Women5 year tamoxifenPlacebo15 year breast malignancy mortality RR 0.70 (95% CI 0.64C0.75), 0.00001[24]5 year tamoxifen + LHRH agonist5 year tamoxifenBenefit in high-risk, e.g., 8 12 months DFS HR 0.76 (95% CI 0.60C0.97) in those receiving adjuvant chemotherapy[8]5 12 months AI + LHRH agonist5 12 months tamoxifenBenefit in high-risk, e.g., 8 12 months DFS HR 0.68 (95% CI 0.53C0.88) in those receiving adjuvant chemotherapy[8]Chemotherapy and Other Systemic TherapyAnthracycline + taxane regimenAnthracycline w/o taxane regimen8 y breast malignancy mortality RR 0.86 (95% CI 0.79C0.93)[27]BisphosphonateNo bisphosphonateIn postmenopausal women, OS HR 0.77 (95% CI 0.66-0.90), = 0.001; no benefit seen in premenopausal women[28] Advanced Breast Malignancy Endocrine + Targeted Therapy in Postmenopausal WomenAI + CDK4/6 inhibitorAI + placeboSee Table 2 Fulvestrant + CDK4/6 inhibitorFulvestrant + placeboSee Table 2 Fulvestrant + alpelisibFulvestrant + placeboIn patients with 0.001[20]Exemestane + everolimusExemestane + placeboMedian PFS 6.9 vs. 2.8 month, HR 0.43 (95% CI 0.35C0.54), 0.001[21]Endocrine + Targeted Therapy in Premenopausal WomenAs a general theory, many targeted strategies with AI or fulvestrant backbone above can be combined with LHRH agonist for premenopausal womenTamoxifen + ribociclibTamoxifen + placeboSee Table 2 Chemotherapy and Other Systemic TherapySequential mono-chemotherapyNAe.g., taxane, anthracycline, capecitabine, eribulin, vinorelbine, gemcitabine[29]Combination chemotherapyNAConsider in patients with visceral crisis[29]PARP inhibitor Physicians choice chemotherapyIn patients with germline 0.001[30]DenosumabBisphosphonate *Skeletal-related event RR 0.78 (95% CI 0.72C0.85), 0.001[28] Open in a separate window AI: aromatase inhibitor; AC: doxorubicin (Adriamycin) and cyclophosphamide; BRCA1/2: breast malignancy gene 1/2; CDK4/6: cyclin-dependent kinase 4/6; HR: hazard ratio; LHRH: luteinising hormone-releasing hormone; OR: odds ratio; RR: risk ratio; DFS: disease-free survival; PFS: progression-free survival; OS: overall survival; mth: month. * For patients with bone metastases. In the metastatic setting, endocrine therapy, including selective ER degraders (SERDs), are used in combination with cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i), and represent the current gold standard for early lines of therapy [15,16,17,18,19]. These therapies have improved survival end-points, with a median progression-free survival (PFS) of up 28 months and a median overall survival (OS) of up to 40 months in the first-line setting reported to date (Table 2). Therapies that target the phosphatidylinositol 3-kinase (PI4K)-mammalian target of rapamycin (mTOR) such as everolimus (an mTOR inhibitor) and PIK3C inhibitors have also shown to be effective in combination with endocrine therapy in metastatic disease [20,21,22,23] (Table 1). Table 2 Seminal trials of CDK4/6i in advanced breast malignancy. 0.0010.54; 0.0010.57; 0.0010.55; 0.0010.46; 0.00010.55; 0.001 0.59; 0.001NA OS (mth) NRNRNRNot reached vs. 40.934.9 vs. 28.046.7 vs. 37.3.Low and unfavorable expression of PR in ER+ tumours is associated with a more aggressive and proliferative disease, resulting in poorer prognosis and clinical outcome [44,80]. and human epidermal growth factor receptor 2 (HER2) still represent the best prognostic and predictive biomarkers for HR+ breast cancer, a significant proportion of patients either do not respond to endocrine therapy or develop endocrine resistant disease. Genomic assessments have emerged as a useful adjunct prognostication tool and lead the addition of chemotherapy to endocrine therapy. In the treatment-resistant setting, mutational profiling has been used to identify mutations as predictive molecular biomarkers to newer therapies. Additionally, pharmacodynamic biomarkers are being progressively used and considered in the metastatic setting. In this review, we summarise the current state-of-the-art therapies; prognostic, predictive, and pharmacodynamic molecular biomarkers; and how these are impacted by emerging therapies for HR+ breast malignancy. mutations (range 12C56%) compared to main breast cancers (0.4%, The Malignancy Genome Atlas (TCGA), https://www.cancer.gov/tcga (accessed on30 December 2020).) [10,11,12,13,14]. Table 1 Summary of current treatment strategies for hormone receptor-positive (HR+) breast malignancy. 0.00001[24]5 year total therapy (tamoxifen AI)5 year tamoxifen10 year breast cancer mortality RR 0.85 (95% CI 0.75C0.96), = 0.015[9]5 year AI5 year tamoxifen10 year breast cancer mortality RR 0.85 (95% CI 0.75C0.96), = 0.009[9]5 year total therapy (AI tamoxifen)5 year AI8 year DFS HR 1.06 (95% CI 0.91C1.23), = 0.48[25]10 year extended therapy (tamoxifen)5 year tamoxifenBenefit highest after 10 year, e.g., 10C14 12 months breast malignancy mortality RR 0.71 (95% CI 0.58C0.88), = 0.01[6]10 year extended therapy (AI)5 year AI 5 year placebo5 year DFS HR 0.66 (95% CI 0.48C0.91), = 0.01[26]Endocrine Therapy in Premenopausal Women5 year tamoxifenPlacebo15 year breast malignancy mortality RR 0.70 (95% CI 0.64C0.75), 0.00001[24]5 year tamoxifen + LHRH agonist5 year tamoxifenBenefit in high-risk, e.g., 8 12 months DFS HR 0.76 (95% CI 0.60C0.97) in those receiving adjuvant chemotherapy[8]5 12 months AI + LHRH agonist5 12 months tamoxifenBenefit in high-risk, e.g., 8 12 months DFS HR 0.68 (95% CI 0.53C0.88) in those receiving adjuvant chemotherapy[8]Chemotherapy and Other Systemic TherapyAnthracycline + taxane regimenAnthracycline w/o taxane regimen8 y breast malignancy mortality RR 0.86 (95% CI 0.79C0.93)[27]BisphosphonateNo bisphosphonateIn postmenopausal women, OS HR 0.77 (95% CI 0.66-0.90), = 0.001; no benefit seen in premenopausal women[28] Advanced Breast Malignancy Endocrine + Targeted Therapy in Postmenopausal WomenAI + CDK4/6 inhibitorAI + placeboSee Table 2 Fulvestrant + CDK4/6 inhibitorFulvestrant + placeboSee Table 2 Fulvestrant + alpelisibFulvestrant + placeboIn patients with 0.001[20]Exemestane + everolimusExemestane + placeboMedian PFS 6.9 vs. 2.8 month, HR 0.43 (95% CI 0.35C0.54), 0.001[21]Endocrine + Targeted Therapy in Premenopausal WomenAs a general theory, many targeted strategies Fonadelpar with AI or fulvestrant backbone above can be combined with LHRH agonist for premenopausal womenTamoxifen + ribociclibTamoxifen + placeboSee Table 2 Chemotherapy and Other Systemic TherapySequential mono-chemotherapyNAe.g., taxane, anthracycline, capecitabine, eribulin, vinorelbine, gemcitabine[29]Combination chemotherapyNAConsider in patients with visceral crisis[29]PARP inhibitor Physicians choice chemotherapyIn patients with germline 0.001[30]DenosumabBisphosphonate *Skeletal-related event RR 0.78 (95% CI 0.72C0.85), 0.001[28] Open in a separate window AI: aromatase inhibitor; AC: doxorubicin (Adriamycin) and cyclophosphamide; BRCA1/2: breast malignancy gene 1/2; CDK4/6: cyclin-dependent kinase 4/6; HR: hazard ratio; LHRH: luteinising hormone-releasing hormone; OR: odds ratio; RR: risk ratio; DFS: disease-free survival; PFS: progression-free survival; OS: overall survival; mth: month. * For patients with bone metastases. In the metastatic setting, endocrine therapy, including selective ER degraders (SERDs), are used in combination with cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i), and represent the current gold standard for early lines of therapy [15,16,17,18,19]. These therapies have improved survival end-points, with a median progression-free survival (PFS) of up 28 months and a median overall survival (OS) of up to 40 months in the first-line setting reported to date (Table 2). Therapies that target the phosphatidylinositol 3-kinase (PI4K)-mammalian target of rapamycin (mTOR) such as everolimus (an mTOR inhibitor) and PIK3C inhibitors have also shown to be effective in combination with endocrine therapy in metastatic disease [20,21,22,23] (Table 1). Table 2 Seminal trials of CDK4/6i in advanced breast malignancy. 0.0010.54; 0.0010.57; 0.0010.55; 0.0010.46; 0.00010.55; 0.001 0.59; 0.001NA OS (mth) NRNRNRNot reached vs. 40.934.9 vs. 28.046.7 vs. 37.3 Not reached vs. 40.017.7 HR —0.71; =.