Systematic Review of Molecular Biomarkers Predictive of Resistance to CDK4/6 Inhibition in Metastatic Breast Cancer

Abstract

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have revolutionized the treatment of hormone-positive metastatic breast cancers (mBCs). They are currently established as standard therapies in combination with endocrine therapy as first- and second-line systemic treatment options for both endocrine-sensitive and endocrine-resistant mBC populations. In the first-line metastatic setting, the median progression-free survival for the three currently approved CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, with aromatase inhibitors is greater than 2 years (palbociclib 27.6 months; ribociclib 25.3 months; and abemaciclib 28.18 months). Although CDK4/6 inhibitors have significant clinical benefits and enable physicians to delay starting chemotherapy, they are expensive and can be associated with drug toxicities. Here, we have performed a systemic review of the reported molecular markers predictive of drug response including intrinsic and acquired resistance for CDK4/6 inhibition in mBC. The rapidly emerging molecular landscape is captured through next-generation sequencing of breast cancers (DNA with or without RNA), liquid biopsies (circulating tumor DNA), and protein analyses. Individual molecular candidates with robust and reliable evidence are discussed in more depth.

FIG 1.

PRISMA flow diagram outlining the steps undertaken for systematic review. CDK4/6, cyclin-dependent kinase 4 and 6; ESMO, European Society for Medical Oncology; mBC, metastatic breast cancer; SABC, San Antonio Breast Cancer Conference.

FIG 2.

Potential resistance biomarkers from ctDNA analyzed for drug response to CDK4/6 inhibitors in HR+ve mBC (n = 1892; gene alterations associated with drug resistance [ctDNA]). Intrinsic (baseline samples) and acquired resistance biomarkers (end of treatment samples) identified from PALOMA-3 (n = 195 paired samples; palbociclib/placebo plus fulvestrant; n = 331 baseline); Pooled analyses for MONALEESA-2, MONALEESA-3, and MONALEESA-7 (n = 1,503 baseline samples; ribociclib/placebo plus endocrine therapy); MONARCH-3 (n = 187 paired samples; abemaciclib/placebo plus aromatase inhibitor); and nextMONARCH 1 (n = 79 paired samples; abemaciclib monotherapy arm). Genetic aberrations to suggest pathway overactivations are as a result of amplifications in MET, EGFR, and myc and mutations/amplifications in FGFR2 and HER2. Genetic aberrations to suggest loss of pathway signaling: RB1 loss (biallelic or loss of heterozygosity) and loss of CDKN2A(p16)/2B(p15)/2C(p18). AR, gene for androgen receptor; ATM, ataxia telangiectasia mutated; CDKN2A (gene for p16 and p14 proteins), cyclin-dependent kinase inhibitor 2A; CDKN2B (gene for p15); CDKN2C (gene for p18); CHD4, chromodomain helicase DNA binding-4; ctDNA, circulating tumor DNA; EGFR, epidermal growth factor receptor; ER, estrogen receptor; FGFR2, fibroblast growth factor receptor 2; HER2, human epidermal growth factor receptor 2; HR+ve, hormone-positive (ER+ve; HER2–); mBC, metastatic breast cancer; MET, mesenchymal-epithelial transition factor; RB1, Retinoblastoma 1 gene.

FIG 3.

Potential resistance biomarkers from tumor analyses of primary tumor or metastases in patients with HR+ve mBC (n = 1,162; Molecular alterations associated with drug resistance [solid tumors: DNA, RNA, or protein]). Intrinsic and acquired resistance biomarkers from PALOMA2 (n = 454 palbociclib plus letrozole), PALOMA3 (gene expression analyses n = 302 paired samples; palbociclib plus fulvestrant), the study by Wander et al (n = 58; paired samples CDK4/6i plus endocrine therapy), and the study by Li et al for FAT1 loss (CDK4/6i plus endocrine therapy; n = 348). AURKA, aurora kinase A; CDK4/6, cyclin-dependent kinase 4 and 6; EGFR, epidermal growth factor receptor; ER, estrogen receptor; FAT1, FAT atypical cadherin 1; FGFR2, fibroblast growth factor receptor 2; HER2, human epidermal growth factor receptor 2; IGFR1, insulin-like growth factor 1 receptor; MET, mesenchymal-epithelial transition factor; PLK, polo-like kinase; RAS, rat sarcoma virus; RB1, Retinoblastoma 1 gene. Left: Biomarkers divided into intrinsic and acquired drug resistance categories, ↓ loss of activity and ↑ increased activity.