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Randomized Controlled Trial
. 2024 May 15;30(10):2233-2244.
doi: 10.1158/1078-0432.CCR-22-3573.

Landscape of Baseline and Acquired Genomic Alterations in Circulating Tumor DNA with Abemaciclib Alone or with Endocrine Therapy in Advanced Breast Cancer

Matthew P Goetz  1 , Erika P Hamilton  2 , Mario Campone  3 , Sara A Hurvitz  4 , Javier Cortes  5   6 , Stephen Johnston  7 , Antonio Llombart-Cussac  8 , Peter A Kaufman  9 , Masakazu Toi  10 , Guy Jerusalem  11 , Hillary Graham  12 , Hong Wang  12 , Valerie M Jansen  12 , Lacey M Litchfield  12 , Miguel Martin  13
Affiliations
Randomized Controlled Trial

Landscape of Baseline and Acquired Genomic Alterations in Circulating Tumor DNA with Abemaciclib Alone or with Endocrine Therapy in Advanced Breast Cancer

Matthew P Goetz et al. Clin Cancer Res. .

Abstract

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.

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Figures

Figure 1. Gene alterations at baseline. Heat maps of somatic alterations at baseline by gene (TR population) for MONARCH 3 (A) and nextMONARCH (B). CNA, copy-number alterations; INDEL, insertions/deletions; SNV, single-nucleotide variant; TR, translational research.
Figure 1.
Gene alterations at baseline. Heat maps of somatic alterations at baseline by gene (TR population) for MONARCH 3 (A) and nextMONARCH (B). CNA, copy-number alterations; INDEL, insertions/deletions; SNV, single-nucleotide variant; TR, translational research.
Figure 2. Frequency of gene alterations at baseline. Bar graphs representing frequency of gene alterations at baseline by gene and type of alteration in MONARCH 3 (A; n = 295, TR population) and nextMONARCH (B; n = 139, TR population). CNA, copy-number alterations; INDEL, insertions/deletions; SNV, single-nucleotide variant; TR, translational research.
Figure 2.
Frequency of gene alterations at baseline. Bar graphs representing frequency of gene alterations at baseline by gene and type of alteration in MONARCH 3 (A; n = 295, TR population) and nextMONARCH (B; n = 139, TR population). CNA, copy-number alterations; INDEL, insertions/deletions; SNV, single-nucleotide variant; TR, translational research.
Figure 3. Forest plots of PFS for patients with and without specific genomic alterations at baseline in MONARCH 3 (TR population). Cell cycle–related genes consist of CCND1, CCND2, CDK4, CDK5, CDKN2A, CCNE1, RB1, and TP53. MAPK genes consist of ARAF, BRAF, HRAS, KRAS, MAPK1, MAP2K1, MAP2K2, MAP3K1, NRAS, and RAF1 (CRAF). CI, confidence interval; ITT, intent-to-treat; NA, not achieved; PFS, progression-free survival; TR, translation research.
Figure 3.
Forest plots of PFS for patients with and without specific genomic alterations at baseline in MONARCH 3 (TR population). Cell cycle–related genes consist of CCND1, CCND2, CDK4, CDK5, CDKN2A, CCNE1, RB1, and TP53. MAPK genes consist of ARAF, BRAF, HRAS, KRAS, MAPK1, MAP2K1, MAP2K2, MAP3K1, NRAS, and RAF1 (CRAF). CI, confidence interval; ITT, intent-to-treat; NA, not achieved; PFS, progression-free survival; TR, translation research.
Figure 4. Forest plot of PFS for patients with and without specific genomic alterations at baseline in nextMONARCH (TR population). Cell cycle–related genes consist of CCND1, CCND2, CDK4, CDK5, CDKN2A, CCNE1, RB1, and TP53. CI, confidence interval; ITT, intent-to-treat; NA, not achieved; PFS, progression-free survival; TR, translation research.
Figure 4.
Forest plot of PFS for patients with and without specific genomic alterations at baseline in nextMONARCH (TR population). Cell cycle–related genes consist of CCND1, CCND2, CDK4, CDK5, CDKN2A, CCNE1, RB1, and TP53. CI, confidence interval; ITT, intent-to-treat; NA, not achieved; PFS, progression-free survival; TR, translation research.
Figure 5. Genomic alterations in the abemaciclib and placebo groups in MONARCH 3 and the abemaciclib monotherapy group in nextMONARCH (TR2 population). A, Acquired genomic alterations. *, P < 0.05 abemaciclib versus placebo in MONARCH 3. B, The frequency of individual ESR1 mutations (found in ≥2 patients) acquired during treatment. C, Genomic alterations detected at baseline but not detected at EOT. TR2 population consists of patients with a valid ctDNA sample at both baseline and EOT. NSAI, nonsteroidal aromatase inhibitor.
Figure 5.
Genomic alterations in the abemaciclib and placebo groups in MONARCH 3 and the abemaciclib monotherapy group in nextMONARCH (TR2 population). A, Acquired genomic alterations. *, P < 0.05 abemaciclib versus placebo in MONARCH 3. B, The frequency of individual ESR1 mutations (found in ≥2 patients) acquired during treatment. C, Genomic alterations detected at baseline but not detected at EOT. TR2 population consists of patients with a valid ctDNA sample at both baseline and EOT. NSAI, nonsteroidal aromatase inhibitor.
Figure 6. PFS in patients with and without acquired ESR1 alterations in MONARCH 3 (A) and nextMONARCH (B). CI, confidence interval; HR, hazard ratio.
Figure 6.
PFS in patients with and without acquired ESR1 alterations in MONARCH 3 (A) and nextMONARCH (B). CI, confidence interval; HR, hazard ratio.
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References

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