Table 1.
Somatic alterations associated with endocrine resistance
| Gene | Alteration | Frequency in primary (%) | Frequency in metastatic (%) | Sufficient to drive endocrine resistance? (preclinical) | Clinical association | Targeted therapies | Stage of development |
|---|---|---|---|---|---|---|---|
| ESR1 | Mutation | 1.8 | 16.3 | Yes (Jeselsohn et al., 2014; Toy et al., 2013) | Yes (Jeselsohn et al., 2014; O’Leary et al., 2018; Toy et al., 2013) | Next-generation SERMs, SERDs, PROTACs; CDK7 inhibitor | Phase I-approved |
| ESR1 | Fusion* | Very rare | >1 (Hartmaier et al., 2018) | Yes (Hartmaier et al., 2018; Lei et al., 2018) | Yes (Hartmaier et al., 2018; Lei et al., 2018) | CDK4/6 inhibitor | Approved |
| ERBB2 (HER2) | Amplification | 0.8 | 2.1 | Yes (tamoxifen) (Benz et al., 1992) | Yes (Johnston et al., 2009; Kaufman et al., 2009) | HER2-targeting antibodies or antibody-drug conjugates | Approved |
| ERBB2 (HER2) | Mutation | 2.4 | 6.7 | Yes (Croessmann et al., 2019; Nayar et al., 2019) | Yes (Croessmann et al., 2019; Nayar et al., 2019; Razavi et al., 2018; Smyth et al., 2020) | HER2 TKIs | Phase II (HER2-mutant) |
| EGFR | Amplification | 0.7 | 1.4 | Yes (Razavi et al., 2018) | Yes (Razavi et al., 2018) | EGFR antibodies or TKIs | Approved (other cancer types) |
| FGFR1 | Amplification | 10.2 | 14.9 | Yes (Formisano et al., 2019; Turner et al., 2010) | Yes (Giltnane et al., 2017) | FGFR TKIs | Phase II |
| PIK3CA | Mutation | 43.7 | 38.1 | ND | Yes (Andre et al., 2019) | PI3Ka inhibitor; mTOR inhibitor | Approved |
| PTEN | Mutation/deletion | 9.3 | 9.6 | Yes (PTEN knockdown) (Fu et al., 2014) | ND | AKT inhibitor | Phase III (TNBC) |
| AKT1 | Mutation | 5.5 | 6.6 | No (Lauring et al., 2010) | Yes (Turner et al., 2020) | AKT inhibitor; mTOR inhibitor | Phase III (TNBC); approved |
| NF1 | Mutation/deletion | 2.7 | 6.4 | Yes (NF1 knockdown) (Pearson et al., 2020; Razavi et al., 2018; Sokol et al., 2019) | Yes (Griffith et al., 2018; Pearson et al., 2020; Razavi et al., 2018; Sokol et al., 2019) | MEK or ERK inhibitor; CDK4/6 inhibitor | Phase II-approved |
| KRAS | Mutation | 0.3 | 0.9 | ND | Yes (Fribbens et al., 2018; Razavi et al., 2018) | KRAS inhibitor or PROTAC | Preclinical |
| BRAF | Mutation | 0.7 | 0.5 | ND | Yes (Razavi et al., 2018) | BRAF+MEK inhibitor | Approved (other cancer types) |
| MAP2K1 | Mutation | 0.5 | 0.2 | ND | Yes (Razavi et al., 2018) | MEK inhibitor | Approved (other cancer types) |
| MYC | Amplification | 4.7 | 8.7 | ND | Yes (Miller et al., 2011b; Razavi et al., 2018) | Myc inhibitor; BET/BRD4 inhibitor | Preclinical-Phase II |
| FOXA1 | Mutation | 3.3 | 5 | ND | Yes (Razavi et al., 2018) | SERDs | Approved |
| CTCF | Mutation | 1.5 | 2.3 | ND | Yes (Razavi et al., 2018) | BET/BRD4 inhibitor? | Phase II |
| ARID1A | Mutation/deletion | 4.6 | 7.1 | Yes (Nagarajan et al., 2020; Xu et al., 2020) | Yes (Razavi et al., 2018; Xu et al., 2020) | BET/BRD4 inhibitor | Phase II |
| ARID2 | Mutation/deletion | 0.5 | 3.8 | ND | Yes (Razavi et al., 2018) | BET/BRD4 inhibitor? | Phase II |
Select somatic alterations associated with endocrine resistance are shown. Unless otherwise indicated, frequencies in primary (n=615) and metastatic (n=564) ER+/HER2− breast cancers were retrieved from www.cBioPortal.org (selected study: MSK, Cancer Cell 2018). ER+/HER2− status was based on the primary tumor. Preclinical evidence for sufficiency includes overexpression (for amplification), knockdown (for gene deletion/loss-of-function mutations), or ectopic or knock-in expression of gene mutations being sufficient to drive increased growth under estrogen deprivation, tamoxifen treatment, or fulvestrant treatment. Clinical association includes 1) acquired alterations following treatment with tamoxifen, AIs, or fulvestrant in matched patient samples; 2) alteration is associated with poor response to endocrine therapy in clinical studies; or 3) evidence that targeting the alteration restores endocrine sensitivity in clinical trials.
ESR1 fusions were not reported in the MSK study