CDK4/6 Inhibition – Therapy Sequences and the Quest to Find the Best Biomarkers – an Overview of Current Programs

Abstract

In recent years, new targeted therapies have been developed to treat patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) breast cancer. Some of these therapies have not just become the new therapy standard but also led to significantly longer overall survival rates. The cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have become the therapeutic standard for first-line therapy. Around 70 – 80% of patients are treated with a CDK4/6i. In recent years, a number of biomarkers associated with progression, clonal selection or evolution have been reported for CDK4/6i and their endocrine combination partners. Understanding the mechanisms behind treatment efficacy and resistance is important. A better understanding could contribute to planning the most effective therapeutic sequences and utilizing basic molecular information to overcome endocrine resistance. One study with large numbers of patients which aims to elucidate these mechanisms is the Comprehensive Analysis of sPatial, TempORal and molecular patterns of ribociclib efficacy and resistance in advanced Breast Cancer patients (CAPTOR BC) trial. This overview summarizes the latest clinical research on resistance to endocrine therapies, focusing on CDK4/6 inhibitors and discussing current study concepts.

Keywords

breast cancer - therapy - CDK4/6

• References/Literatur

• 1 Finn RS, Dering J, Conklin D. 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: R77
• 2 Engler T, Fasching PA, Luftner D. et al. Implementation of CDK4/6 Inhibitors and its Influence on the Treatment Landscape of Advanced Breast Cancer Patients – Data from the Real-World Registry PRAEGNANT. Geburtshilfe Frauenheilkd 2022; 82: 1055-1067
• 3 Schneeweiss A, Ettl J, Luftner D. et al. Initial experience with CDK4/6 inhibitor-based therapies compared to antihormone monotherapies in routine clinical use in patients with hormone receptor positive, HER2 negative breast cancer – Data from the PRAEGNANT research network for the first 2 years of drug availability in Germany. Breast 2020; 54: 88-95
• 4 Thill M, Kolberg-Liedtke C, Albert US. et al. AGO Recommendations for the Diagnosis and Treatment of Patients with Locally Advanced and Metastatic Breast Cancer: Update 2023. Breast Care (Basel) 2023; 18: 306-315
• 5 Harbeck N, Rastogi P, Martin M. et al. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol 2021; 32: 1571-1581
• 6 Slamon D, Stroyakovskiy D, Yardley D. et al. Phase III NATALEE trial of ribociclib + endocrine therapy as adjuvant treatment in patients with HR+/HER2− early breast cancer. ASCO Annual Meeting 2023; 2023: LBA500
• 7 Finn RS, Crown JP, Lang I. 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: 25-35
• 8 Turner NC, Ro J, Andre F. et al. Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med 2015; 373: 209-219
• 9 OʼLeary B, Cutts RJ, Liu Y. 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: 1390-1403
• 10 Tolaney SM, Toi M, Neven P. et al. Clinical Significance of PIK3CA and ESR1 Mutations in Circulating Tumor DNA: Analysis from the MONARCH 2 Study of Abemaciclib plus Fulvestrant. Clinical Cancer Research 2022; 28: 1500-1506
• 11 Prat A, Chaudhury A, Solovieff N. et al. Correlative Biomarker Analysis of Intrinsic Subtypes and Efficacy Across the MONALEESA Phase III Studies. J Clin Oncol 2021; 39: 1458-1467
• 12 Andre F, Su F, Solovieff N. et al. Pooled ctDNA analysis of the MONALEESA (ML) phase III advanced breast cancer (ABC) trials. J Clin Oncol 2020; 38: 1009
• 13 Bianchini G, Malorni L, Arpino G. et al. Circulating tumor DNA (ctDNA) dynamics in patients with hormone receptor positive (HR+)/HER2 negative (HER2-) advanced breast cancer (aBC) treated in first line with ribociclib (R) and letrozole (L) in the BioItaLEE trial. San Antonio Breast Cancer Symposium 2021; 2021: GS3-07
• 14 Bagegni N, Thomas S, Liu N. et al. Serum thymidine kinase 1 activity as a pharmacodynamic marker of cyclin-dependent kinase 4/6 inhibition in patients with early-stage breast cancer receiving neoadjuvant palbociclib. Breast Cancer Res 2017; 19: 123
• 15 Malorni L, Bianchini G, Caputo R. et al. Serum thymidine kinase activity in patients with HR-positive/HER2-negative advanced breast cancer treated with ribociclib plus letrozole: Results from the prospective BioItaLEE trial. Eur J Cancer 2023; 186: 1-11
• 16 Safonov A, Bandlamudi C, Tallón de Lara P. et al. Comprehensive genomic profiling of patients with breast cancer identifies germline-somatic interactions mediating therapy resistanc. San Antonio Breast Cancer Symposium 2021; 2021: GS4-08
• 17 Marra A, Gazzo A, Gupta A. et al. Mutational signature analysis reveals patterns of genomic instability linked to resistance to endocrine therapy (ET) ± CDK 4/6 inhibition (CDK4/6i) in estrogen receptor-positive/HER2-negative (ER+/HER2-) metastatic breast cancer (MBC). Ann Oncol 2022; 33 (Suppl. 7) S88-S121
• 18 Alexandrov LB, Stratton MR. Mutational signatures: the patterns of somatic mutations hidden in cancer genomes. Curr Opin Genet Dev 2014; 24: 52-60
• 19 Alexandrov LB, Kim J, Haradhvala NJ. et al. The repertoire of mutational signatures in human cancer. Nature 2020; 578: 94-101
• 20 COSMIC. Mutational Signatures (v3.3 – June 2022)- Single Base Substitution (SBS) Signatures. 2022 Online (Stand: 12.11.2022): https://cancer.sanger.ac.uk/signatures/sbs/
• 21 Toy W, Weir H, Razavi P. et al. Activating ESR1 Mutations Differentially Affect the Efficacy of ER Antagonists. Cancer Discov 2017; 7: 277-287
• 22 Robinson DR, Wu YM, Vats P. et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet 2013; 45: 1446-1451
• 23 Spoerke JM, Gendreau S, Walter K. et al. Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant. Nat Commun 2016; 7: 11579
• 24 Wang P, Bahreini A, Gyanchandani R. et al. Sensitive Detection of Mono- and Polyclonal ESR1 Mutations in Primary Tumors, Metastatic Lesions, and Cell-Free DNA of Breast Cancer Patients. Clin Cancer Res 2016; 22: 1130-1137
• 25 Schiavon G, Hrebien S, Garcia-Murillas I. et al. Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer. Sci Transl Med 2015; 7: 313ra182
• 26 Zhang K, Hong R, Xu F. et al. Clinical value of circulating ESR1 mutations for patients with metastatic breast cancer: a meta-analysis. Cancer Manag Res 2018; 10: 2573-2580
• 27 Fanning SW, Mayne CG, Dharmarajan V. et al. Estrogen receptor alpha somatic mutations Y537S and D538 G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation. Elife 2016; 5: e12792
• 28 Fanning SW, Jeselsohn R, Dharmarajan V. et al. The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells. Elife 2018; 7: e37161
• 29 Bidard FC, Kaklamani VG, Neven P. et al. Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial. J Clin Oncol 2022; 40: 3246-3256
• 30 Bidard FC, Hardy-Bessard AC, Dalenc F. et al. Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol 2022; 23: 1367-1377
• 31 Breast Cancer Association Consortium. Dorling L, Carvalho S, Allen J. et al. Breast Cancer Risk Genes – Association Analysis in More than 113,000 Women. N Engl J Med 2021; 384: 428-439
• 32 Fachal L, Aschard H, Beesley J. et al. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes. Nat Genet 2020; 52: 56-73
• 33 Garcia-Closas M, Couch FJ, Lindstrom S. et al. Genome-wide association studies identify four ER negative-specific breast cancer risk loci. Nat Genet 2013; 45: 392-398 398e1–398e2
• 34 Ghoussaini M, Fletcher O, Michailidou K. et al. Genome-wide association analysis identifies three new breast cancer susceptibility loci. Nat Genet 2012; 44: 312-318
• 35 Michailidou K, Beesley J, Lindstrom S. et al. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer. Nat Genet 2015; 47: 373-380
• 36 Michailidou K, Hall P, Gonzalez-Neira A. et al. Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Nat Genet 2013; 45: 353-361 361e1–361e2
• 37 Milne RL, Kuchenbaecker KB, Michailidou K. et al. Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer. Nat Genet 2017; 49: 1767-1778
• 38 Michailidou K, Lindstrom S, Dennis J. et al. Association analysis identifies 65 new breast cancer risk loci. Nature 2017; 551: 92-94
• 39 Fasching PA, Liu D, Scully S. et al. Identification of Two Genetic Loci Associated with Leukopenia after Chemotherapy in Breast Cancer Patients. Clin Cancer Res 2022; 28: 3342-3355
• 40 Hlevnjak M, Schulze M, Elgaafary S. et al. CATCH: A Prospective Precision Oncology Trial in Metastatic Breast Cancer. JCO Precis Oncol 2021; 5: PO.20.00248
• 41 Hortobagyi GN, Stemmer SM, Burris HA. et al. Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer. N Engl J Med 2022; 386: 942-950
• 42 Hortobagyi GN, Stemmer SM, Burris HA. et al. Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. N Engl J Med 2016; 375: 1738-1748
• 43 European Medicines Agency. Verzenios Summary of product characteristics (SmPC). 2022 Online (Stand: 26.03.2022): https://www.ema.europa.eu/en/documents/product-information/verzenios-epa-product-information_en.pdf
• 44 Goetz MP, Toi M, Campone M. et al. MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. J Clin Oncol 2017; 35: 3638-3646
• 45 Finn RS, Martin M, Rugo HS. et al. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med 2016; 375: 1925-1936
• 46 Finn RS, Rugo HS, Dieras VC. et al. Overall survival (OS) with first-line palbociclib plus letrozole (PAL+LET) versus placebo plus letrozole (PBO+LET) in women with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (ER+/HER2− ABC): Analyses from PALOMA-2. J Clin Oncol 2022; 40: LBA1003
• 47 Im SA, Lu YS, Bardia A. et al. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. N Engl J Med 2019; 381: 307-316
• 48 Tripathy D, Im S-A, Colleoni M. et al. Abstract PD2-04: Updated overall survival (OS) results from the phase III MONALEESA-7 trial of pre- or perimenopausal patients with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib. Cancer Res 2021; 81: PD2-04
• 49 Tripathy D, Im SA, Colleoni M. 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: 904-915
• 50 Fasching PA, Esteva FJ, Pivot X. et al. Patient-reported outcomes (PROs) in advanced breast cancer (ABC) treated with ribociclib plus fulvestrant: Results from MONALEESA-3. Ann Oncol 2018;
• 51 Slamon DJ, Neven P, Chia S. et al. Overall Survival Results from the Phase 3 MONALEESA-3 Study of Fulvestrant ± Ribociclib in Postmenopausal Patients With HR+/HER2− Advanced Breast Cancer. Ann Oncol 2019; 30 (Suppl. 5) v851-v934
• 52 Slamon DJ, Neven P, Chia S. et al. Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer. N Engl J Med 2020; 382: 514-524
• 53 Slamon DJ, Neven P, Chia S. 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: 2465-2472
• 54 Sledge jr. GW, Toi M, Neven P. 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 2020; 6: 116-124
• 55 Sledge jr. GW, Toi M, Neven P. 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: 2875-2884
• 56 Cristofanilli M, Rugo HS, Im S-A. et al. Overall survival (OS) with palbociclib (PAL) + fulvestrant (FUL) in women with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC): Updated analyses from PALOMA-3. J Clin Oncol 2021; 39: 1000
• 57 Turner NC, Slamon DJ, Ro J. et al. Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer. N Engl J Med 2018; 379: 1926-1936
• 58 Xu B, Zhang Q, Zhang P. et al. Dalpiciclib or placebo plus fulvestrant in hormone receptor-positive and HER2-negative advanced breast cancer: a randomized, phase 3 trial. Nat Med 2021; 27: 1904-1909
• 59 Brett JO, Spring LM, Bardia A. et al. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Res 2021; 23: 85