Optimizing therapeutic approaches for HR+/HER2- advanced breast cancer: clinical perspectives on biomarkers and treatment strategies post-CDK4/6 inhibitor progression

Abstract

This review offers an expert perspective on biomarkers, CDK4/6 inhibitor efficacy, and therapeutic approaches for managing hormone receptor-positive (HR+), human epidermal growth factor receptor-negative (HER2-) advanced breast cancer (ABC), particularly after CDK4/6 inhibitor progression. Key trials have demonstrated that combining CDK4/6 inhibitors with endocrine therapy (ET) significantly improves progression-free survival (PFS), with median durations ranging from 14.8 to 26.7 months, and overall survival (OS), with median durations reaching up to 53.7 months. Actionable biomarkers, such as PIK3CA and ESR1 mutations, have emerged as pivotal tools to guide second-line treatment decisions, enabling the use of targeted therapies like alpelisib and elacestrant and emphasizing the important role of biomarkers in guiding the selection of therapy. This overview aims to provide clinicians with a practical and up-to-date framework to inform treatment decisions and improve patient care in the context of this challenging disease. Additionally, we review emerging biomarkers and novel treatment strategies to address this difficult clinical landscape.

Keywords

HR+/HER2- / CDK4/6 inhibitors / advanced breast cancer / biomarkers / prognosis

References

[1] Spring LM,Andre F,Turner NC.Cyclin-dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer: past, present, and future.Lancet2020;395:817-27

[2] Finn RS,Ettl J.Efficacy and safety of palbociclib in combination with letrozole as first-line treatment of ER-positive, HER2-negative, advanced breast cancer: expanded analyses of subgroups from the randomized pivotal trial PALOMA-1/TRIO-18.Breast Cancer Res2016;18:67 PMCID:PMC4924326

[3] Rugo HS,Diéras V.Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up.Breast Cancer Res Treat2019;174:719-29 PMCID:PMC6438948

[4] Turner NC, Ro J, André F, et al; PALOMA3 Study Group. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med. 2015;373:209-19.

[5] Turner NC,Ro J.Overall survival with palbociclib and fulvestrant in advanced breast cancer.N Engl J Med2018;379:1926-36

[6] Goetz MP,Campone M.MONARCH 3: abemaciclib as initial therapy for advanced breast cancer.J Clin Oncol2017;35:3638-46

[7] Johnston S,Di Leo A.MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer.NPJ Breast Cancer2019;5:5 PMCID:PMC6336880

[8] Sledge GW Jr,Neven P.The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor-positive, ERBB2-negative breast cancer that progressed on endocrine therapy-MONARCH 2: a randomized clinical trial.JAMA Oncol2020;6:116-24 PMCID:PMC6777264

[9] Sledge GW Jr,Neven P.MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy.J Clin Oncol2017;35:2875-84

[10] Cristofanilli M,Im S.Overall survival (OS) with palbociclib (PAL) + fulvestrant (FUL) in women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC): updated analyses from PALOMA-3.JCO2021;39:1000

[11] Im SA,Bardia A.Overall survival with ribociclib plus endocrine therapy in breast cancer.N Engl J Med2019;381:307-16

[12] Slamon DJ,Chia S.Overall survival with ribociclib plus fulvestrant in advanced breast cancer.N Engl J Med2020;382:514-24

[13] Slamon DJ,Chia SKL.Updated overall survival (OS) results from the phase III MONALEESA-3 trial of postmenopausal patients (pts) with HR+/HER2- advanced breast cancer (ABC) treated with fulvestrant (FUL) ± ribociclib (RIB).JCO2021;39:1001

[14] Lloyd MR,Bardia A.Mechanisms of resistance to CDK4/6 blockade in advanced hormone receptor-positive, HER2-negative breast cancer and emerging therapeutic opportunities.Clin Cancer Res2022;28:821-30

[15] Gennari A, André F, Barrios CH, et al; ESMO Guidelines Committee. Electronic address: [e-mail]. ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol. 2021;32:1475-95.

[16] Perou CM,Eisen MB.Molecular portraits of human breast tumours.Nature2000;406:747-52

[17] Holm J,Johansson A.Concordance of Immunohistochemistry-based and gene expression-based subtyping in breast cancer.JNCI Cancer Spectr2021;5:pkaa087 PMCID:PMC7791620

[18] Cejalvo JM,Fernández-Martínez A.Clinical implications of the non-luminal intrinsic subtypes in hormone receptor-positive breast cancer.Cancer Treat Rev2018;67:63-70

[19] Prat A,Galván P.Prognostic value of intrinsic subtypes in hormone receptor-positive metastatic breast cancer treated with letrozole with or without lapatinib.JAMA Oncol2016;2:1287-94 PMCID:PMC6587151

[20] Cejalvo JM,Galván P.Intrinsic subtypes and gene expression profiles in primary and metastatic breast cancer.Cancer Res2017;77:2213-21 PMCID:PMC5822682

[21] Prat A,Cheng Y.Everolimus plus exemestane for hormone receptor-positive advanced breast cancer: a PAM50 intrinsic subtype analysis of BOLERO-2.Oncologist2019;24:893-900 PMCID:PMC6656445

[22] Turner NC,Zhu Z.Cyclin E1 expression and palbociclib efficacy in previously treated hormone receptor-positive metastatic breast cancer.J Clin Oncol2019;37:1169-78 PMCID:PMC6506420

[23] Finn RS,Zhu Z.Biomarker analyses of response to cyclin-dependent kinase 4/6 inhibition and endocrine therapy in women with treatment-naïve metastatic breast cancer.Clin Cancer Res2020;26:110-21

[24] Guerrero-Zotano Á,Zielinski C.CCNE1 and PLK1 mediate resistance to palbociclib in HR+/HER2- metastatic breast cancer.Clin Cancer Res2023;29:1557-68 PMCID:PMC10102847

[25] Prat A,Solovieff N.Correlative biomarker analysis of intrinsic subtypes and efficacy across the MONALEESA phase III studies.J Clin Oncol2021;39:1458-67 PMCID:PMC8196091

[26] Aftimos P,Irrthum A.Genomic and transcriptomic analyses of breast cancer primaries and matched metastases in AURORA, the breast international group (BIG) molecular screening initiative.Cancer Discov2021;11:2796-811 PMCID:PMC9414283

[27] Dupont Jensen J,Knoop A.PIK3CA mutations may be discordant between primary and corresponding metastatic disease in breast cancer.Clin Cancer Res2011;17:667-77

[28] O'Leary B,Morden JP.Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer.Nat Commun2018;9:896 PMCID:PMC5832789

[29] O'Leary B,Liu Y.The genetic landscape and clonal evolution of breast cancer resistance to palbociclib plus fulvestrant in the PALOMA-3 trial.Cancer Discov2018;8:1390-403 PMCID:PMC6368247

[30] Juric D,Rubovszky G.Abstract GS3-08: alpelisib + fulvestrant for advanced breast cancer: subgroup analyses from the phase III SOLAR-1 trial.Cancer Research2019;79:GS3-08

[31] André F, Ciruelos E, Rubovszky G, et al; SOLAR-1 Study Group. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med. 2019;380:1929-40.

[32] Bardia A,Solovieff N.Genomic profiling of premenopausal HR+ and HER2- metastatic breast cancer by circulating tumor DNA and association of genetic alterations with therapeutic response to endocrine therapy and ribociclib.JCO Precis Oncol2021;5:PO.20.00445 PMCID:PMC8423397

[33] André F,Juric D.Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1.Ann Oncol2021;32:208-17

[34] Fillbrunn M,André F.PIK3CA mutation status, progression and survival in advanced HR + /HER2- breast cancer: a meta-analysis of published clinical trials.BMC Cancer2022;22:1002 PMCID:PMC9490901

[35] Tolaney SM,Marmé F.Final overall survival (OS) analysis from the phase 3 TROPiCS-02 study of sacituzumab govitecan (SG) in patients (pts) with hormone receptor–positive/HER2-negative (HR+/HER2-) metastatic breast cancer (mBC).JCO2023;41:1003-1003

[36] Dent S,Im YH.Phase III randomized study of taselisib or placebo with fulvestrant in estrogen receptor-positive, PIK3CA-mutant, HER2-negative, advanced breast cancer: the SANDPIPER trial.Ann Oncol2021;32:197-207 PMCID:PMC8457522

[37] Hong R,Song K.Abstract PD4-14: GDC-0077 is a selective PI3Kalpha inhibitor that demonstrates robust efficacy in PIK3CA mutant breast cancer models as a single agent and in combination with standard of care therapies.Cancer Research2018;78:PD4-14

[38] Turner NC,Saura C.Inavolisib-based therapy in PIK3CA-mutated advanced breast cancer.N Engl J Med2024;391:1584-96

[39] Jeselsohn R,Buchwalter G.Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer.Clin Cancer Res2014;20:1757-67 PMCID:PMC3998833

[40] Bidard FC,Dalenc F.Prognostic impact of ESR1 mutations in ER+ HER2- MBC patients prior treated with first line AI and palbociclib: an exploratory analysis of the PADA-1 trial.JCO2020;38:1010

[41] Turner NC,Kilburn L.ESR1 Mutations and overall survival on fulvestrant versus exemestane in advanced hormone receptor-positive breast cancer: a combined analysis of the phase III SoFEA and EFECT trials.Clin Cancer Res2020;26:5172-7

[42] Martin M,Ruiz-Borrego M.Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase III randomised controlled trial-PEARL.Ann Oncol2021;32:488-99

[43] Bidard FC,Neven P.Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from the randomized phase III EMERALD trial.J Clin Oncol2022;40:3246-56 PMCID:PMC9553388

[44] Oliveira M,Nowecki Z.Abstract GS3-02: GS3-02 camizestrant, a next generation oral SERD vs fulvestrant in post-menopausal women with advanced ER-positive HER2-negative breast cancer: results of the randomized, multi-dose phase 2 SERENA-2 trial.Cancer Research2023;83:GS3-02

[45] Martin Jimenez M,Chavez Mac Gregor M.211MO giredestrant (GDC-9545) vs physician choice of endocrine monotherapy (PCET) in patients (pts) with ER+, HER2- locally advanced/metastatic breast cancer (LA/mBC): primary analysis of the phase II, randomised, open-label acelERA BC study.Ann Oncol2022;33:S633-4

[46] Hamilton E,Han HS.Abstract PD13-08: first-in-human safety and activity of ARV-471, a novel PROTAC® estrogen receptor degrader, in ER+/HER2- locally advanced or metastatic breast cancer.Cancer Research2022;82:PD13-08 PMCID:PMC11720534

[47] Dustin D,Fuqua SAW.ESR1 mutations in breast cancer.Cancer2019;125:3714-28 PMCID:PMC6788940

[48] Turner N,Kalinsky K.Design of SERENA-6, a phase III switching trial of camizestrant in ESR1-mutant breast cancer during first-line treatment.Future Oncol2023;19:559-73

[49] Bhave MA,Tukachinsky H.Comprehensive genomic profiling of ESR1, PIK3CA, AKT1, and PTEN in HR(+)HER2(-) metastatic breast cancer: prevalence along treatment course and predictive value for endocrine therapy resistance in real-world practice.Breast Cancer Res Treat2024;207:599-609 PMCID:PMC11420341

[50] Bidard FC, Hardy-Bessard AC, Dalenc F, et al; PADA-1 investigators. Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2022;23:1367-77.

[51] Chaudhary N,Collier A.CDK4/6i-treated HR+/HER2- breast cancer tumors show higher ESR1 mutation prevalence and more altered genomic landscape.NPJ Breast Cancer2024;10:15 PMCID:PMC10883990

[52] Lloyd MR,Carmeli A et al.CDK4/6 inhibitor efficacy in ESR1-mutant metastatic breast cancer.NEJM Evidence2024;3:EVIDoa2300231

[53] Jhaveri K,Wildiers H.Neratinib + fulvestrant + trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: outcomes and biomarker analysis from the SUMMIT trial.Ann Oncol2023;34:885-98 PMCID:PMC11335023

[54] Desmedt C,Rothé F.ESR1 mutations in metastatic lobular breast cancer patients.NPJ Breast Cancer2019;5:9 PMCID:PMC6384916

[55] Modi S,Yamashita T et al.Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer.N Engl J Med2022;387:9-20 PMCID:PMC10561652

[56] Almstedt K,Kappenberg F.Discordance of HER2-low between primary tumors and matched distant metastases in breast cancer.Cancers2023;15:1413 PMCID:PMC10000561

[57] Miglietta F,Bottosso M.Evolution of HER2-low expression from primary to recurrent breast cancer.NPJ Breast Cancer2021;7:137 PMCID:PMC8511010

[58] Curigliano G,Dent RA.Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): primary results from DESTINY-Breast06 (DB-06).JCO2024;42:LBA1000

[59] Bardia A,Dent R et al.Trastuzumab deruxtecan after endocrine therapy in metastatic breast cancer.N Engl J Med2024;391:2110-22

[60] Litton JK,Ettl J.Talazoparib in patients with advanced breast cancer and a germline BRCA mutation.N Engl J Med2018;379:753-63 PMCID:PMC10600918

[61] Robson M,Senkus E.Olaparib for metastatic breast cancer in patients with a germline BRCA mutation.N Engl J Med2017;377:523-33

[62] Robson ME,Senkus E.OlympiAD extended follow-up for overall survival and safety: olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer.Eur J Cancer2023;184:39-47 PMCID:PMC10585240

[63] Robson ME,Conte P.OlympiAD final overall survival and tolerability results: olaparib versus chemotherapy treatment of physician's choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer.Ann Oncol2019;30:558-66 PMCID:PMC6503629

[64] Tung NM,Ventz S.TBCRC 048: phase II study of olaparib for metastatic breast cancer and mutations in homologous recombination-related genes.J Clin Oncol2020;38:4274-82

[65] Condorelli R,O'Shaughnessy J.Polyclonal RB1 mutations and acquired resistance to CDK 4/6 inhibitors in patients with metastatic breast cancer.Ann Oncol2018;29:640-5

[66] André F,Solovieff N.Pooled ctDNA analysis of MONALEESA phase III advanced breast cancer trials.Ann Oncol2023;34:1003-14

[67] Gerratana L,Velimirovic M.Cyclin-dependent kinase 4/6 inhibitors beyond progression in metastatic breast cancer: a retrospective real-world biomarker analysis.JCO Precis Oncol2023;7:e2200531 PMCID:PMC10309576

[68] Davis AA,Zheng T.Genomic complexity predicts resistance to endocrine therapy and CDK4/6 inhibition in hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer.Clin Cancer Res2023;29:1719-29 PMCID:PMC10150240

[69] National Cancer Institute Center for Cancer Genomics. The Cancer Genome Atlas Program (TCGA). Available from: https://www.cancer.gov/tcga. [Last accessed on 14 Jan 2025].

[70] AACR Project GENIE Consortium,Arnedos M et al.AACR project GENIE: powering precision medicine through an international consortium.Cancer Discov2017;7:818-31

[71] Abu-Khalaf M,Zhang Z.Genomic aberrations in circulating tumor DNAs from palbociclib-treated metastatic breast cancer patients reveal a novel resistance mechanism.Cancers2022;14:2872 PMCID:PMC9221535

[72] Wander SA,Gong X.The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors in patients with hormone receptor-positive metastatic breast cancer.Cancer Discov2020;10:1174-93

[73] Al-Qasem AJ,Ehmsen S.Co-targeting CDK2 and CDK4/6 overcomes resistance to aromatase and CDK4/6 inhibitors in ER+ breast cancer.NPJ Precis Oncol2022;6:68 PMCID:PMC9509389

[74] Guarducci C,Benelli M.Cyclin E1 and Rb modulation as common events at time of resistance to palbociclib in hormone receptor-positive breast cancer.NPJ Breast Cancer2018;4:38 PMCID:PMC6261939

[75] Caruso JA,Carey JPW,Keyomarsi K.Low-molecular-weight cyclin E in human cancer: cellular consequences and opportunities for targeted therapies.Cancer Res2018;78:5481-91 PMCID:PMC6168358

[76] Karakas C,Bui T.Cytoplasmic cyclin E and phospho-cyclin-dependent kinase 2 are biomarkers of aggressive breast cancer.Am J Pathol2016;186:1900-12 PMCID:PMC4929404

[77] Pascual J,Proszek P.Baseline mutations and ctDNA dynamics as prognostic and predictive factors in ER-positive/HER2-negative metastatic breast cancer patients.Clin Cancer Res2023;29:4166-77 PMCID:PMC10570672

[78] O'Leary B,Huang X.Circulating tumor DNA markers for early progression on fulvestrant with or without palbociclib in ER+ advanced breast cancer.J Natl Cancer Inst2021;113:309-17 PMCID:PMC7936069

[79] Cardoso F,Senkus E.5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5).Ann Oncol2020;31:1623-49 PMCID:PMC7510449

[80] Lambertini M,Bisagni G.Prognostic and clinical impact of the endocrine resistance/sensitivity classification according to international consensus guidelines for advanced breast cancer: an individual patient-level analysis from the Mammella InterGruppo (MIG) and Gruppo Italiano Mammella (GIM) studies.EClinicalMedicine2023;59:101931 PMCID:PMC10225659

[81] Agostinetto E,Ignatiadis M.Clinico-molecular characteristics associated with outcomes in breast cancer patients treated with CDK4/6 inhibitors: results from the AURORA molecular screening initiative.JCO2023;41:1019

[82] Guerrero A,Antolín Novoa S.Comprehensive clinical characteristics and ctDNA mutational profile analysis of endocrine resistance/sensitivity to adjuvant ET therapy in luminal breast cancer from the GEICAM/2014-03_RegistEM registry.JCO2024;42:1011

[83] Llombart-Cussac A,Bellet- Ezquerra M et al. PARSIFAL-LONG: extended follow-up of hormone receptor-positive /HER2-negative advanced breast cancer patients treated with fulvestrant and palbociclib vs. letrozole and palbociclib in the PARSIFAL study. Available from: https://de170d6b23836ee9498a-9e3cbe05dc55738dcbe22366a8963ae7.ssl.cf1.rackcdn.com/2564236-1791205-003.pdf. [Last accessed on 14 Jan 2025].

[84] Genome Atlas Network. Comprehensive molecular portraits of human breast tumours.Nature2012;490:61-70 PMCID:PMC3465532

[85] Kalinsky K,Heguy A.PIK3CA mutation associates with improved outcome in breast cancer.Clin Cancer Res2009;15:5049-59

[86] Hortobagyi GN,Burris HA.Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer.Ann Oncol2018;29:1541-7

[87] Tolaney SM,Neven P.Clinical significance of PIK3CA and ESR1 mutations in circulating tumor DNA: analysis from the MONARCH 2 study of abemaciclib plus fulvestrant.Clin Cancer Res2022;28:1500-6 PMCID:PMC10234145

[88] Baselga J,Iwata H.Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Oncol2017;18:904-16 PMCID:PMC5549667

[89] Rugo HS,Ciruelos E.Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study.Lancet Oncol2021;22:489-98

[90] Bello Roufai D,De La Motte Rouge T.Alpelisib and fulvestrant in PIK3CA-mutated hormone receptor-positive HER2-negative advanced breast cancer included in the French early access program.Oncogene2023;42:1951-6

[91] Turner S,Kanakamedala H.Effectiveness of alpelisib + Fulvestrant compared with real-world standard treatment among patients with HR+, HER2-, PIK3CA-mutated breast cancer.Oncologist2021;26:e1133-42 PMCID:PMC8265362

[92] Jones RH,Carucci M.Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): a multicentre, randomised, controlled, phase 2 trial.Lancet Oncol2020;21:345-57 PMCID:PMC7052734

[93] Turner NC, Oliveira M, Howell SJ, et al; CAPItello-291 Study Group. Capivasertib in hormone receptor-positive advanced breast cancer. N Engl J Med. 2023;388:2058-70. PMCID:PMC11335038

[94] Howell SJ,Carucci M.Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive, HER2-negative breast cancer (FAKTION): overall survival, updated progression-free survival, and expanded biomarker analysis from a randomised, phase 2 trial.Lancet Oncol2022;23:851-64 PMCID:PMC9630162

[95] Oliveira M,Howell S.187O capivasertib and fulvestrant for patients (pts) with aromatase inhibitor (AI)-resistant HR+/HER2- advanced breast cancer (ABC): subgroup analyses from the phase III CAPItello-291 trial.ESMO Open2023;8:101376

[96] Herrera-Abreu MT,Asghar U.Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer.Cancer Res2016;76:2301-13 PMCID:PMC5426059

[97] Pascual J,Macpherson IR.Triplet therapy with palbociclib, taselisib, and fulvestrant in PIK3CA-mutant breast cancer and doublet palbociclib and taselisib in pathway-mutant solid cancers.Cancer Discov2021;11:92-107

[98] Tolaney SM,Calvo E.Phase Ib study of ribociclib plus fulvestrant and ribociclib plus fulvestrant plus PI3K inhibitor (alpelisib or buparlisib) for HR⁺ advanced breast cancer.Clin Cancer Res2021;27:418-28

[99] Henry NL,Dayao Z.Biomarkers for systemic therapy in metastatic breast cancer: ASCO Guideline Update.J Clin Oncol2022;40:3205-21

[100] Rugo HS,Schrock AB.Biology and targetability of the extended spectrum of PIK3CA mutations detected in breast carcinoma.Clin Cancer Res2023;29:1056-67 PMCID:PMC10011882

[101] Schiavon G,Garcia-Murillas I.Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer.Sci Transl Med2015;7:313ra182 PMCID:PMC4998737

[102] Fribbens C,Kilburn L.Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer.J Clin Oncol2016;34:2961-8

[103] Raghav KPS,Takashima A.Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-overexpressing/amplified (HER2+) metastatic colorectal cancer (mCRC): Primary results from the multicenter, randomized, phase 2 DESTINY-CRC02 study.JCO2023;41:3501

[104] Bardia A,Neven P.Abstract GS3-01: GS3-01 EMERALD phase 3 trial of elacestrant versus standard of care endocrine therapy in patients with ER+/HER2- metastatic breast cancer: updated results by duration of prior CDK4/6i in metastatic setting.Cancer Research2023;83:GS3-01

[105] Burstein HJ, DeMichele A, Somerfield MR, Henry NL; Biomarker Testing and Endocrine and Targeted Therapy in Metastatic Breast Cancer Expert Panels. Testing for ESR1 mutations to guide therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: ASCO Guideline rapid recommendation update. J Clin Oncol. 2023;41:3423-5.

[106] Tarantino P,Tolaney SM.HER2-low breast cancer: pathological and clinical landscape.J Clin Oncol2020;38:1951-62

[107] Molinelli C,Blondeaux E.The journey of patients affected by metastatic hormone receptor-positive/HER2-negative breast cancer from CDK 4/6 inhibitors to second-line treatment: a real-world analysis of 701 patients enrolled in the GIM14/BIOMETA study.Eur J Cancer2024;213:115113

[108] Vaz Batista M,Cortez P.Trastuzumab deruxtecan in patients with previously treated HER2-low advanced breast cancer and active brain metastases: the DEBBRAH trial.ESMO Open2024;9:103699 PMCID:PMC11415677

[109] Zou Y,Chen B.crVDAC3 alleviates ferroptosis by impeding HSPB1 ubiquitination and confers trastuzumab deruxtecan resistance in HER2-low breast cancer.Drug Resist Updat2024;77:101126

[110] Pereira B,Rueda OM.The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes.Nat Commun2016;7:11479 PMCID:PMC4866047

[111] Sanchez-Vega F, Mina M, Armenia J, et al; Cancer Genome Atlas Research Network. Oncogenic signaling pathways in the cancer genome atlas. Cell. 2018;173:321-37.e10. PMCID:PMC6070353

[112] Nayar U,Kapstad C.Acquired HER2 mutations in ER⁺ metastatic breast cancer confer resistance to estrogen receptor-directed therapies.Nat Genet2019;51:207-16

[113] Gudmundsdottir K.The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability.Oncogene2006;25:5864-74

[114] Bruno L,Waisberg F.Cyclin-dependent kinase 4/6 inhibitor outcomes in patients with advanced breast cancer carrying germline pathogenic variants in DNA repair-related genes.JCO Precis Oncol2022;6:e2100140

[115] Safonov A,de Lara PT.Abstract GS4-08: comprehensive genomic profiling of patients with breast cancer identifies germline-somatic interactions mediating therapy resistance.Cancer Research2022;82:GS4-08

[116] Park SY,Lee DW.Prognostic role of tumor subtype and germline BRCA mutation in advanced breast cancer patients treated with palbociclib plus endocrine therapy.Breast Cancer Res Treat2022;196:121-8

[117] Lee S,Kim GM.Exploratory analysis of biomarkers associated with clinical outcomes from the study of palbociclib plus endocrine therapy in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer.Breast2022;62:52-60 PMCID:PMC8819475

[118] Litton JK,Mina LA.Talazoparib versus chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer: final overall survival results from the EMBRACA trial.Ann Oncol2020;31:1526-35 PMCID:PMC10649377

[119] Curigliano G,Gennari A,Criscitiello CT. ESMO metastatic breast cancer living guidelines, v1.1 May 2023. Available from: https://www.esmo.org/living-guidelines/esmo-metastatic-breast-cancer-living-guideline. [Last accessed on 14 Jan 2025].

[120] Han E,Chae H.Detection of BRCA1/2 large genomic rearrangement including BRCA1 promoter-region deletions using next-generation sequencing.Clin Chim Acta2020;505:49-54

[121] Cam H.Emerging roles for E2F: beyond the G1/S transition and DNA replication.Cancer Cell2003;3:311-6

[122] Li Z,Zhang J.Mechanisms of CDK4/6 inhibitor resistance in luminal breast cancer.Front Pharmacol2020;11:580251 PMCID:PMC7751736

[123] Mayer EL,Wagle N.PACE: a randomized phase II study of fulvestrant, palbociclib, and avelumab after progression on cyclin-dependent kinase 4/6 inhibitor and aromatase inhibitor for hormone receptor-positive/human epidermal growth factor receptor-negative metastatic breast cancer.J Clin Oncol2024;42:2050-60

[124] Pascual J,Bidard FC.ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: a report from the ESMO precision medicine working group.Ann Oncol2022;33:750-68

[125] Albanell J,Gil-Gil M.Palbociclib rechallenge for hormone receptor-positive/HER-negative advanced breast cancer: findings from the phase II BioPER Trial.Clin Cancer Res2023;29:67-80 PMCID:PMC9811162

[126] Malorni L,Ciani Y.A gene expression signature of retinoblastoma loss-of-function is a predictive biomarker of resistance to palbociclib in breast cancer cell lines and is prognostic in patients with ER positive early breast cancer.Oncotarget2016;7:68012-22 PMCID:PMC5356535

[127] Gong X,Webster Y.Genomic aberrations that activate D-type cyclins are associated with enhanced sensitivity to the CDK4 and CDK6 inhibitor abemaciclib.Cancer Cell2017;32:761-76.e6

[128] Finn RS,Lang I.The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study.Lancet Oncol2015;16:25-35

[129] Yang C,Bhatt T.Acquired CDK6 amplification promotes breast cancer resistance to CDK4/6 inhibitors and loss of ER signaling and dependence.Oncogene2017;36:2255-64 PMCID:PMC5393973

[130] Formisano L,Servetto A.Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer.Nat Commun2019;10:1373 PMCID:PMC6435685

[131] Fagundes R.Cyclin E/CDK2: DNA replication, replication stress and genomic instability.Front Cell Dev Biol2021;9:774845 PMCID:PMC8652076

[132] Keyomarsi K,Buchholz TA.Cyclin E and survival in patients with breast cancer.N Engl J Med2002;347:1566-75

[133] Wander SA,Zangardi ML.Clinical outcomes with abemaciclib after prior CDK4/6 inhibitor progression in breast cancer: a multicenter experience.J Natl Compr Canc Netw2021;Online ahead of print:

[134] Vijayaraghavan S,Doostan I.CDK4/6 and autophagy inhibitors synergistically induce senescence in Rb positive cytoplasmic cyclin E negative cancers.Nat Commun2017;8:15916 PMCID:PMC5490269

[135] Pascual J,Zielinski C.CCNE1 mRNA and cyclin E1 protein expression as predictive biomarkers for efficacy of palbociclib plus fulvestrant versus capecitabine in the phase III PEARL study.JCO2021;39:1014

[136] Guerrero A,Zielinski C.Cyclin E cytoplasmatic isoform to predict outcome and benefit to capecitabine treatment in patients with HR+/HER2- metastatic breast cancer from the GEICAM/2013-02 PEARL study.JCO2023;41:1023

[137] Knudsen ES,Nambiar R.CDK/cyclin dependencies define extreme cancer cell-cycle heterogeneity and collateral vulnerabilities.Cell Rep2022;38:110448 PMCID:PMC9022184

[138] Zhang Z,Meyerson M.Functional genomic analysis of CDK4 and CDK6 gene dependency across human cancer cell lines.Cancer Res2022;82:2171-84 PMCID:PMC9618034

[139] Grote I,Kandt L.TP53 mutations are associated with primary endocrine resistance in luminal early breast cancer.Cancer Med2021;10:8581-94 PMCID:PMC8633262

[140] Finn RS,Rugo HS.Palbociclib and letrozole in advanced breast cancer.N Engl J Med2016;375:1925-36

[141] Tripathy D,Colleoni M.Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial.Lancet Oncol2018;19:904-15

[142] Hortobagyi GN,Burris HA.Overall survival with ribociclib plus letrozole in advanced breast cancer.N Engl J Med2022;386:942-50

[143] Garcia-Saenz JA,Echavarria I.SEOM-GEICAM-SOLTI clinical guidelines in advanced breast cancer (2022).Clin Transl Oncol2023;25:2665-78 PMCID:PMC10425299

[144] Llombart-cussac A,Perello A.Second-line endocrine therapy (ET) with or without palbociclib (P) maintenance in patients (pts) with hormone receptor-positive (HR[+])/human epidermal growth factor receptor 2-negative (HER2[-]) advanced breast cancer (ABC): PALMIRA trial.JCO2023;41:1001-1001

[145] Kalinsky K,Chiuzan C.Randomized phase II trial of endocrine therapy with or without ribociclib after progression on cyclin-dependent kinase 4/6 inhibition in hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: MAINTAIN trial.J Clin Oncol2023;41:4004-13

[146] Seki H,Sakurada A,Shimizu K.Subsequent-abemaciclib treatment after disease progression on palbociclib in patients with ER-positive HER2-negative metastatic breast cancer.Anticancer Res2022;42:1099-106

[147] Navarro-Yepes J,Rao X.Abemaciclib is effective in palbociclib-resistant hormone receptor-positive metastatic breast cancers.Cancer Res2023;83:3264-83 PMCID:PMC10592446

[148] Brett JO,Johnson GN.A gene panel associated with abemaciclib utility in ESR1-mutated breast cancer after prior cyclin-dependent kinase 4/6-inhibitor progression.JCO Precis Oncol2023;7:e2200532 PMCID:PMC10530719

[149] Kalinsky K,Hamilton EP.Abemaciclib plus fulvestrant vs fulvestrant alone for HR+, HER2- advanced breast cancer following progression on a prior CDK4/6 inhibitor plus endocrine therapy: primary outcome of the phase 3 postMONARCH trial.JCO2024;42:LBA1001

[150] Schiff R.Is ctDNA the road map to the landscape of the clonal mutational evolution in drug resistance?.Cancer Discov2018;8:1352-4 PMCID:PMC6217858

[151] Baselga J,Piccart M.Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer.N Engl J Med2012;366:520-9 PMCID:PMC5705195

[152] Cook MM,Kaempf AJ,Savin MA.Everolimus plus exemestane treatment in patients with metastatic hormone receptor-positive breast cancer previously treated with CDK4/6 inhibitor therapy.Oncologist2021;26:101-6 PMCID:PMC7873317

[153] Raphael A,Epstein J,Sonnenblick A.Alpelisib efficacy in hormone receptor-positive HER2-negative PIK3CA-mutant advanced breast cancer post-everolimus treatment.Genes2022;13:1763 PMCID:PMC9601363

[154] Bardia A,Vahdat LT.Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer.N Engl J Med2019;380:741-51

[155] Rugo HS,Marmé F.Primary results from TROPiCS-02: a randomized phase 3 study of sacituzumab govitecan (SG) versus treatment of physician’s choice (TPC) in patients (Pts) with hormone receptor–positive/HER2-negative (HR+/HER2-) advanced breast cancer.JCO2022;40:LBA1001

[156] Bardia A,Punie K.Biomarker analyses in the phase III ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer.Ann Oncol2021;32:1148-56

[157] Mateo J,Dienstmann R.A framework to rank genomic alterations as targets for cancer precision medicine: the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT).Ann Oncol2018;29:1895-902 PMCID:PMC6158764

[158] Terraf P,Brown DN.Comprehensive assessment of germline pathogenic variant detection in tumor-only sequencing.Ann Oncol2022;33:426-33 PMCID:PMC9172914

[159] Chakravarty D,Sklar J.Somatic genomic testing in patients with metastatic or advanced cancer: ASCO provisional clinical opinion.J Clin Oncol2022;40:1231-58

[160] Fisher RP.Cdk7: a kinase at the core of transcription and in the crosshairs of cancer drug discovery.Transcription2019;10:47-56 PMCID:PMC6602562

[161] Martin L,Ribas R.Abstract P3-03-09: resistance to palbociclib depends on multiple targetable mechanisms highlighting the potential of drug holidays and drug switching to improve therapeutic outcome.Cancer Research2017;77:P3-03

[162] Li B,Fan Y.Therapeutic rationale to target highly expressed CDK7 conferring poor outcomes in triple-negative breast cancer.Cancer Res2017;77:3834-45

[163] Sava GP,Coombes RC,Ali S.CDK7 inhibitors as anticancer drugs.Cancer Metastasis Rev2020;39:805-23 PMCID:PMC7497306

[164] Coombes RC,Lord SR.Dose escalation and expansion cohorts in patients with advanced breast cancer in a phase I study of the CDK7-inhibitor samuraciclib.Nat Commun2023;14:4444 PMCID:PMC10366102

[165] Stewart MD,Arend RC.Homologous recombination deficiency: concepts, definitions, and assays.Oncologist2022;27:167-74 PMCID:PMC8914493

[166] Llop-guevara A,Schneeweiss A.2O association of RAD51 with homologous recombination deficiency (HRD) and clinical outcomes in untreated triple-negative breast cancer (TNBC): analysis of the GeparSixto randomized clinical trial.Ann Oncol2021;32:S22

[167] Serra Elizalde V,Pearson A.1O detection of homologous recombination repair deficiency (HRD) in treatment-naive early triple-negative breast cancer (TNBC) by RAD51 foci and comparison with DNA-based tests.Ann Oncol2021;32:S21-2

[168] Pack LR,Chung M.Clinical CDK4/6 inhibitors induce selective and immediate dissociation of p21 from cyclin D-CDK4 to inhibit CDK2.Nat Commun2021;12:3356 PMCID:PMC8184839

[169] Yap TA,Hamilton EP.First-in-human first-in-class phase 1/2a study of the next generation CDK4-selective inhibitor PF-07220060 in patients (pts) with advanced solid tumors, enriched for HR+ HER2- mBC who progressed on prior CDK4/6 inhibitors and endocrine therapy.JCO2023;41:3009

[170] Yap TA,Grisham RN.First-in-human phase 1/2a study of a potent and novel CDK2-selective inhibitor PF-07104091 in patients (pts) with advanced solid tumors, enriched for CDK4/6 inhibitor resistant HR+/HER2- breast cancer.JCO2023;41:3010

[171] Arora M,Hoffman TE.Rapid adaptation to CDK2 inhibition exposes intrinsic cell-cycle plasticity.Cell2023;186:2628-43.e21

[172] Dietrich C,Ahn A.INX-315, a selective CDK2 inhibitor, induces cell cycle arrest and senescence in solid tumors.Cancer Discov2024;14:446-67 PMCID:PMC10905675

[173] Mukohara T,Sommerhalder D.A phase 1 dose expansion study of a first-in-class KAT6 inhibitor (PF-07248144) in patients with advanced or metastatic ER+ HER2- breast cancer.JCO2024;42:3006 PMCID:PMC10950136

[174] Jiang B,He S,Jin Z.Deep learning applications in breast cancer histopathological imaging: diagnosis, treatment, and prognosis.Breast Cancer Res2024;26:137 PMCID:PMC11416021

[175] Gamble P,Wang H.Determining breast cancer biomarker status and associated morphological features using deep learning.Commun Med2021;1:14 PMCID:PMC9037318

[176] Rakhshaninejad M,Shirkoohi R,Gandomi AH.Refining breast cancer biomarker discovery and drug targeting through an advanced data-driven approach.BMC Bioinformatics2024;25:33 PMCID:PMC10810249

[177] Moiso E,Cabel L.Predicting CDK4/6 inhibitors outcomes in pts with HR+/HER2- metastatic breast cancer: a machine learning approach.JCO2024;42:1074