Rebecca Waugh

Background: In America breast cancer is the most frequently diagnosed malignancy in women^2,5. Hormone receptor-positive human epidermal growth factor receptor-2 negative (HR+/HER2-) tumors categorize 65-70% of all cases and has one of the lowest survival rates^1,2. Recent meta-analysis incorporate modulation CDK 4/6 inhibitors (CDKi) with endocrine therapy as the best approach for better outcomes³. However, endocrine resistance is still a big issue with this dual-therapy treatment⁶. Acquired resistance is inevitable and targeting CDK4/6 inhibitor resistance is critical to improving treatments⁴. Pre-clinical studies suggest up-regulation of the PI3K/AKT/mTOR signaling pathway causes CDK4/6 resistance.⁸ So this could be a good target for trying to overcome resistance and may suggest a new third therapeutic agent be added to treatment.

Objective: In this narrative review, we look at triple combination treatments to overpower acquired resistance in HR+/HER2- metastatic breast cancer.

Search Methods: PubMed database was utilized to conduct an online search, papers were limited from 2018 to 2023 using the key words: “CDKi therapy”, “acquired CDKi resistance”, “HR+/HER2- breast cancer treatments”.

Results: MONSALEESA-3 trial follows up with patients 5 years after the phase III trials began with dual therapy.⁷ Combined endocrine therapy with a CDK4/6 inhibitor has been proven to improve progression free survival and overall survival^7,8,9. However 15.5% develop resistance⁷. Multiple cell line studies found acquired CDKi 4/6 resistance creates cross-resistance to other CDK4/6 inhibitors.^8,9,10,11 These cell lines also had nearly no response to fulvestrant, a common endocrine therapy⁹. One study showed using either inhibitor, mTOR or PI3K, they were able to suppress growth in the resistant cells⁹. Thus, a PI3K or mTOR inhibitor adjunct may be the step forward needed. In CDKi 4/6 resistant cell lines, a mTOR inhibitor significantly caused growth inhibition¹⁰. Combination of mTOR inhibitor with CDK4/6 inhibition reportedly prevented early adaptation, delayed the onset of resistance, and caused long term growth arrest¹⁰. In another study, xenograft models were given a mTOR or PI3K inhibitor as a monotherapy and in combination. When recombined with the PI3K inhibitor, CDKi, and fulvestrant the tumors exhibited robust regression durable throughout treatment.¹¹ A short phase Ib study using triple combination with PI3K inhbitor against the dual-therapy, CDKi 4/6 and endocrine therapy, revealed the highest overall response rate was seen with the triple therapy. However, there was unforeseen toxicity, so the study was stopped¹². TRINITI phase I/II trials showed triple combination with an mTOR inhibitor was tolerable and by day 24 the clinical benefit was 10% higher than hypothesized¹³.

Conclusion: In vitro, in vivo, and clinical trials indicate that the triple combination of CDKi 4/6, endocrine therapy, and PI3K/mTOR inhibitor is a promising approach to overcome and prevent resistance in treating HR+/HER2- metastatic breast cancer. Further study into which combination has the best tolerability and outcome is needed. Personalized medicine would also help prevent resistance; hence biomarkers may be a useful avenue in the future.

Works Cited:

1. Werutsky G, Reinert T, Rosa ML, Barrios CH. Real-world Data on First-line Systemic Therapy for Hormone Receptor-positive HER2-negative Metastatic Breast Cancer: A Trend Shift in the Era of CDK 4/6 Inhibitors. Clin Breast Cancer. 2021;21(6):e688-e692. doi:10.1016/j.clbc.2021.04.003
2. Cersosimo RJ. Cyclin-dependent kinase 4/6 inhibitors for the management of advanced or metastatic breast cancer in women. Am J Health Syst Pharm. 2019;76(16):1183-1202. doi:10.1093/ajhp/zxz121
3. Xi J, Ma CX. Sequencing Endocrine Therapy for Metastatic Breast Cancer: What Do We Do After Disease Progression on a CDK4/6 Inhibitor?. Curr Oncol Rep. 2020;22(6):57. Published 2020 May 16. doi:10.1007/s11912-020-00917-8
4. Spring LM, Wander SA, Zangardi M, Bardia A. CDK 4/6 Inhibitors in Breast Cancer: Current Controversies and Future Directions. Curr Oncol Rep. 2019;21(3):25. Published 2019 Feb 26. doi:10.1007/s11912-019-0769-3
5. Zheng J, Wu J, Wang C, Zhuang S, Chen J, Ye F. Combination cyclin-dependent kinase 4/6 inhibitors and endocrine therapy versus endocrine monotherapy for hormonal receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: A systematic review and meta-analysis. PLoS One. 2020;15(6):e0233571. Published 2020 Jun 4. doi:10.1371/journal.pone.0233571
6. Ogata R, Kishino E, Saitoh W, Koike Y, Kurebayashi J. Resistance to cyclin-dependent kinase (CDK) 4/6 inhibitors confers cross-resistance to other CDK inhibitors but not to chemotherapeutic agents in breast cancer cells. Breast Cancer. 2021;28(1):206-215. doi:10.1007/s12282-020-01150-8
7. Slamon DJ, Neven P, Chia S, et al. Ribociclib plus fulvestrant for postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in the phase III randomized MONALEESA-3 trial: updated overall survival [published correction appears in Ann Oncol. 2021 Oct;32(10):1307]. Ann Oncol. 2021;32(8):1015-1024. doi:10.1016/j.annonc.2021.05.353
8. Ogata R, Kishino E, Saitoh W, Koike Y, Kurebayashi J. Resistance to cyclin-dependent kinase (CDK) 4/6 inhibitors confers cross-resistance to other CDK inhibitors but not to chemotherapeutic agents in breast cancer cells. Breast Cancer. 2021;28(1):206-215. doi:10.1007/s12282-020-01150-8
9. Iida M, Toyosawa D, Nakamura M, et al. Decreased ER dependency after acquired resistance to CDK4/6 inhibitors. Breast Cancer. 2020;27(5):963-972. doi:10.1007/s12282-020-01090-3
10. Michaloglou C, Crafter C, Siersbaek R, et al. Combined Inhibition of mTOR and CDK4/6 Is Required for Optimal Blockade of E2F Function and Long-term Growth Inhibition in Estrogen Receptor-positive Breast Cancer. Mol Cancer Ther. 2018;17(5):908-920. doi:10.1158/1535-7163.MCT-17-0537
11. O’Brien NA, McDermott MSJ, Conklin D, et al. Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer. Breast Cancer Res. 2020;22(1):89. Published 2020 Aug 14. doi:10.1186/s13058-020-01320-8
12. Tolaney SM, Im YH, Calvo E, et al. Phase Ib Study of Ribociclib plus Fulvestrant and Ribociclib plus Fulvestrant plus PI3K Inhibitor (Alpelisib or Buparlisib) for HR⁺ Advanced Breast Cancer. Clin Cancer Res. 2021;27(2):418-428. doi:10.1158/1078-0432.CCR-20-0645
13. Bardia A, Hurvitz SA, DeMichele A, et al. Phase I/II Trial of Exemestane, Ribociclib, and Everolimus in Women with HR⁺/HER2^– Advanced Breast Cancer after Progression on CDK4/6 Inhibitors (TRINITI-1). Clin Cancer Res. 2021;27(15):4177-4185. doi:10.1158/1078-0432.CCR-20-2114
14. Lee JS, Yost SE, Li SM, et al. Genomic Markers of CDK 4/6 Inhibitor Resistance in Hormone Receptor Positive Metastatic Breast Cancer. Cancers (Basel). 2022;14(13):3159. Published 2022 Jun 28. doi:10.3390/cancers14133159