Lacey M. Litchfield

Purpose: We explored the clinical and genomic characteristics of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) after progression on cyclin-dependent kinase 4 and 6 inhibitors (CDK4 & 6i) +/- endocrine therapy (ET) to understand potential resistance mechanisms that may aid in identifying treatment options. Experimental Design: US patients with HR+, HER2- MBC had tumor biopsies collected from metastatic site during routine care following progression on a CDK4 & 6i +/- ET (CohortPost) or prior to initiating CDK4 & 6i treatment (CohortPre) and analyzed using a targeted mutation panel and RNA-seq. Clinical and genomic characteristics were described. Results: The mean age at MBC diagnosis was 59 years in CohortPre (n=133) and 56 years in CohortPost (n=223); 14% and 45% of patients had prior chemotherapy/ET and 35% and 26% had de novo stage IV MBC, respectively. The most common biopsy site was liver (CohortPre, 23%; CohortPost, 56%). CohortPost had significantly higher tumor mutational burden (TMB), (median 3.16 vs 1.67 Mut/Mb, P<0.0001), ESR1 alteration frequency (mutations: 37% vs 10%, FDR<0.0001; fusions: 9% vs 2%, P=0.0176), and higher copy number amplification of genes on chr12q15, including MDM2, FRS2, and YEATS4 versus CohortPre patients. Additionally, CDK4 copy number gain on chr12q13 was significantly higher in CohortPost vs. CohortPre (27% vs. 11%, P=0.0005). Conclusions: Distinct mechanisms potentially associated with resistance to CDK4 & 6i +/- ET, including alterations in ESR1 and amplification of chr12q15 and CDK4 copy number gain, were identified.

Purpose:To identify potential predictors of response and resistance mechanisms in patients with hormone receptor–positive (HR+), HER2-negative (HER2−) advanced breast cancer (ABC) treated with the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor abemaciclib ± endocrine therapy (ET), baseline and acquired genomic alterations in circulating tumor DNA (ctDNA) were analyzed and associated with clinical outcomes.Experimental Design:MONARCH 3: postmenopausal women with HR+, HER2− ABC and no prior systemic therapy in the advanced setting were randomly assigned to abemaciclib or placebo plus nonsteroidal aromatase inhibitor (NSAI). nextMONARCH: women with HR+, HER2− metastatic breast cancer that progressed on/after prior ET and chemotherapy were randomly assigned to abemaciclib alone (two doses) or plus tamoxifen. Baseline and end-of-treatment plasma samples from patients in MONARCH 3 and nextMONARCH (monotherapy arms) were analyzed to identify somatic genomic alterations. Association between genomic alterations and median progression-free survival (mPFS) was assessed.Results:Most patients had ≥1 genomic alteration detected in baseline ctDNA. In MONARCH 3, abemaciclib+NSAI was associated with improved mPFS versus placebo+NSAI, regardless of baseline alterations. ESR1 alterations were less frequently acquired in the abemaciclib+NSAI arm than placebo+NSAI. Acquired alterations potentially associated with resistance to abemaciclib ± NSAI included RB1 and MYC.Conclusions:In MONARCH 3, certain baseline ctDNA genomic alterations were prognostic for ET but not predictive of abemaciclib response. Further studies are warranted to assess whether ctDNA alterations acquired during abemaciclib treatment differ from other CDK4/6 inhibitors. Findings are hypothesis generating; further exploration is warranted into mechanisms of resistance to abemaciclib and ET.See related commentary by Wander and Bardia, p. 2008

Purpose:To identify potential predictors of response and resistance mechanisms in patients with hormone receptor–positive (HR+), HER2-negative (HER2−) advanced breast cancer (ABC) treated with the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor abemaciclib ± endocrine therapy (ET), baseline and acquired genomic alterations in circulating tumor DNA (ctDNA) were analyzed and associated with clinical outcomes.Experimental Design:MONARCH 3: postmenopausal women with HR+, HER2− ABC and no prior systemic therapy in the advanced setting were randomly assigned to abemaciclib or placebo plus nonsteroidal aromatase inhibitor (NSAI). nextMONARCH: women with HR+, HER2− metastatic breast cancer that progressed on/after prior ET and chemotherapy were randomly assigned to abemaciclib alone (two doses) or plus tamoxifen. Baseline and end-of-treatment plasma samples from patients in MONARCH 3 and nextMONARCH (monotherapy arms) were analyzed to identify somatic genomic alterations. Association between genomic alterations and median progression-free survival (mPFS) was assessed.Results:Most patients had ≥1 genomic alteration detected in baseline ctDNA. In MONARCH 3, abemaciclib+NSAI was associated with improved mPFS versus placebo+NSAI, regardless of baseline alterations. ESR1 alterations were less frequently acquired in the abemaciclib+NSAI arm than placebo+NSAI. Acquired alterations potentially associated with resistance to abemaciclib ± NSAI included RB1 and MYC.Conclusions:In MONARCH 3, certain baseline ctDNA genomic alterations were prognostic for ET but not predictive of abemaciclib response. Further studies are warranted to assess whether ctDNA alterations acquired during abemaciclib treatment differ from other CDK4/6 inhibitors. Findings are hypothesis generating; further exploration is warranted into mechanisms of resistance to abemaciclib and ET.See related commentary by Wander and Bardia, p. 2008

Progression-free survival (PFS) and overall survival (OS) for intrinsic subtypes.

Progression-free survival (PFS) and overall survival (OS) for intrinsic subtypes in Arm C.