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. 2024 Jan 25;25(3):1498.
doi: 10.3390/ijms25031498.

Identification of a Panel of miRNAs Associated with Resistance to Palbociclib and Endocrine Therapy

Rosalba Torrisi  1 , Valentina Vaira  2   3 , Laura Giordano  4 , Bethania Fernandes  5 , Giuseppe Saltalamacchia  1 , Raffaella Palumbo  6 , Carlo Carnaghi  7 , Vera Basilico  8 , Francesco Gentile  2 , Giovanna Masci  1 , Rita De Sanctis  1   9 , Armando Santoro  1   9
Affiliations

Identification of a Panel of miRNAs Associated with Resistance to Palbociclib and Endocrine Therapy

Rosalba Torrisi et al. Int J Mol Sci. .

Abstract

We investigated whether we could identify a panel of miRNAs associated with response to treatment in tumor tissues of patients with Hormone Receptor-positive/HER2-negative metastatic breast cancer treated with endocrine therapy (ET) and the CDK4/6 inhibitor (CDK4/6i)i palbociclib. In total, 52 patients were evaluated, with 41 receiving treatment as the first line. The overall median PFS was 20.8 months (range 2.5-66.6). In total, 23% of patients experienced early progression (<6 months). Seven miRNAs (miR-378e, miR-1233, miR-99b-5p, miR-1260b, miR-448, -miR-1252-5p, miR-324-3p, miR-1233-3p) showed a statistically significant negative association with PFS. When we considered PFS < 6 months, miR-378e, miR-99b-5p, miR-877-5p, miR-1297, miR-455-5p, and miR-4536-5p were statistically associated with a poor outcome. In the multivariate analysis, the first three miRNAs confirmed a significant and independent impact on PFS. The literature data and bioinformatic tools provide an underlying molecular rationale for most of these miRNAs, mainly involving the PI3K/AKT/mTOR pathway and cell-cycle machinery as cyclin D1, CDKN1B, and protein p27Kip1 and autophagy. Our findings propose a novel panel of miRNAs associated with a higher likelihood of early progression in patients treated with ET and Palbociclib and may contribute to shed some light on the mechanisms of de novo resistance to CDK4/6i, but this should be considered exploratory and evaluated in larger cohorts.

Keywords: hormone receptor positive/HER2 negative; metastatic breast cancer; miRNAs; palbociclib; sTILs.

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Conflict of interest statement

R.T. honoraria and advisory board consultancy from Lilly, Pfizer, Gilead (all outside the submitted work). R.D.S. honoraria and advisory board consultancy from Lilly, Novartis, Istituto Clinico Gentili, Amgen, and Eisai (all outside the submitted work). A.S. Advisory Board: BMS (BRISTOL-MYERS-SQUIBB)/SERVIER/GILEAD/PFIZER/EISAI/BAYER/MSD (MERCK SHARP & DOHME) Consultancy: SANOFI/INCYTE Speaker’s Bureau: TAKEDA/BMS/ROCHE/ABB-VIE/AMGEN/CELGENE/SERVIER/GILEAD/ASTRAZENECA/PFIZER/ARQULE/LILLY/SANDOZ/EISAI/NOVARTIS/BAYER/MSD. The other authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
(A) STRING analysis with potential targets of the miRNAs miR-99-5p, −378e, and miR-877-5p (listed in Supplementary Table S1) was performed and gene networks were searched using Gene Ontology (GO), KEGG, or Reactome tools implemented within STRING. The human genome was used as a reference. (B) The full list of identified enriched terms is shown in Supplementary Table S2. FDR, false discovery rate q value.
See this image and copyright information in PMC

References

    1. Howlader N., Altekruse S.F., Li C.I., Chen V.W., Clarke C.A., Ries L.A., Cronin K.A. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J. Natl. Cancer Inst. 2014;106:dju055. doi: 10.1093/jnci/dju055. - DOI - PMC - PubMed
    1. Hortobagyi G.N., Stemmer S.M., Burris H.A., Yap Y.-S., Sonke G.S., Hart L., Campone M., Petrakova K., Winer E.P., Janni W., et al. Overall survival with Ribociclib plus Letrozole in advanced breast cancer. N. Engl. J. Med. 2022;386:942–950. doi: 10.1056/NEJMoa2114663. - DOI - PubMed
    1. Slamon D.J., Neven P., Chia S., Jerusalem G., De Laurentiis M., Im S., Petrakova K., Bianchi G.V., Martín M., Nusch A., 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. Ann. Oncol. 2021;32:1015–1024. doi: 10.1016/j.annonc.2021.05.353. - DOI - PubMed
    1. Lu Y.-S., Im S.-A., Colleoni M., Franke F., Bardia A., Cardoso F., Harbeck N., Hurvitz S., Chow L., Sohn J., et al. Updated overall survival of ribociclib plus endocrine therapy versus endocrine therapy alone in pre- and Peri-menopausal patients with HRþ/HER2_ advanced breast cancer in MONALEESA-7: A phase III randomized clinical trial. Clin. Cancer Res. 2022;28:851–859. doi: 10.1158/1078-0432.CCR-21-3032. - DOI - PMC - PubMed
    1. Rugo H.S., Finn R.S., Diéras V., Ettl J., Lipatov O., Joy A.A., Harbeck N., Castrellon A., Iyer S., Lu D.R., et al. 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. Treat. 2019;174:719–729. doi: 10.1007/s10549-018-05125-4. - DOI - PMC - PubMed

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