CDK4/6 inhibitors as neoadjuvant treatment in breast cancer—what can we learn?
Authors: M. Brandão, M. Ignatiadis
Journal: Annals of Oncology (2018)

As in other subtypes of breast cancer, the goals of neoadjuvant treatment in estrogen receptor (ER)-positive/HER2-negative disease are to increase breast-conserving surgery rates, to tailor adjuvant systemic treatment and to advance drug and biomarker development [1.Untch M. Konecny G.E. Paepke S. von Minckwitz G. Current and future role of neoadjuvant therapy for breast cancer.Breast. 2014; 23: 526-537Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar]. Meanwhile, the combination of CDK4/6 inhibitors (CDK4/6i) and endocrine treatment (ET) has resulted in a significant benefit for patients with ER-positive/HER2-negative advanced disease [2.Finn R.S. Martin M. Rugo H.S. et al.Palbociclib and letrozole in advanced breast cancer.N Engl J Med. 2016; 375: 1925-1936Crossref PubMed Scopus (1469) Google Scholar, 3.Turner N.C. Ro J. André F. et al.Palbociclib in hormone-receptor-positive advanced breast cancer.N Engl J Med. 2015; 373: 209-219Crossref PubMed Scopus (995) Google Scholar]. Thus, this strategy is now being tested in the early setting either as adjuvant [e.g. PALLAS trial (NCT02513394)] or as neoadjuvant treatment. There are already four trials reporting results of CDK4/6i + ET as a neoadjuvant treatment: NeoPalAna [4.Ma C.X. Gao F. Luo J. et al.NeoPalAna: neoadjuvant Palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor-positive breast cancer.Clin Cancer Res. 2017; 23: 4055-4065Crossref PubMed Scopus (180) Google Scholar], neoMONARCH [5.Martin M. Hurvitz S.A. Chan D. et al.Abstract PD5-01: final results of NeoMONARCH: a phase 2 neoadjuvant study of abemaciclib in postmenopausal women with hormone receptor positive (HR+), HER2 negative breast cancer (BC).Cancer Res. 2018; 78Google Scholar], N007 [6.Chow L.W.C. Morita S. Chow C.Y.C. et al.Neoadjuvant palbociclib on ER+ breast cancer (N007): clinical response and EndoPredict's value.Endocr Relat Cancer. 2018; 25: 123-130Crossref PubMed Scopus (29) Google Scholar] and, more recently, the study that accompanies this editorial: NeoPAL [7.Cottu P. D'Hondt V. Dureau S. et al.Letrozole and palbociclib versus chemotherapy as neoadjuvant therapy of high-risk luminal breast cancer.Ann Oncol. 2018; Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar]. They have demonstrated that the combination leads to cell cycle arrest (CCA—defined as a Ki67 proliferation index <2.7%) 2 weeks after the beginning of treatment in 68%–87% of patients compared with 14%–26% of patients with ET alone. Similar results were observed at surgery (Table 1). Still, there were no dramatic improvements in pathological complete response (pCR) rates compared with other treatments (Table 1) [8.Spring L.M. Gupta A. Reynolds K.L. et al.Neoadjuvant endocrine therapy for estrogen receptor-positive breast cancer: a systematic review and meta-analysis.JAMA Oncol. 2016; 2: 1477-1486Crossref PubMed Scopus (196) Google Scholar, 9.Eiermann W. Paepke S. Appfelstaedt J. et al.Preoperative treatment of postmenopausal breast cancer patients with letrozole: a randomized double-blind multicenter study.Ann Oncol. 2001; 12: 1527-1532Abstract Full Text PDF PubMed Scopus (638) Google Scholar, 10.Baselga J. Semiglazov V. van Dam P. et al.Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer.J Clin Oncol. 2009; 27: 2630-2637Crossref PubMed Scopus (561) Google Scholar, 11.Ellis M.J. Suman V.J. Hoog J. et al.Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype—ACOSOG Z1031.J Clin Oncol. 2011; 29: 2342-2349Crossref PubMed Scopus (390) Google Scholar, 12.Palmieri C. Cleator S. Kilburn L.S. et al.NEOCENT: a randomised feasibility and translational study comparing neoadjuvant endocrine therapy with chemotherapy in ER-rich postmenopausal primary breast cancer.Breast Cancer Res Treat. 2014; 148: 581-590Crossref PubMed Scopus (61) Google Scholar, 13.Saura C. de Azambuja E. Hlauschek D. et al.LBA10_PRPrimary results of LORELEI: a phase II randomized, double-blind study of neoadjuvant letrozole (LET) plus taselisib versus LET plus placebo (PLA) in postmenopausal patients (pts) with ER+/HER2-negative early breast cancer (EBC).Ann Oncol. 2017; Abstract Full Text Full Text PDF Google Scholar, 14.Kuter I. Gee J.M.W. Hegg R. et al.Dose-dependent change in biomarkers during neoadjuvant endocrine therapy with fulvestrant: results from NEWEST, a randomized Phase II study.Breast Cancer Res Treat. 2012; 133: 237-246Crossref PubMed Scopus (73) Google Scholar]. However, in patients treated with neoadjuvant ET alone, Ki67 levels have been suggested as a surrogate marker of treatment response and prognosis at different time points: 2 weeks after beginning of treatment [15.Dowsett M. Smith I.E. Ebbs S.R. et al.Prognostic value of Ki67 expression after short-term presurgical endocrine therapy for primary breast cancer.J Natl Cancer Inst. 2007; 99: 167-170Crossref PubMed Scopus (508) Google Scholar] and at surgery [16.Ellis M.J. Tao Y. Luo J. et al.Outcome prediction for estrogen receptor-positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics.J Natl Cancer Inst. 2008; 100: 1380-1388Crossref PubMed Scopus (448) Google Scholar]. Interestingly, data from the POETIC trial [17.JFR Robertson, M Dowsett, JM Bliss et al. Abstract GS1-03: Peri-operative aromatase inhibitor treatment in determining or predicting longterm outcome in early breast cancer – The POETIC* Trial (CRUK/07/015). Cancer Res 2018; doi: 10.1158/1538-7445. http://cancerres.aacrjournals.org/content/78/4_Supplement/GS1-03 (26 October 2018, date last accessed).Google Scholar] showed that Ki67 levels at baseline and after 2 weeks of ET may define different patients' subgroups in terms of endocrine-sensitivity and prognosis. Yet, there are well known problems with the Ki67 reproducibility and there is no validated Ki67 cutoff for treatment decision-making [18.Dowsett M. Nielsen T.O. A'Hern R. et al.Assessment of Ki67 in breast cancer: recommendations from the international Ki67 in breast cancer working group.J Natl Cancer Inst. 2011; 103: 1656-1664Crossref PubMed Scopus (1266) Google Scholar]. Gene expression signatures provide a more reproducible way for the assessment of disease proliferation, but there are few data for their role in the dynamic assessment of tumor proliferation [19.Ignatiadis M. Sotiriou C. Luminal breast cancer: from biology to treatment.Nat Rev Clin Oncol. 2013; 10: 494-506Crossref PubMed Scopus (148) Google Scholar].Table 1Selected studies in the neoadjuvant setting with treatment duration of 16–20 weeks in estrogen receptor (ER)-positive/HER2-negative breast cancer patientsStudyDesignPopulationNaNumber of assessable patients in that arm.Treatment armpCR rateRadiological RRbRadiological response rate by ultrasound (according to RECIST criteria); clinical response by caliper.Clinical RRbRadiological response rate by ultrasound (according to RECIST criteria); clinical response by caliper.BCS rateKi67 changes rateOther end pointsET onlyAromatase inhibitorsEiermann, 2001 (P024) [9.Eiermann W. Paepke S. Appfelstaedt J. et al.Preoperative treatment of postmenopausal breast cancer patients with letrozole: a randomized double-blind multicenter study.Ann Oncol. 2001; 12: 1527-1532Abstract Full Text PDF PubMed Scopus (638) Google Scholar]Phase IIb/III, randomizedHR+, cT2–4c/N0–2, post-menopausal, not candidates for BCS154Letrozole×16 weeks0.6%35.0%55.0%45.0%NR–Baselga, 2009 [10.Baselga J. Semiglazov V. van Dam P. et al.Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer.J Clin Oncol. 2009; 27: 2630-2637Crossref PubMed Scopus (561) Google Scholar]Phase II, randomizedER+, T≥2 cm, post-menopausal132Letrozole×4 months0.8%47.0%59.1%NRLn(Ki67)<1% at D15: 30%–Ellis, 2011 (ACOSOG Z1031) [11.Ellis M.J. Suman V.J. Hoog J. et al.Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype—ACOSOG Z1031.J Clin Oncol. 2011; 29: 2342-2349Crossref PubMed Scopus (390) Google Scholar]Phase II, randomizedER+ (Allred scores ≥6), stage II–III (not eligible for BCS), post-menopausal124Exemestane×16–18 weeksNRNR62.9%67.8%Ki67≤10% or no invasive tumor at week 2: 79%PEPI score 0: 15.6%, 15.9%, 17.3%128Letrozole×16–18 weeks74.8%60.8%125Anastrozole×16–18 weeks69.1%76.9%Palmieri, 2014 (NEOCENT) [12.Palmieri C. Cleator S. Kilburn L.S. et al.NEOCENT: a randomised feasibility and translational study comparing neoadjuvant endocrine therapy with chemotherapy in ER-rich postmenopausal primary breast cancer.Breast Cancer Res Treat. 2014; 148: 581-590Crossref PubMed Scopus (61) Google Scholar]Phase III, randomizedER+ (Allred scores ≥6), T ≥2 cm, post-menopausal22Letrozole×18–23 weeks059.1%90.9%NRMean fold decrease at surgery: 0.18–Saura, 2017 (LORELEI) [13.Saura C. de Azambuja E. Hlauschek D. et al.LBA10_PRPrimary results of LORELEI: a phase II randomized, double-blind study of neoadjuvant letrozole (LET) plus taselisib versus LET plus placebo (PLA) in postmenopausal patients (pts) with ER+/HER2-negative early breast cancer (EBC).Ann Oncol. 2017; Abstract Full Text Full Text PDF Google Scholar]Phase II, randomizedER+/HER2-, stage I–III (T ≥2 cm), post-menopausal168Letrozole×16 weeks0.6%39.3%cFE75C or FE100C; a switch to docetaxel (100 mg/m2 administered every 3 weeks for three cycles) was required after three cycles if either the disease was considered stable or progressive, clinically or on ultrasound according to RECIST criteria (V1.1).NRNRNR–TamoxifenEiermann, 2001 (P024) [9.Eiermann W. Paepke S. Appfelstaedt J. et al.Preoperative treatment of postmenopausal breast cancer patients with letrozole: a randomized double-blind multicenter study.Ann Oncol. 2001; 12: 1527-1532Abstract Full Text PDF PubMed Scopus (638) Google Scholar]Phase IIb/III, randomizedHR+, cT2–4c/N0–2, post-menopausal, not candidates for BCS170Tamoxifen×16 weeks0.6%25.0%36.0%35.0%NR–FulvestrantKuter, 2012 (NEWEST) [14.Kuter I. Gee J.M.W. Hegg R. et al.Dose-dependent change in biomarkers during neoadjuvant endocrine therapy with fulvestrant: results from NEWEST, a randomized Phase II study.Breast Cancer Res Treat. 2012; 133: 237-246Crossref PubMed Scopus (73) Google Scholar]Phase II, randomizedER+, post-menopausal, cT2-T4b/N0–3109Fulvestrant 500 mg×16 weeksNR36.2%NENRDecrease in Ki67 LI at week 4: −78.8% versus −47.4%Decrease in ER H score at w4: −50.3% versus −13.7%102Fulvestrant 250mg×16 weeks30.4%ChemotherapyPalmieri, 201 NEOCENT [12.Palmieri C. Cleator S. Kilburn L.S. et al.NEOCENT: a randomised feasibility and translational study comparing neoadjuvant endocrine therapy with chemotherapy in ER-rich postmenopausal primary breast cancer.Breast Cancer Res Treat. 2014; 148: 581-590Crossref PubMed Scopus (61) Google Scholar]Phase III, randomizedER+ (Allred scores ≥6), T ≥2 cm, post-menopausal22FEC×6 cyclesdBy MRI.054.5%77.3%NRMean fold decrease at surgery: 0.38−Cottu, 2018 (NeoPAL) [7.Cottu P. D'Hondt V. Dureau S. et al.Letrozole and palbociclib versus chemotherapy as neoadjuvant therapy of high-risk luminal breast cancer.Ann Oncol. 2018; Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar]Phase II, randomizedER+/HER2-, Luminal A N+ and Luminal B (by PAM50), post-menopausal, stage II–III51FEC100×3 cycles → docetaxel×3 cycles5.9%; RCB 0/I: 15.7%53.3%76%68.6%Geometric mean (%) at baseline: 27.7% versus at surgery: 3.7%PEPI score 0 rate: 8.0%Endocrine therapy+targeted therapyBaselga, 2009 [10.Baselga J. Semiglazov V. van Dam P. et al.Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer.J Clin Oncol. 2009; 27: 2630-2637Crossref PubMed Scopus (561) Google Scholar]Phase II, randomizedER+, T≥2 cm, post-menopausal138Letrozole+everolimus×4 months1.4%58.0%68.1%NRLn(Ki67)<1% at D15: 57%−Saura, 2017 (LORELEI) [13.Saura C. de Azambuja E. Hlauschek D. et al.LBA10_PRPrimary results of LORELEI: a phase II randomized, double-blind study of neoadjuvant letrozole (LET) plus taselisib versus LET plus placebo (PLA) in postmenopausal patients (pts) with ER+/HER2-negative early breast cancer (EBC).Ann Oncol. 2017; Abstract Full Text Full Text PDF Google Scholar]Phase II, randomizedER+/HER2-, stage I–III (T ≥2 cm), post-menopausal165Letrozole+taselisib× 16 weeks1.8%50.0%dBy MRI.NRNRNRpCR in PIK3CAmut patients: 1.4%ET+CDK4/6 inhibitorsMa, 2017 (NeoPalAna) [4.Ma C.X. Gao F. Luo J. et al.NeoPalAna: neoadjuvant Palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor-positive breast cancer.Clin Cancer Res. 2017; 23: 4055-4065Crossref PubMed Scopus (180) Google Scholar]Phase II, single-armER+/HER2-, stage II-III, pre-/post-menopausal39Anastrozole×4 weeks (C0) → anastrozole+palbociclib×4 cycles0%41.0%80.0%NRCCCA at C1D1: → at C1D15: 87%–Martin, 2017 (neoMONARCH) [5.Martin M. Hurvitz S.A. Chan D. et al.Abstract PD5-01: final results of NeoMONARCH: a phase 2 neoadjuvant study of abemaciclib in postmenopausal women with hormone receptor positive (HR+), HER2 negative breast cancer (BC).Cancer Res. 2018; 78Google Scholar]Phase II, randomizedER+/HER2-, stage I (T≥1 cm)-IIIB, post-menopausal224Anastrozole versus abemaciclib+ anastrozole versus abemaciclib×2 weeks → Abemaciclib + anastrozole×14 weeks3.7%46.4%53.6%NRCCCA at C1D15: anastrozole: 14%, abemaciclib: 58%, abemaciclib+ anastrozole: 68%–Chow, 2018 (N007) [6.Chow L.W.C. Morita S. Chow C.Y.C. et al.Neoadjuvant palbociclib on ER+ breast cancer (N007): clinical response and EndoPredict's value.Endocr Relat Cancer. 2018; 25: 123-130Crossref PubMed Scopus (29) Google Scholar]Phase II, single-armER+/HER2-, T≥2 cm, post-menopausal20Letrozole+palbociclib×4 cycles5%70%85.0%NRCCCA at C1D15: 71%PEPI score 0 rate: 5%Cottu, 2018 (NeoPAL) [7.Cottu P. D'Hondt V. Dureau S. et al.Letrozole and palbociclib versus chemotherapy as neoadjuvant therapy of high-risk luminal breast cancer.Ann Oncol. 2018; Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar]Phase II, randomizedER+/HER2-, Luminal A N+ and Luminal B (by PAM50), post-menopausal, stage II–III52Letrozole+palbociclib×19 weeks3.8%; RCB 0/I: 7.7%55.5%74.5%69.2%Geometric mean (%) at baseline: 24.1% versus at surgery: 1.17%PEPI score 0 rate: 17.6%BCS, breast-conserving surgery; CCCA, complete cell cycle arrest, defined as Ki67 < 2.7%; HR, hormone-receptor; LI, labeling index; Ln, natural logarithm; N+, metastatic lymph nodes; NE, not evaluated; NR, not reported; pCR, pathological complete response (primary breast tumor and axillary lymph nodes—ypT0/is ypN0); PEPI, Preoperative Endocrine Prognostic Index; RCB, residual cancer burden.a Number of assessable patients in that arm.b Radiological response rate by ultrasound (according to RECIST criteria); clinical response by caliper.c FE75C or FE100C; a switch to docetaxel (100 mg/m2 administered every 3 weeks for three cycles) was required after three cycles if either the disease was considered stable or progressive, clinically or on ultrasound according to RECIST criteria (V1.1).d By MRI. Open table in a new tab BCS, breast-conserving surgery; CCCA, complete cell cycle arrest, defined as Ki67 < 2.7%; HR, hormone-receptor; LI, labeling index; Ln, natural logarithm; N+, metastatic lymph nodes; NE, not evaluated; NR, not reported; pCR, pathological complete response (primary breast tumor and axillary lymph nodes—ypT0/is ypN0); PEPI, Preoperative Endocrine Prognostic Index; RCB, residual cancer burden. Additionally, no long-term survival data have been reported from these four CDK4/6i+ET neoadjuvant trials. Therefore, it is not known whether CCA at 2 weeks or at surgery is associated with improved long-term outcome. Currently, the clinical development of CDK4/6i in the adjuvant setting is largely focused in patients with high risk ER-positive/HER2-negative breast cancer that have been already exposed to (neo)adjuvant chemotherapy. Thus, it is difficult to know whether the promising activity of CDK4/6i in suppressing tumor proliferation reported in the above neoadjuvant studies can predict a positive outcome of the ongoing adjuvant trials. Even so, these CDK4/6i+ET neoadjuvant trials might be an excellent platform for research aiming to identify clinical useful biomarkers of response/resistance, beyond ER status. Studies with CDK4/6i+ET in metastatic ER-positive/HER2-negative breast cancer failed to identify any biomarker associated with the benefit of adding CDK4/6i to ET. In the MONALEESA-2 trial, this benefit has been observed independently of the tumor protein expression of total Rb, Ki67, or p16, mRNA levels of CDKN2A, CCND1, or ESR1 genes and of TP53 and PIK3CA mutational status [20.Hortobagyi G.N. Stemmer S.M. Burris H.A. et al.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 Oncol. 2018; 29: 1541-1547Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar]. Moreover, in the PALOMA-2 trial, assessment of ER, Rb, p16, cyclin D1, and Ki67 in primary tumor and metastatic samples did not predict benefit from adding palbociclib to ET [21.Finn R. Jiang Y. Rugo H. et al.Biomarker analyses from the phase 3 PALOMA-2 trial of palbociclib (P) with letrozole (L) compared with placebo (PLB) plus L in postmenopausal women with ER +/HER2– advanced breast cancer (ABC).Ann Oncol. 2016; Abstract Full Text Full Text PDF Scopus (34) Google Scholar]. In the PALOMA-3, PIK3CA mutational status in circulating tumor DNA did not predict benefit from palbociclib [22.O'Leary B. Hrebien S. Morden J.P. et al.Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer.Nat Commun. 2018; 9: 896Crossref PubMed Scopus (235) Google Scholar]. Preclinical data suggested that acquired resistance to CDK4/6i results from CCNE1 amplification or RB1 loss [23.Herrera-Abreu M.T. Palafox M. Asghar U. et al.Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer.Cancer Res. 2016; 76: 2301-2313Crossref PubMed Scopus (379) Google Scholar]. However, data from metastatic patients showed that RB1 loss is not a common acquired resistance mechanism. Indeed, using targeted next-generation sequencing of paired baseline and end-of-treatment plasma samples from the PALOMA-3 trial, Turner et al. demonstrated that mutational profiles of resistance to fulvestrant/palbociclib versus fulvestrant alone are largely similar and are characterized by acquired PIK3CA and ESR1 Y537S mutations; yet, RB1 mutations are detected in only 5% of patients treated with the combination but not in patients treated with fulvestrant alone [24.O'Leary B. Cutts R.J. Liu Y. et al.The genetic landscape and clonal evolution of breast cancer resistance to palbociclib plus fulvestrant in the PALOMA-3 trial.Cancer Discov. 2018; Crossref PubMed Scopus (270) Google Scholar]. In the neoadjuvant setting, biomarker analysis in baseline samples from the NeoPalAna trial showed that palbociclib increased rates of CCA at week 2 independent of Luminal subtype A versus B, PIK3CA mutational status and across different mutational profiles. However, there was increased mRNA expression of CCND3, CCNE1, and CDKN2D compared with baseline in patients without CCA at week 2, suggesting an active E2F transcription program in tumors with intrinsic resistance [4.Ma C.X. Gao F. Luo J. et al.NeoPalAna: neoadjuvant Palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor-positive breast cancer.Clin Cancer Res. 2017; 23: 4055-4065Crossref PubMed Scopus (180) Google Scholar]. We have recently demonstrated that activating T172 phosphorylation of CDK4 is the central rate-limiting event that promotes cell cycle transition from the G1 to S phase and that absence of the T172-phosphorylated CDK4 form is associated with resistance to CDK4/6i in breast cancer cell lines. Additionally, we have developed an 11-gene signature that can capture the CDK4 phosphorylation status and we hypothesize that it can identify the subgroup of patients with intrinsic resistance to CDK4/6i [25.Raspé E. Coulonval K. Pita J.M. et al.CDK4 phosphorylation status and a linked gene expression profile predict sensitivity to palbociclib.EMBO Mol Med. 2017; 9: 1052-1066Crossref PubMed Scopus (54) Google Scholar]. We aim to validate the above hypothesis in the context of the ongoing NeoRHEA study (NCT03065621), in which patients with ER-positive/HER2-negative early breast cancer receive palbociclib + ET for 4 months before surgery. Currently, there are 16 trials registered in ClinicalTrials.gov testing neoadjuvant CDK4/6i+ET in single-arm studies or comparing it to chemotherapy or ET in patients with ER-positive/HER2-negative tumors, comprising a total of 2290 patients. Analysis of baseline and surgical samples from these neoadjuvant trials might help to identify biomarkers of intrinsic or acquired resistance to CDK4/6i, but also further provide evidence on the role of these compounds in modulating antitumor immune response [26.Goel S. DeCristo M.J. Watt A.C. et al.CDK4/6 inhibition triggers anti-tumour immunity.Nature. 2017; 548: 471-475Crossref PubMed Scopus (728) Google Scholar, 27.Deng J. Wang E.S. Jenkins R.W. et al.CDK4/6 inhibition augments antitumor immunity by enhancing T-cell activation.Cancer Discov. 2018; 8: 216-233Crossref PubMed Scopus (351) Google Scholar]. The standardization of assessments and outcomes, a long-term follow-up and the sharing of these neoadjuvant trials' data might help further refine treatment options in case the ongoing phase III adjuvant trials with CDK4/6i are positive. Moreover, data from these studies might provide further evidence for the selection of patients' subgroups to be included in trials with ET + CDK4/6i in combination with other agents such as inhibitors of PI3K/AKT and MAPK pathways or with immunotherapy. None declared.