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Current Oncology Reports
Erschienen in: Current Oncology Reports 6/2020

01.06.2020 | Breast Cancer (B Overmoyer, Section Editor)

Sequencing Endocrine Therapy for Metastatic Breast Cancer: What Do We Do After Disease Progression on a CDK4/6 Inhibitor?

verfasst von: Jing Xi, Cynthia X. Ma

Erschienen in: Current Oncology Reports | Ausgabe 6/2020

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Abstract

Purpose of Review

Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors have revolutionized the treatment landscape for patients with hormone receptor-positive (HR+) and HER2-negative (HER2−) metastatic breast cancer (MBC). However, optimal therapy after CDK4/6 inhibitors is unknown. This review provides an update on recent understanding of potential resistance mechanisms to CDK4/6 inhibitors and therapeutic strategies.

Recent Findings

CDK4/6 inhibitors are broadly effective for HR+/HER2− MBC. However, intrinsic and acquired resistance is inevitable. Although there are no established clinical predictors of response aside from ER positivity, several cell cycle-specific and non-specific mechanisms have emerged as potential resistance biomarkers and therapeutic targets in recent studies. Examples include loss of function mutations in RB1 or FAT1, overexpression or amplification of CDK6 and CCNE1, alterations of FGFR, and PI3K/mTOR-mediated CDK2 activation.

Summary

Biomarker studies and clinical trials targeting CDK4/6 inhibitor resistance are critical to improve treatments for HR+/HER2− MBC.
Literatur
1.
2.
Mariotto AB, et al. Estimation of the number of women living with metastatic breast cancer in the United States. Cancer Epidemiol Biomark Prev. 2017;26(6):809–15.CrossRef
3.
Finn RS, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 2009;11(5):R77.PubMedCentralCrossRefPubMed
4.
Oza A, Ma CX. New insights in estrogen receptor (ER) biology and implications for treatment. Current Breast Cancer Reports. 2017;9(1):13–25.CrossRef
5.
Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16(1):25–35.CrossRefPubMed
6.
• Hortobagyi GN, et al. Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. N Engl J Med. 2016;375(18):1738–48 This randomized trial (MONALEESA-2) demonstrated the improved efficacy outcome with ribociclib plus letrozole compared with letrozole alone (progression-free survival rate 63.0% vs. 42.2%, overall response rate 52.7% vs. 37.1% at 18 months) in post-menopausal women with HR-positive, HER2-negative advanced breast cancer. This trial led to FDA approval of ribociclib as first-line therapy in this setting.CrossRefPubMed
7.
• Hortobagyi GN, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol. 2018;29(7):1541–7 Updated results from MONALEESA-2 continues to show improved efficacy outcome with first-line ribociclib plus letrozole (progression-free survival of 25.3 months vs. 16.0 months in letrozole alone) and manageable tolerability with longer follow-up (26.4 months).CrossRefPubMed
8.
• Finn RS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375(20):1925–36 This randomized trial (PALOMA-2) demonstrated the improved efficacy outcome with palbociclib plus letrozole compared with letrozole alone (progression-free survival 24.8 months vs. 14.5 months) in post-menopausal women with HR-positive, HER2-negative advanced breast cancer. This trial confirmed results observed from PALOMA-1 trial, which led to FDA approval of palbociclib as first-line therapy in this setting in 2015.CrossRefPubMed
9.
• Goetz MP, et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017;35(32):3638–46 This randomized trial demonstrated significantly prolonged median progression-free survival in abemaciclib plus letrozole or anastrozole compared to endocrine therapy alone with letrozole or anastrozole (not reached vs. 14.7 months), as well as improved objective response rate in abemaciclib arm (59% vs. 44%). This trial led to the FDA approval of this combination as first line therapy for HR+ HER2- MBC.CrossRefPubMed
10.
• Johnston S, et al. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer. 2019;5:5 The updated results of MONARCH-3 trial continue to demonstrate the superior efficacy outcome with abemaciclib, which showed doubling the progression-free survival compared to the endocrine therapy alone arm (28.18 vs. 14.76 months). Objective response rate continued to be better in abemaciclib arm (61.0% vs. 45.5%).PubMedCentralCrossRefPubMed
11.
• Rugo HS, et al. Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up. Breast Cancer Res Treat. 2019;174(3):719–29 This updated results of PALOMA-2 trial continued to demonstrate improved progression-free survival with palbociclib plus letrozole compared with letrozole alone in overall population (27.6 vs. 14.5 months) and across all patient subgroups after a median follow-up of 38 months.PubMedCentralCrossRefPubMed
12.
• Tripathy D, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018;19(7):904–15 This randomized trial in premenopausal women with HR-positive, HER2-negative advanced breast cancer showed improved progression-free survival compared with endocrine therapy alone in the first-line therapy setting (23.8 months vs. 13.0 months). This trial led to the FDA expansion of indication for ribociclib in combination with aromatase inhibitor, in combination with GnRH agonist, for pre/perimenopausal women with HR-positive, HER2-negative advanced breast cancer.CrossRefPubMed
13.
Turner NC, et al. Palbociclib in hormone-receptor-positive advanced breast Cancer. N Engl J Med. 2015;373: 209–219
14.
• Sledge GW Jr, et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35(25):2875–84 This randomized trial in women with HR-positive, HER2-negative metastatic breast cancer with disease progression following endocrine therapy demonstrated significantly extended progression-free survival (16.4 vs. 9.3 months). This trial led to FDA approval of abemaciclib in combination with fulvestrant in the second-line or endocrine-resistant setting.CrossRefPubMed
15.
• Slamon DJ, et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol. 2018;36(24):2465–72 This randomized trial demonstrated treatment effects in patients who were treatment naïve in the advanced setting as well as in patients who had received up to one line of prior endocrine therapy for advanced disease. The median progression-free survival was significantly improved with ribociclib plus fulvestrant compared with fulvestrant alone (20.5 vs. 12.8 months). Overall response rate was better in ribociclib arm (40.9% vs. 28.7%). This trial led to the FDA approval of this combination in this setting.CrossRefPubMed
16.
• Cristofanilli M, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016;17(4):425–39 This randomized trial demonstrated more than doubled progression-free survival with palbociclib plus fulvestrant compared with fulvestrant alone in pretreated patients with HR-positive, HER2-negative breast cancer (9.5 vs. 4.6 months). This trial led to the FDA approval of palbociclib plus fulvestrant in second-line or endocrine resistant setting.CrossRefPubMed
17.
• Dickler MN, et al. MONARCH 1: a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR(+)/HER2(−) metastatic breast cancer. Clin Cancer Res. 2017;23(17):5218–24 This single arm phase II trial demonstrated that single agent abemaciclib is effective in patients with refractory HR+ HER2- MBC who had progressed on or after prior ET and had 1 or 2 chemotherapy in the metastatic setting, with an objective response rate 19.7% (95% CI, 13.3–27.5; 15% not excluded); clinical benefit rate (CR+PR+SD>/=6 months) of 42.4%, and median progression-free survival of 6.0 months. This trial led to the FDA approval of single agent abemaciclib in this setting.PubMedCentralCrossRefPubMed
18.
Xi J, Oza A, Thomas S, Ademuyiwa F, Weilbaecher K, Suresh R, et al. Retrospective analysis of treatment patterns and effectiveness of palbociclib and subsequent regimens in metastatic breast cancer. J Natl Compr Cancer Netw. 2019;17(2):141–7.CrossRef
19.
20.
Taylor-Stokes G, Mitra D, Waller J, Gibson K, Milligan G, Iyer S. Treatment patterns and clinical outcomes among patients receiving palbociclib in combination with an aromatase inhibitor or fulvestrant for HR+/HER2-negative advanced/metastatic breast cancer in real-world settings in the US: results from the IRIS study. Breast. 2019;43:22–7.CrossRefPubMed
21.
• Im S-A, et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. 2019;381(4):307–16 The updated result of MONALEESA-7 trial in premenopausal women with HR-positive, HER2-negative advanced breast cancer showed significantly longer overall survival with ribociclib plus endocrine therapy compared to endocrine therapy alone (overall survival rate 70.2% vs. 46.0% at 42 months).CrossRefPubMed
22.
• Slamon DJ, et al. LBA7_PROverall survival (OS) results of the phase III MONALEESA-3 trial of postmenopausal patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2−) advanced breast cancer (ABC) treated with fulvestrant (FUL) ± ribociclib (RIB). Ann Oncol. 2019;30(Supplement_5) The updated result of MONALEESA-3 trial demonstrated significant overall survival prolongation of ribociclib plus fulvestrant over fulvestrant alone (not reached vs. 40 months) after a median follow-up of 39.4 months. The overall survival benefit with ribociclib plus fulvestrant was consistant across all subgroups including the first-line subgroup and early-relapse/second-line subgroup. Time to progression on next-line therapy or death was also longer with ribociclib arm (39.8 vs. 29.4 months).
23.
• Sledge GW Jr, et al. The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor-positive, ERBB2-negative breast cancer that progressed on endocrine therapy-MONARCH 2: a randomized clinical trial. JAMA Oncol. 2019;6(1):116–124. The updated result of MONARCH-2 trial showed that abemaciclib plus fulvestrant resulted in a statistically significant and clinically meaningful median overall survival improvement of 9.4 months for patients (25.5 vs. 18.2 months) with HR-positive, HER2-negative advanced breast cancer who progressed after prior endocrine therapy regardless of menopausal status.
24.
• Finn RS, et al. Overall survival results from the randomized phase II study of palbociclib (P) in combination with letrozole (L) vs letrozole alone for frontline treatment of ER+/HER2– advanced breast cancer (PALOMA-1; TRIO-18). J Clin Oncol. 2017;35(15_suppl):1001 This randomized phase 2 trial demonstrated significantly improved progression-free survival with palbociclib and letrozole compared with letrozole alone in women with HR-positive, HER2-negative advanced breast cancer. The updated result from PALOMA-1 trial demonstrated improved overall survival in palbociclib plus letrozole arm compared with letrozole alone arm, although the difference in overall survival was not statistically significant potentially due to insufficient power of the study and insufficient length of follow-up.CrossRef
25.
• Turner NC, et al. Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer. N Engl J Med. 2018;379(20):1926–36 In PALOMA-3 trial, the median overall survival was 34.9 months (95% confidence interval [CI], 28.8 to 40.0) in the palbociclib-fulvestrant group and 28.0 months (95% CI, 23.6 to 34.6) in the placebo-fulvestrant group (hazard ratio for death, 0.81; 95% CI, 0.64 to 1.03; P=0.09; absolute difference, 6.9 months), which did not reach statistical significance. However, a statistically significant longer overall survival was observed with the combination therapy among patients with sensitivity to previous endocrine therapy, the median overall survival was 39.7 months (95% CI, 34.8 to 45.7) in the palbociclib-fulvestrant group and 29.7 months (95% CI, 23.8 to 37.9) in the placebo-fulvestrant group (hazard ratio, 0.72; 95% CI, 0.55 to 0.94; absolute difference, 10.0 months).CrossRefPubMed
26.
• Petrelli F, et al. Comparative efficacy of palbociclib, ribociclib and abemaciclib for ER+ metastatic breast cancer: an adjusted indirect analysis of randomized controlled trials. Breast Cancer Res Treat. 2019;174(3):597–604 This comparative analysis included six randomized trials of CDK 4/6 inhibitors involving 3743 patients. This result demonstrated that for progression-free survival and overall response rate, the three currently approved CDK 4/6 inhibitors were similar in both first- and second-line studies. All grade 3 and 4 toxicities were similar with reduced risk of diarrhea for palbociclib vs. abemaciclib and of QTc prolongation for palbociclib vs. ribociclib.CrossRefPubMed
27.
Gelbert LM, Cai S, Lin X, Sanchez-Martinez C, del Prado M, Lallena MJ, et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Investig New Drugs. 2014;32(5):825–37.CrossRef
28.
• Hafner M, et al. Multiomics profiling establishes the polypharmacology of FDA-approved CDK4/6 inhibitors and the potential for differential clinical activity. Cell Chem Biol. 2019;26(8):1067–1080.e8 This study used different phenotypic and biochemical assays to compare three currently approved CDK 4/6 inhibitors, which found significantly different transcriptional, proteomic and phenotypic changes induced by those three agents. Abemaciclib was demonstrated to have sedonary targets including CDK1-cyclin B and CDK2-cyclin A/E complexes. In addition, abemaciclib is the only agent that induces G2 cell-cycle arrest and a pan-CDK transcriptional signature. Palbociclib-resistant and -adapted cells respond to abemaciclib but not ribociclib.PubMedCentralCrossRefPubMed
29.
• Wander S, et al. A multicenter analysis of abemaciclib after progression on palbociclib in patients (pts) with hormone receptor-positive (HR+)/HER2- metastatic breast cancer (MBC). J Clin Oncol. 2019;37:1057 This retrospective analysis demonstrated that a substantial proportion of patients continue to derived clinical benefit with abemaciclib after prior CDK4/6 inhibitor. cfDNA analysis revealed RB1 and FGFR1 alterations in patients who progressed on abemaciclib.CrossRef
30.
Raub TJ, et al. Brain exposure of two selective dual CDK4 and CDK6 inhibitors and the antitumor activity of CDK4 and CDK6 inhibition in combination with temozolomide in an intracranial glioblastoma xenograft. Drug Metab Dispos. 2015;43(9):1360.CrossRefPubMed
31.
Sanchez-Martinez C, et al. Abstract B234: LY2835219, a potent oral inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6) that crosses the blood-brain barrier and demonstrates in vivo activity against intracranial human brain tumor xenografts. Mol Cancer Ther. 2011;10(11 Supplement):B234.
32.
• Tolaney SM, et al. Abstract P1-19-01: a phase 2 study of abemaciclib in patients with leptomeningeal metastases secondary to HR+, HER2- breast cancer. Cancer Res. 2019;79(4 Supplement):P1–19-01 This phase 2 randomized trial, which includes a subgroup of cohort of patients with HR-positive, HER2-negative metastatic breast cancer with leptomeningeal metastatasis, reported a median overall survival of 8.4 months with single-agent abemaciclib treatment. Concurrent intracranial and extracranial disease control was observed with this approach.
33.
• Ma CX, et al. NeoPalAna: neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor-positive breast cancer. Clin Cancer Res. 2017;23(15):4055–65 This single-arm phase II neoadjuvant trial assessed the antiproliferative activity of palbociclib showed that palbociclib enhanced cell-cycle control over anastrozole monotherapy regardless of luminal subtype (A vs. B) and PIK3CA status. Ki67 recovery at surgery following palbociclib washout may suggest necessity of prolonged administration of palbociclib to maintain the antiproliferation effect.PubMedCentralCrossRefPubMed
34.
• O’Leary B, et al. The genetic landscape and clonal evolution of breast cancer resistance to palbociclib plus fulvestrant in the PALOMA-3 trial. Cancer Discov. 2018;8(11):1390–403 This study performed paired baseline and end-of-treatment circulating tumor DNA sequencing of 195 patients in the PALOMA-3 trial. The study revealed acquired mutations including ESR1 Y537S from fulvestrant are a major driver of resistance to fulvestrant and palbociclib combination therapy.PubMedCentralCrossRefPubMed
35.
Fribbens C, et al. Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2016;34(25):2961–8.CrossRefPubMed
36.
• Li Z, et al. Loss of the FAT1 tumor suppressor promotes resistance to CDK4/6 inhibitors via the Hippo pathway. Cancer Cell. 2018;34(6):893–905 e8 This study conducted genomic analysis of ER-positive breast cancers treated with CDK 4/6 inhibitors and identified loss-of-function mutations affecting FAT1 and RB1 linked to drug resistance. FAT1 loss led to marked elevations in CDK6, which conferred resistance to CDK4/6 inhibitors.PubMedCentralCrossRefPubMed
37.
DeMichele A, Clark AS, Tan KS, Heitjan DF, Gramlich K, Gallagher M, et al. CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment. Clin Cancer Res. 2015;21(5):995–1001.CrossRefPubMed
38.
Dean JL, Thangavel C, McClendon A, Reed CA, Knudsen ES. Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure. Oncogene. 2010;29(28):4018–32.CrossRefPubMed
39.
Herrera-Abreu MT, Palafox M, Asghar U, Rivas MA, Cutts RJ, Garcia-Murillas I, et al. Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer. Cancer Res. 2016;76(8):2301–13.PubMedCentralCrossRefPubMed
40.
• Condorelli R, et al. Polyclonal RB1 mutations and acquired resistance to CDK 4/6 inhibitors in patients with metastatic breast cancer. Ann Oncol. 2018;29(3):640–5 This study genotyped tumor tissue or blood at baseline and after disease progression on CDK 4/6 inhibitor in three patients with HR+ HER2- MBC, and discovered the emergence of somatic RB1 mutations after exposure to palbociclib or ribociclib.CrossRefPubMed
41.
Network TCGA. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70.CrossRef
42.
Lefebvre C, Bachelot T, Filleron T, Pedrero M, Campone M, Soria JC, et al. Mutational profile of metastatic breast cancers: a retrospective analysis. PLoS Med. 2016;13(12):e1002201.PubMedCentralCrossRefPubMed
43.
• Yang C, et al. Acquired CDK6 amplification promotes breast cancer resistance to CDK4/6 inhibitors and loss of ER signaling and dependence. Oncogene. 2017;36(16):2255–64 This study revealed that CDK6 overexpression not only mediated drug resistance to CDK 4/6 inhibitors, but also reduced ER/PR expression, which dimished responsiveness to ER antagonism.CrossRefPubMed
44.
• Cornell L, et al. MicroRNA-mediated suppression of the TGF-beta pathway confers transmissible and reversible CDK4/6 inhibitor resistance. Cell Rep. 2019;26(10):2667–2680 e7 This study identified increased CDK6 expression as an acquired mechanism of resistance to CDK 4/6 inhibitors. The increased CDK4/6 expression was observed to be dependent on TGF-β pathway suppression via miR-432-5P expression. It was also found that CDK 4/6 inhibitor resistance phenotype was reversible in vitro and in vivo by a prolonged drug holiday.PubMedCentralCrossRefPubMed
45.
Alves CL, Elias D, Lyng M, Bak M, Kirkegaard T, Lykkesfeldt AE, et al. High CDK6 protects cells from fulvestrant-mediated apoptosis and is a predictor of resistance to fulvestrant in estrogen receptor-positive metastatic breast cancer. Clin Cancer Res. 2016;22(22):5514–26.CrossRefPubMed
46.
47.
Asghar US, Barr AR, Cutts R, Beaney M, Babina I, Sampath D, et al. Single-cell dynamics determines response to CDK4/6 inhibition in triple-negative breast cancer. Clin Cancer Res. 2017;23(18):5561–72.PubMedCentralCrossRefPubMed
48.
• Turner NC, et al. Cyclin E1 expression and palbociclib efficacy in previously treated hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2019;37(14):1169–78 Targeted gene expression was analyzed for tumor tissues from 302 patients in the PALOMA-3 trial. Palbociclib efficacy was lower in patients with high versus low cyclin E1 (CCNE1) mRNA expression (median PFS: palbociclib arm, 7.6 v 14.1 months; placebo arm, 4.0 v 4.8 months, respectively; interaction P unadjusted = .00238; false discovery rate-adjusted P = .0238). No significant interaction was found between treatment and expression levels of CDK4, CDK6, cyclin D1, and RB1. Palbociclib was efficacious in both luminal A and luminal B tumors.PubMedCentralCrossRefPubMed
49.
• Lu Y-S, et al. In-depth gene expression analysis of premenopausal patients with HR+/HER2− advanced breast cancer (ABC) treated with ribociclib-containing therapy in the Phase III MONALEESA-7 trial. J Clin Oncol. 2019;37:1018 This study conducted gene expression analysis of baseline tumor mRNA from MONALEESA-7, which revealed more pronounced progression-free survival benefit with ribociclib in patients with high expression of CCND1, IGF1R, ERBB3, as well as in patients with low expression of CCNE1 and MYC.CrossRef
50.
Guarducci C, et al. Cyclin E1 and Rb modulation as common events at time of resistance to palbociclib in hormone receptor-positive breast cancer. NPJ Breast Cancer. 2018;4(1):38.PubMedCentralCrossRefPubMed
51.
• Jansen VM, et al. Kinome-wide RNA interference screen reveals a role for PDK1 in acquired resistance to CDK4/6 inhibition in ER-positive breast cancer. Cancer Res. 2017;77(9):2488–99 The study used kinome-wide siRNA screen to identify kinases which when downregulated, yield sensitivity to ribociclib. Result highlighted a role for PI3K-PDK1 signaling pathway in mediating acquired resistance to CDK4/6 inhibitors. Ribociclib in combination with alpelisib was shown to decrease xenograft tumor growth more potently than single agent alone.PubMedCentralCrossRefPubMed
52.
• de Leeuw R, et al. MAPK Reliance via Acquired CDK4/6 Inhibitor Resistance in Cancer. Clin Cancer Res. 2018;24(17):4201–14 This study revealed MAPK reliance in acquired CDK4/6 inhibitor resistance, which may suggest MEK inhibition as a novel therapeutic strategy for CDK 4/6 inhibitor resistance.PubMedCentralCrossRefPubMed
53.
• Formisano L, et al. Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer. Nat Commun. 2019;10(1):1373 This trial identified FGFR1 amplification as a mechanism of CDK4/6 inhibitor resistance. The resistance was found to be abrogated by treatment with FGFR tyrosine kinase inhibitor.PubMedCentralCrossRefPubMed
54.
Princic N, et al. Predictors of systemic therapy sequences following a CDK 4/6 inhibitor-based regimen in post-menopausal women with hormone receptor positive, HEGFR-2 negative metastatic breast cancer. Curr Med Res Opin. 2018:1–8.
55.
Giridhar KV, et al. Abstract P6-18-09: clinical management of metastatic breast cancer (MBC) after CDK 4/6 inhibitors: a retrospective single-institution study. Cancer Res. 2019;79(4 Supplement):P6–18 -09.
56.
Schiavon G, et al. Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer. Sci Transl Med. 2015;7(313):313ra182.PubMedCentralCrossRefPubMed
57.
Fribbens C, Garcia Murillas I, Beaney M, Hrebien S, O'Leary B, Kilburn L, et al. Tracking evolution of aromatase inhibitor resistance with circulating tumour DNA analysis in metastatic breast cancer. Ann Oncol. 2018;29(1):145–53.CrossRefPubMed
58.
Toy W, Shen Y, Won H, Green B, Sakr RA, Will M, et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet. 2013;45(12):1439–45.PubMedCentralCrossRefPubMed
59.
60.
Gyanchandani R, Kota KJ, Jonnalagadda AR, Minteer T, Knapick BA, Oesterreich S, et al. Detection of ESR1 mutations in circulating cell-free DNA from patients with metastatic breast cancer treated with palbociclib and letrozole. Oncotarget. 2017;8(40):66901–11.CrossRefPubMed
61.
Du Y, et al. The predictive ability of plasma ESR1 mutations for the efficacy of endocrine therapy in hormone-receptor-positive advanced breast cancer. Onco Targets Ther. 2018;11:6023–9.PubMedCentralCrossRefPubMed
62.
Jeselsohn R, Bergholz JS, Pun M, Cornwell M, Liu W, Nardone A, et al. Allele-specific chromatin recruitment and therapeutic vulnerabilities of ESR1 activating mutations. Cancer Cell. 2018;33(2):173–86 e5.PubMedCentralCrossRefPubMed
63.
• Martin LA, et al. Discovery of naturally occurring ESR1 mutations in breast cancer cell lines modelling endocrine resistance. Nat Commun. 2017;8(1):1865 This study reported natually occuring ESR1 Y537C and ESR1 Y537S mutations in breast cancer cell lines after acquisition of resistance to long-term-estrogen-deprivation and subseqeunt resistance to fulvestrant.PubMedCentralCrossRefPubMed
64.
65.
• Bihani T, et al. Elacestrant (RAD1901), a Selective Estrogen Receptor Degrader (SERD), Has Antitumor Activity in Multiple ER(+) Breast Cancer Patient-derived Xenograft Models. Clin Cancer Res. 2017;23(16):4793–804 This study demonstrated that elacestrant, either as a single agent or in combination with palbociclib or everolimus, induces the degradation of ER, inhibits ER-mediated signaling and growth of ER-positive breast cancer cell lines and PDX models. When used as a combination, it portends greater efficacy.CrossRefPubMed
66.
Ma CX, Reinert T, Chmielewska I, Ellis MJ. Mechanisms of aromatase inhibitor resistance. Nat Rev Cancer. 2015;15(5):261–75.CrossRefPubMed
67.
68.
Hernandez-Aya LF, Gonzalez-Angulo AM. Targeting the phosphatidylinositol 3-kinase signaling pathway in breast cancer. Oncologist. 2011;16(4):404–14.PubMedCentralCrossRefPubMed
69.
• Zhang J, et al. Inhibition of Rb phosphorylation leads to mTORC2-mediated activation of Akt. Mol Cell. 2016;62(6):929–42 This study reported hyper-phosphrylated Rb directly binds to and suppresses the function of mTORC2, which leads to elevated Akt activation to confer resistance. This study provided a molecular basis for the synergistic usage of CDK4/6 and Akt inhibitors.PubMedCentralCrossRefPubMed
70.
Baselga J, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520–9.CrossRefPubMed
71.
• Kornblum N, et al. Randomized phase II trial of fulvestrant plus everolimus or placebo in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer resistant to aromatase inhibitor therapy: results of PrE0102. J Clin Oncol. 2018;36(16):1556–63 This randomized trial demonstrated longer median progression-free survival in everolimus plus fulvestrant compared to fulvestrant alone (10.3 vs. 5.1 months) in aromatase inhibitor-resistant, ER-positive metastatic breast cancer.PubMedCentralCrossRefPubMed
72.
Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol. 2012;30(22):2718–24.CrossRefPubMed
73.
• Michaloglou C, et al. Combined inhibition of mTOR and CDK4/6 Is required for optimal blockade of E2F function and long-term growth inhibition in estrogen receptor-positive breast cancer. Mol Cancer Ther. 2018;17(5):908–20 This study showed combination of an mTORC1/2 inhibitor with a CDK4/6 inhibitor results in more profound effects on E2F-dependent transcription, which translates into more durable growth arrest and delay in the onset of resistance. It also showed that CDK4/6 inhibitor-resistant cell lines remain sensititve to mTORC1/2 inhibition, which may suggest a role of mTORC1/2 inhibitors in patients that have relapsed on CDK4/6 inhibitors.PubMedCentralCrossRefPubMed
74.
Bardia A, et al. Triplet therapy (continuous ribociclib, everolimus, exemestane) in HR+/HER2− advanced breast cancer postprogression on a CDK4/6 inhibitor (TRINITI-1): efficacy, safety, and biomarker results. J Clin Oncol. 2019;37:1016.CrossRef
75.
• Andre F, et al. Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2019;380(20):1929–40 This randomized trial demonstrated improved progression-free survival with alpelisib plus fulvestrant compared with fulvestrant alone (11.0 vs. 5.7 months) in patients with PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer. This trial led to the FDA approval of the first PI3K agent in the treatment of breast cancer.CrossRefPubMed
76.
Vora SR, Juric D, Kim N, Mino-Kenudson M, Huynh T, Costa C, et al. CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell. 2014;26(1):136–49.PubMedCentralCrossRefPubMed
77.
Anjos C, et al. A large retrospective analysis of CDK 4/6 inhibitor retreatment in ER+ metastatic breast cancer (MBC). J Clin Oncol. 2019;37:1053.CrossRef
78.
Turner N, Pearson A, Sharpe R, Lambros M, Geyer F, Lopez-Garcia MA, et al. FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res. 2010;70(5):2085–94.PubMedCentralCrossRefPubMed
79.
Guarducci C, et al. Abstract PD7-12: Inhibition of CDK7 overcomes resistance to CDK4/6 inhibitors in hormone receptor positive breast cancer cells. Cancer Res. 2019;79(4 Supplement):PD7–12.
80.
Dawson SJ, Makretsov N, Blows FM, Driver KE, Provenzano E, le Quesne J, et al. BCL2 in breast cancer: a favourable prognostic marker across molecular subtypes and independent of adjuvant therapy received. Br J Cancer. 2010;103(5):668–75.PubMedCentralCrossRefPubMed
81.
• Lok SW, et al. A phase Ib dose-escalation and expansion study of the BCL2 inhibitor venetoclax combined with tamoxifen in ER and BCL2-positive metastatic breast cancer. Cancer Discov. 2019;9(3):354–69 This is the first clinical study to evaluate venetoclax in a solid tumor. The study demonstrated that combining venetoclax with endocrine therapy has a tolerable safety profile with notable activity (radiologic response rate 54%, clinical benefit rate 75%) in ER-positive, BCL2-positive metastatic breast cancer.CrossRefPubMed
82.
83.
Witkiewicz AK, Chung S, Brough R, Vail P, Franco J, Lord CJ, et al. Targeting the vulnerability of RB tumor suppressor loss in triple-negative breast cancer. Cell Rep. 2018;22(5):1185–99.PubMedCentralCrossRefPubMed
84.
Zhu D, Xu S, Deyanat-Yazdi G, Peng SX, Barnes LA, Narla RK, et al. Synthetic lethal strategy identifies a potent and selective TTK and CLK1/2 inhibitor for treatment of triple-negative breast cancer with a compromised G1-S checkpoint. Mol Cancer Ther. 2018;17(8):1727–38.CrossRefPubMed
85.
Oser MG, Fonseca R, Chakraborty AA, Brough R, Spektor A, Jennings RB, et al. Cells lacking the RB1 tumor suppressor gene are hyperdependent on Aurora B kinase for survival. Cancer Discov. 2019;9(2):230–47.CrossRefPubMed
86.
Gong X, du J, Parsons SH, Merzoug FF, Webster Y, Iversen PW, et al. Aurora A kinase inhibition is synthetic lethal with loss of the RB1 tumor suppressor gene. Cancer Discov. 2019;9(2):248–63.CrossRefPubMed
87.
• Goel S, et al. CDK4/6 inhibition triggers anti-tumour immunity. Nature. 2017;548(7668):471–5 This preclinical study demonstrated that the CDK4/6 inhibitors not only induce tumor cell cycle arrest, but also promote anti-tumor immunity by enhancing tumor antigen presentation through activating tumor cell expression of endogenous retroviral elements, also by suppressing the proliferation of regulatory T cells, which leads to reduced activity of E2F target.PubMedCentralCrossRefPubMed
88.
Deng J, Wang ES, Jenkins RW, Li S, Dries R, Yates K, et al. CDK4/6 inhibition augments antitumor immunity by enhancing T-cell activation. Cancer Discov. 2018;8(2):216–33.CrossRefPubMed
Metadaten
Titel
Sequencing Endocrine Therapy for Metastatic Breast Cancer: What Do We Do After Disease Progression on a CDK4/6 Inhibitor?
verfasst von
Jing Xi
Cynthia X. Ma
Publikationsdatum
01.06.2020
Verlag
Springer US
Erschienen in
Current Oncology Reports / Ausgabe 6/2020
Print ISSN: 1523-3790
Elektronische ISSN: 1534-6269
DOI
https://doi.org/10.1007/s11912-020-00917-8

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