Waks, A. G. & Winer, E. P. Breast cancer treatment: a review. JAMA 321, 288–300 (2019).
Mouabbi, J. A., Osborne, C. K., Schiff, R. & Rimawi, M. F. Management of hormone receptor-positive, human epidermal growth factor 2-negative metastatic breast cancer. Breast Cancer Res. Treat. 190, 189–201 (2021).
Dowsett, M. et al. Comparison of PAM50 risk of recurrence score with oncotype DX and IHC4 for predicting risk of distant recurrence after endocrine therapy. J. Clin. Oncol. 31, 2783–2790 (2013).
Kaklamani, V. G. & Gradishar, W. J. Gene expression in breast cancer. Curr. Treat. Options Oncol. 7, 123–128 (2006).
Sinn, P. et al. Multigene assays for classification, prognosis, and prediction in breast cancer: a critical review on the background and clinical utility. Geburtshilfe Frauenheilkd. 73, 932–940 (2013).
Negoita, S. & Ramirez-Pena, E. Prevention of late recurrence: an increasingly important target for breast cancer research and control. J. Natl Cancer Inst. 114, 340–341 (2022).
Sgroi, D. C. et al. Prediction of late distant recurrence in patients with oestrogen-receptor-positive breast cancer: a prospective comparison of the breast-cancer index (BCI) assay, 21-gene recurrence score, and IHC4 in the TransATAC study population. Lancet Oncol. 14, 1067–1076 (2013).
Gao, J. J. et al. CDK4/6 inhibitor treatment for patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer: a US Food and Drug Administration pooled analysis. Lancet Oncol. 21, 250–260 (2020).
Goldner, M. et al. Combined endocrine and targeted therapy in luminal breast cancer. Expert Rev. Anticancer Ther. 21, 1237–1251 (2021).
O’Leary, B., Finn, R. S. & Turner, N. C. Treating cancer with selective CDK4/6 inhibitors. Nat. Rev. Clin. Oncol. 13, 417–430 (2016).
Cristofanilli, M. et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 17, 425–439 (2016).
Richard, S. F. et al. Final results of a randomized phase II study of PD 0332991, a cyclin-dependent kinase (CDK)-4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (PALOMA-1; TRIO-18). Cancer Res. 74, CT101 (2014).
Finn, R. S. et al. Long-term pooled safety analysis of palbociclib in combination with endocrine therapy for hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: updated analysis with up to 5 years of follow-up. Oncologist 26, e749–e755 (2021).
Slamon, D. J. et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J. Clin. Oncol. 36, 2465–2472 (2018).
Sledge, G. W. Jr. et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J. Clin. Oncol. 35, 2875–2884 (2017).
Goetz, M. P. et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J. Clin. Oncol. 35, 3638–3646 (2017).
Finn, R. S. et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 11, R77 (2009).
Dean, J. L., Thangavel, C., McClendon, A. K., Reed, C. A. & Knudsen, E. S. Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure. Oncogene 29, 4018–4032 (2010).
Witkiewicz, A. K., Knudsen, K. E., Dicker, A. P. & Knudsen, E. S. The meaning of p16(ink4a) expression in tumors: functional significance, clinical associations and future developments. Cell Cycle 10, 2497–2503 (2011).
Bertucci, F. et al. Genomic characterization of metastatic breast cancers. Nature 569, 560–564 (2019).
Wander, S. A. et al. 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 Discov. 10, 1174–1193 (2020).
Asghar, U. S., Kanani, R., Roylance, R. & Mittnacht, S. Systematic review of molecular biomarkers predictive of resistance to CDK4/6 inhibition in metastatic breast cancer. JCO Precis. Oncol. 6, e2100002 (2022).
Turner, N. C. et al. Cyclin E1 expression and palbociclib efficacy in previously treated hormone receptor-positive metastatic breast cancer. J. Clin. Oncol. 37, 1169–1178 (2019).
Li, Z. et al. Loss of the FAT1 tumor suppressor promotes resistance to CDK4/6 inhibitors via the Hippo pathway. Cancer Cell 34, 893.e8–905.e8 (2018).
Yang, C. et al. Acquired CDK6 amplification promotes breast cancer resistance to CDK4/6 inhibitors and loss of ER signaling and dependence. Oncogene https://doi.org/10.1038/onc.2016.379 (2016).
Freeman-Cook, K. et al. Expanding control of the tumor cell cycle with a CDK2/4/6 inhibitor. Cancer Cell 39, 1404.e1–1421.e1 (2021).
Chaikovsky, A. C. et al. The AMBRA1 E3 ligase adaptor regulates the stability of cyclin D. Nature 592, 794–798 (2021).
Anurag, M., Haricharan, S. & Ellis, M. J. CDK4/6 inhibitor biomarker research: are we barking up the wrong tree? Clin. Cancer Res. 26, 3–5 (2020).
Dowsett, M. & Dunbier, A. K. Emerging biomarkers and new understanding of traditional markers in personalized therapy for breast cancer. Clin. Cancer Res. 14, 8019–8026 (2008).
Albain, K. S., Paik, S. & van’t Veer, L. Prediction of adjuvant chemotherapy benefit in endocrine responsive, early breast cancer using multigene assays. Breast 18, S141–S145 (2009).
Knudsen, E. S. & Knudsen, K. E. Tailoring to RB: tumour suppressor status and therapeutic response. Nat. Rev. Cancer 8, 714–724 (2008).
Desmedt, C. & Sotiriou, C. Proliferation: the most prominent predictor of clinical outcome in breast cancer. Cell Cycle 5, 2198–2202 (2006).
Ertel, A. et al. RB-pathway disruption in breast cancer: differential association with disease subtypes, disease-specific prognosis and therapeutic response. Cell Cycle 9, 4153–4163 (2010).
Herschkowitz, J. I., He, X., Fan, C. & Perou, C. M. The functional loss of the retinoblastoma tumour suppressor is a common event in basal-like and luminal B breast carcinomas. Breast Cancer Res. 10, R75 (2008). bcr2142 [pii].
Bosco, E. E. et al. The retinoblastoma tumor suppressor modifies the therapeutic response of breast cancer. J. Clin. Investig. 117, 218–228 (2007).
Malorni, L. et al. 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. Oncotarget 7, 68012–68022 (2016).
Knudsen, E. S. et al. Pan-cancer molecular analysis of the RB tumor suppressor pathway. Commun. Biol. 3, 158 (2020).
Finn, R. S. et al. Biomarker analyses of response to cyclin-dependent kinase 4/6 inhibition and endocrine therapy in women with treatment-naive metastatic breast cancer. Clin. Cancer Res. 26, 110–121 (2020).
Zhu, Z. et al. Comparative biomarker analysis of PALOMA-2/3 trials for palbociclib. NPJ Precis. Oncol. 6, 56 (2022).
Guerrero-Zotano, A. et al. CCNE1 and PLK1 mediates resistance to palbociclib in HR+/HER2- metastatic breast cancer. Clin. Cancer Res. 29, 1557–1568 (2023).
Turner, N. C. et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 373, 209–219 (2015).
Finn, R. S. et al. 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 Oncol. 16, 25–35 (2015).
Ma, C. X. 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. 23, 4055–4065 (2017).
Kumarasamy, V., Vail, P., Nambiar, R., Witkiewicz, A. K. & Knudsen, E. S. Functional determinants of cell cycle plasticity and sensitivity to CDK4/6 inhibition. Cancer Res. 81, 1347–1360 (2021).
Paquet, E. R. & Hallett, M. T. Absolute assignment of breast cancer intrinsic molecular subtype. J. Natl Cancer Inst. 107, 357 (2015).
Iwanaga, R. et al. Activation of the cyclin D2 and cdk6 genes through NF-kappaB is critical for cell-cycle progression induced by HTLV-I Tax. Oncogene 27, 5635–5642 (2008).
Dey, A. & Li, W. Cell cycle-independent induction of D1 and D2 cyclin expression, but not cyclin-Cdk complex formation or Rb phosphorylation, by IFNgamma in macrophages. Biochim. Biophys. Acta 1497, 135–147 (2000).
Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).
Liberzon, A. et al. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 1, 417–425 (2015).
Shao, X. et al. Ki67 and progesterone receptor status predicts sensitivity to palbociclib: a real-world study. Ann. Transl. Med. 9, 707 (2021).
Curtis, C. et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486, 346–352 (2012).
Zhang, Y., Parmigiani, G. & Johnson, W. E. ComBat-seq: batch effect adjustment for RNA-seq count data. NAR Genom. Bioinform. 2, lqaa078 (2020).
Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139–140 (2010).
Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).
Gu, Z., Eils, R. & Schlesner, M. Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics 32, 2847–2849 (2016).