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Purpose: This analysis evaluated the genomic landscape of premenopausal patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer and the association of genetic alterations with response to ribociclib in the phase III MONALEESA-7 trial., Methods: Premenopausal patients were randomly assigned 1:1 to receive endocrine therapy plus ribociclib or placebo. Plasma collected at baseline was sequenced using targeted next-generation sequencing for approximately 600 relevant cancer genes. The association of circulating tumor DNA alterations with progression-free survival (PFS) was evaluated to identify biomarkers of response and resistance to ribociclib., Results: Baseline circulating tumor DNA was sequenced in 565 patients; 489 had evidence of ≥ 1 alteration. The most frequent alterations included PIK3CA (28%), TP53 (19%), CCND1 (10%), MYC (8%), GATA3 (8%), receptor tyrosine kinases (17%), and the Chr8p11.23 locus (12%). A treatment benefit of ribociclib was seen with wild-type (hazard ratio [HR] 0.45 [95% CI, 0.33 to 0.62]) and altered (HR 0.57 [95% CI, 0.36 to 0.9]) PIK3CA . Overall, patients with altered CCND1 had shorter PFS regardless of treatment, suggesting CCND1 as a potential prognostic biomarker. Benefit with ribociclib was seen in patients with altered (HR 0.21 [95% CI, 0.08 to 0.54]) or wild-type (HR 0.52 [95% CI, 0.39 to 0.68]) CCND1 , but greater benefit was observed with altered, suggesting predictive potential of CCND1 . Alterations in TP53 , MYC , Chr8p11.23 locus, and receptor tyrosine kinases were associated with worse PFS, but ribociclib benefit was independent of alteration status., Conclusion: In this study-to our knowledge, the first large study of premenopausal patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer-multiple genomic alterations were associated with poor outcome. A PFS benefit of ribociclib was observed regardless of gene alteration status, although in this exploratory analysis, a magnitude of benefits varied by alteration., Competing Interests: Aditya Bardia Consulting or Advisory Role: Novartis, Genentech, Pfizer, Spectrum Pharmaceuticals, BioTheranostics, Merck, Radius Pharma, Immunomedics, Sanofi, Puma Biotechnology, Daiichi Sankyo/Astra Zeneca, Foundation Medicine, Philips, Genentech/Roche, Radius Health, Innocrin Pharma Research Funding: Genentech, Novartis, Pfizer, Merck, Sanofi, Radius, Immunomedics, AstraZeneca/Daiichi Sankyo Open Payments Link: https://openpaymentsdata.cms.gov/physician/523675 Fei Su Employment: Novartis Stock and Other Ownership Interests: Novartis Nadia Solovieff Employment: Novartis Stock and Other Ownership Interests: Novartis Seock-Ah Im Consulting or Advisory Role: AstraZeneca, Novartis, Roche/Genentech, Eisai, Pfizer, Amgen, Hanmi, Lilly, GlaxoSmithKline, MSD, Daiichi Sankyo Research Funding: AstraZeneca, Pfizer, Roche/Genentech, Daewoong Pharmaceutical, Eisai Other Relationship: Roche Joohyuk Sohn Research Funding: MSD, Roche, Novartis, Lilly, Pfizer, Bayer, Daiichi Sankyo, AstraZeneca, GlaxoSmithKline Other Relationship: Roche Keun Seok Lee Consulting or Advisory Role: Lilly, MSD Oncology, Novartis, Roche, Pfizer Research Funding: Dong-A ST Saul Campos Gomez Consulting or Advisory Role: Roche, Bristol Myers Squibb, MSD Oncology Kyung Hae Jung Consulting or Advisory Role: Roche, AstraZeneca, Celgene, Eisai, Takeda, Novartis Marco Colleoni Research Funding: Roche Rafael Villanueva Vázquez Consulting or Advisory Role: Novartis Speakers' Bureau: Novartis, Lilly Expert Testimony: Novartis Travel, Accommodations, Expenses: Novartis, Lilly, Eisai, Daiichi Sankyo/AstraZeneca, Roche Sara Hurvitz Stock and Other Ownership Interests: Ideal Implant, ROM Tech Research Funding: Genentech/Roche, Novartis, GlaxoSmithKline, Sanofi, Pfizer, Amgen, OBI Pharma, Puma Biotechnology, Dignitana, Bayer, Biomarin, Lilly, Merrimack, Cascadian Therapeutics, Seattle Genetics, Daiichi Sankyo, Macrogenics, Ambryx, Immunomedics, Pieris Pharmaceuticals, Radius Health, Arvinas, Zymeworks, Gilead Sciences, Phoenix Molecular Designs Travel, Accommodations, Expenses: Lilly Other Relationship: Roche, Pfizer Nadia Harbeck Stock and Other Ownership Interests: West German Study Group Honoraria: Roche, Novartis, Amgen, Pfizer, AstraZeneca, Pierre Fabre, Daiichi Sankyo, Exact Sciences, MSD, Seagen Consulting or Advisory Role: Roche/Genentech, Novartis, Pfizer, Lilly, Sandoz, Daiichi Sankyo, AstraZeneca, West German Study Group, Pierre Fabre, Seagen, MSD Research Funding: Roche/Genentech, Lilly, MSD, AstraZeneca Louis Chow Research Funding: Novartis Tetiana Taran Employment: Novartis Stock and Other Ownership Interests: Novartis Karen Rodriguez Lorenc Employment: Novartis, Regeneron Stock and Other Ownership Interests: Novartis, Regeneron Naveen Babbar Employment: Novartis Stock and Other Ownership Interests: Novartis Debu Tripathy Consulting or Advisory Role: Novartis, Pfizer, GlaxoSmithKline, Genomic Health, AstraZeneca, OncoPep Research Funding: Novartis, Polyphor Travel, Accommodations, Expenses: Novartis, AstraZeneca Yen-Shen Lu Honoraria: Pfizer, Roche, Merck Sharp & Dohme, Novartis, Lilly, Eisai, Eurofarma, Daiichi Sankyo/UCB Japan, AstraZeneca Consulting or Advisory Role: Pfizer, Roche, Novartis, Lilly Research Funding: Novartis, Roche, Merck Sharp & Dohme Travel, Accommodations, Expenses: Roche, Pfizer, Eisai, Novartis No other potential conflicts of interest were reported. Aditya Bardia Consulting or Advisory Role: Novartis, Genentech, Pfizer, Spectrum Pharmaceuticals, BioTheranostics, Merck, Radius Pharma, Immunomedics, Sanofi, Puma Biotechnology, Daiichi Sankyo/Astra Zeneca, Foundation Medicine, Philips, Genentech/Roche, Radius Health, Innocrin Pharma Research Funding: Genentech, Novartis, Pfizer, Merck, Sanofi, Radius, Immunomedics, AstraZeneca/Daiichi Sankyo Open Payments Link: https://openpaymentsdata.cms.gov/physician/523675 Fei Su Employment: Novartis Stock and Other Ownership Interests: Novartis Nadia Solovieff Employment: Novartis Stock and Other Ownership Interests: Novartis Seock-Ah Im Consulting or Advisory Role: AstraZeneca, Novartis, Roche/Genentech, Eisai, Pfizer, Amgen, Hanmi, Lilly, GlaxoSmithKline, MSD, Daiichi Sankyo Research Funding: AstraZeneca, Pfizer, Roche/Genentech, Daewoong Pharmaceutical, Eisai Other Relationship: Roche Joohyuk Sohn Research Funding: MSD, Roche, Novartis, Lilly, Pfizer, Bayer, Daiichi Sankyo, AstraZeneca, GlaxoSmithKline Other Relationship: Roche Keun Seok Lee Consulting or Advisory Role: Lilly, MSD Oncology, Novartis, Roche, Pfizer Research Funding: Dong-A ST Saul Campos Gomez Consulting or Advisory Role: Roche, Bristol Myers Squibb, MSD Oncology Kyung Hae Jung Consulting or Advisory Role: Roche, AstraZeneca, Celgene, Eisai, Takeda, Novartis Marco Colleoni Research Funding: Roche Rafael Villanueva Vázquez Consulting or Advisory Role: Novartis Speakers' Bureau: Novartis, Lilly Expert Testimony: Novartis Travel, Accommodations, Expenses: Novartis, Lilly, Eisai, Daiichi Sankyo/AstraZeneca, Roche Sara Hurvitz Stock and Other Ownership Interests: Ideal Implant, ROM Tech Research Funding: Genentech/Roche, Novartis, GlaxoSmithKline, Sanofi, Pfizer, Amgen, OBI Pharma, Puma Biotechnology, Dignitana, Bayer, Biomarin, Lilly, Merrimack, Cascadian Therapeutics, Seattle Genetics, Daiichi Sankyo, Macrogenics, Ambryx, Immunomedics, Pieris Pharmaceuticals, Radius Health, Arvinas, Zymeworks, Gilead Sciences, Phoenix Molecular Designs Travel, Accommodations, Expenses: Lilly Other Relationship: Roche, Pfizer Nadia Harbeck Stock and Other Ownership Interests: West German Study Group Honoraria: Roche, Novartis, Amgen, Pfizer, AstraZeneca, Pierre Fabre, Daiichi Sankyo, Exact Sciences, MSD, Seagen Consulting or Advisory Role: Roche/Genentech, Novartis, Pfizer, Lilly, Sandoz, Daiichi Sankyo, AstraZeneca, West German Study Group, Pierre Fabre, Seagen, MSD Research Funding: Roche/Genentech, Lilly, MSD, AstraZeneca Louis Chow Research Funding: Novartis Tetiana Taran Employment: Novartis Stock and Other Ownership Interests: Novartis Karen Rodriguez Lorenc Employment: Novartis, Regeneron Stock and Other Ownership Interests: Novartis, Regeneron Naveen Babbar Employment: Novartis Stock and Other Ownership Interests: Novartis Debu Tripathy Consulting or Advisory Role: Novartis, Pfizer, GlaxoSmithKline, Genomic Health, AstraZeneca, OncoPep Research Funding: Novartis, Polyphor Travel, Accommodations, Expenses: Novartis, AstraZeneca Yen-Shen Lu Honoraria: Pfizer, Roche, Merck Sharp & Dohme, Novartis, Lilly, Eisai, Eurofarma, Daiichi Sankyo/UCB Japan, AstraZeneca Consulting or Advisory Role: Pfizer, Roche, Novartis, Lilly Research Funding: Novartis, Roche, Merck Sharp & Dohme Travel, Accommodations, Expenses: Roche, Pfizer, Eisai, Novartis No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

The phase III MONALEESA trials tested the efficacy and safety of the cyclin-dependent kinase (CDK)4/6 inhibitor ribociclib with different endocrine therapy partners as first- or second-line treatment of hormone receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (ABC). Using the largest pooled biomarker dataset of the CDK4/6 inhibitor ribociclib in ABC to date, we identified potential biomarkers of response to ribociclib. Baseline circulating tumour DNA from patients in the MONALEESA trials was assessed using next-generation sequencing. An analysis of correlation between gene alteration status and progression-free survival (PFS) was carried out to identify potential biomarkers of response to ribociclib. Multiple frequently altered genes were identified. Alterations in ERBB2 , FAT3 , FRS2 , MDM2 , SFRP1 , and ZNF217 were associated with a greater PFS benefit with ribociclib versus placebo. Patients with high tumour mutational burden (TMB) and with ANO1 , CDKN2A/2B/2C , and RB1 alterations exhibited decreased sensitivity to ribociclib versus placebo. Although exploratory, these results provide insight into alterations associated with the improved response to ribociclib treatment and may inform treatment sequencing in patients with actionable alterations following progression on CDK4/6 inhibitors. Validation of potential biomarkers identified here and development of prospective trials testing their clinical utility are warranted. NCT01958021, NCT02422615, NCT02278120. • We report an exploratory analysis of the association of gene alteration status and PFS across MONALEESA-2, -3, and -7. • This analysis used the largest pooled biomarker dataset of the CDK4/6 inhibitor ribociclib in ABC to date. • ERBB2 , FAT3 , FRS2 , MDM2 , SFRP1 , and ZNF217 alterations were associated with increased sensitivity to ribociclib. • ANO1 , CDKN2A/2B/2C , and RB1 alterations and high TMB were associated with decreased sensitivity to ribociclib. [ABSTRACT FROM AUTHOR]