p4EBP1 staining predicts outcome in ER-positive endocrine-resistant metastatic breast cancer patients treated with everolimus and exemestane.
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
05 Jan 2024
05 Jan 2024
Historique:
received:
07
06
2023
accepted:
11
12
2023
revised:
27
11
2023
medline:
6
1
2024
pubmed:
6
1
2024
entrez:
5
1
2024
Statut:
aheadofprint
Résumé
To identify patients most likely to respond to everolimus, a mammalian target of rapamycin (mTOR) inhibitor, a prospective biomarker study was conducted in hormone receptor-positive endocrine-resistant metastatic breast cancer patients treated with exemestane-everolimus therapy. Metastatic tumor biopsies were processed for immunohistochemical staining (p4EBP1, PTEN, pAKT, LKB1, and pS6K). ESR1, PIK3CA and AKT1 gene mutations were detected by NGS. The primary endpoint was the association between the p4EBP1 expression and clinical benefit rate (CBR) at 6 months of everolimus plus exemestane treatment. Of 150 patients included, 107 were evaluable for the primary endpoint. p4EBP1 staining above the median (Allred score ≥6) was associated with a higher CBR at 6 months (62% versus 40% in high-p4EBP1 versus low-p4EBP1, χ2 test, p = 0.026) and a longer progression-free survival (PFS) (median PFS of 9.2 versus 5.8 months in high-p4EBP1 versus low-p4EBP1; p = 0.02). When tested with other biomarkers, only p4EBP1 remained a significant predictive marker of PFS in multivariate analysis (hazard ratio, 0.591; p = 0.01). This study identified a subset of patients with hormone receptor-positive endocrine-resistant metastatic breast cancer and poor outcome who would derive less benefit from everolimus and exemestane. p4EBP1 may be a useful predictive biomarker in routine clinical practice. NCT02444390.
Sections du résumé
BACKGROUND
BACKGROUND
To identify patients most likely to respond to everolimus, a mammalian target of rapamycin (mTOR) inhibitor, a prospective biomarker study was conducted in hormone receptor-positive endocrine-resistant metastatic breast cancer patients treated with exemestane-everolimus therapy.
METHODS
METHODS
Metastatic tumor biopsies were processed for immunohistochemical staining (p4EBP1, PTEN, pAKT, LKB1, and pS6K). ESR1, PIK3CA and AKT1 gene mutations were detected by NGS. The primary endpoint was the association between the p4EBP1 expression and clinical benefit rate (CBR) at 6 months of everolimus plus exemestane treatment.
RESULTS
RESULTS
Of 150 patients included, 107 were evaluable for the primary endpoint. p4EBP1 staining above the median (Allred score ≥6) was associated with a higher CBR at 6 months (62% versus 40% in high-p4EBP1 versus low-p4EBP1, χ2 test, p = 0.026) and a longer progression-free survival (PFS) (median PFS of 9.2 versus 5.8 months in high-p4EBP1 versus low-p4EBP1; p = 0.02). When tested with other biomarkers, only p4EBP1 remained a significant predictive marker of PFS in multivariate analysis (hazard ratio, 0.591; p = 0.01).
CONCLUSIONS
CONCLUSIONS
This study identified a subset of patients with hormone receptor-positive endocrine-resistant metastatic breast cancer and poor outcome who would derive less benefit from everolimus and exemestane. p4EBP1 may be a useful predictive biomarker in routine clinical practice.
CLINICAL TRIAL REGISTRATION
BACKGROUND
NCT02444390.
Identifiants
pubmed: 38182687
doi: 10.1038/s41416-023-02549-8
pii: 10.1038/s41416-023-02549-8
doi:
Banques de données
ClinicalTrials.gov
['NCT02444390']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer Nature Limited.
Références
Cardoso F, Senkus E, Costa A, Papadopoulos E, Aapro M, André F, et al. 4th ESO–ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4). Ann Oncol août. 2018;29:1634–57.
doi: 10.1093/annonc/mdy192
Dodwell D, Wardley A, Johnston S. Postmenopausal advanced breast cancer: Options for therapy after tamoxifen and aromatase inhibitors. Breast. 2006;15:584–94.
doi: 10.1016/j.breast.2006.01.007
pubmed: 16504510
Hortobagyi GN, Chen D, Piccart M, Rugo HS, Burris HA, Pritchard KI, et al. Correlative analysis of genetic alterations and everolimus benefit in hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer: results from BOLERO-2. JCO. 2016;34:419–26.
doi: 10.1200/JCO.2014.60.1971
Miller TW, Hennessy BT, González-Angulo AM, Fox EM, Mills GB, Chen H, et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor–positive human breast cancer. J Clin Invest. 2010;120:2406–13.
doi: 10.1172/JCI41680
pubmed: 20530877
pmcid: 2898598
Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X, et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res. 2005;65:2554–9.
doi: 10.1158/0008-5472-CAN-04-3913
pubmed: 15805248
Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol. 2012;30:2718–24.
doi: 10.1200/JCO.2011.39.0708
pubmed: 22565002
Baselga J, Campone M, Piccart M, Burris HA, Rugo HS, Sahmoud T, et al. Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer. N. Engl J Med. 2012;366:520–9.
doi: 10.1056/NEJMoa1109653
pubmed: 22149876
O’Shaughnessy J, Thaddeus Beck J, Royce M. Everolimus-based combination therapies for HR+, HER2− metastatic breast cancer. Cancer Treat Rev. 2018;69:204–14.
doi: 10.1016/j.ctrv.2018.07.013
pubmed: 30092555
Wander SA, Hennessy BT, Slingerland JM. Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy. J Clin Invest. 2011;121:1231–41.
doi: 10.1172/JCI44145
pubmed: 21490404
pmcid: 3069769
Mertins P, Mani DR, Ruggles KV, Gillette MA, Clauser KR, Wang P, et al. Proteogenomics connects somatic mutations to signalling in breast cancer. Nature. 2016;534:55–62.
doi: 10.1038/nature18003
pubmed: 27251275
pmcid: 5102256
The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61–70.
doi: 10.1038/nature11412
pmcid: 3465532
Treilleux I, Arnedos M, Cropet C, Wang Q, Ferrero JM, Abadie-Lacourtoisie S, et al. Translational studies within the TAMRAD randomized GINECO trial: evidence for mTORC1 activation marker as a predictive factor for everolimus efficacy in advanced breast cancer. Ann Oncol. 2015;26:120–5.
doi: 10.1093/annonc/mdu497
pubmed: 25361980
André F. Overall survival (os) results from SOLAR-1, a phase III study of Alpelisib (ALP) + fulvestrant (FUL) for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC). Annals of Oncology (2020) 31 :: S1142-S1215 101016/annonc/annonc325. 2020; Disponible sur: https://oncologypro.esmo.org/meeting-resources/esmo-virtual-congress-2020/overall-survival-os-results-from-solar-1-a-phase-iii-study-of-alpelisib-alp-fulvestrant-ful-for-hormone-receptor-positive-hr-human-epi .
Dent S, Cortés J, Im YH, Diéras V, Harbeck N, Krop IE, et al. 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 Oncol févr. 2021;32:197–207.
doi: 10.1016/j.annonc.2020.10.596
Vanacker H, Cassier PA, Bachelot T. The complex balance of PI3K inhibition. Ann Oncol. 2021;32:127–8.
doi: 10.1016/j.annonc.2020.10.597
pubmed: 33272746
Loi S, Haibe-Kains B, Majjaj S, Lallemand F, Durbecq V, Larsimont D, et al. PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor–positive breast cancer. Proc Natl Acad Sci USA. 2010;107:10208–13.
doi: 10.1073/pnas.0907011107
pubmed: 20479250
pmcid: 2890442
Sabine VS, Crozier C, Brookes CL, Drake C, Piper T, van de Velde CJH, et al. Mutational analysis of PI3K/AKT signaling pathway in tamoxifen exemestane adjuvant multinational pathology study. JCO. 2014;32:2951–8.
doi: 10.1200/JCO.2013.53.8272
Loi S, Michiels S, Baselga J, Bartlett JMS, Singhal SK, Sabine VS, et al. PIK3CA Genotype and a PIK3CA Mutation-Related Gene Signature and Response to Everolimus and Letrozole in Estrogen Receptor Positive Breast Cancer. Sotiropoulou G, éditeur. PLoS ONE. 2013;8:e53292.
Memmott RM, Dennis PA. Akt-dependent and -independent mechanisms of mTOR regulation in cancer. Cell Signal. 2009;21:656–64.
doi: 10.1016/j.cellsig.2009.01.004
pubmed: 19166931
pmcid: 2650010
Kuo CT, Chen CL, Li CC, Huang GS, Ma WY, Hsu WF, et al. Immunofluorescence can assess the efficacy of mTOR pathway therapeutic agent Everolimus in breast cancer models. Sci Rep. 29. 2019;9:10898.
doi: 10.1038/s41598-019-45319-4
Capivasertib Doubles PFS in Some Breast Cancers. Cancer Discovery. 2023;13:250.
Howell SJ, Casbard A, Carucci M, Ingarfield K, Butler R, Morgan S, et al. 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 Oncol. 2022;23:851–64.
doi: 10.1016/S1470-2045(22)00284-4
pubmed: 35671774
pmcid: 9630162
Bertucci F, Ng CKY, Patsouris A, Droin N, Piscuoglio S, Carbuccia N, et al. Genomic characterization of metastatic breast cancers. Nature. 2019;569:560–4.
doi: 10.1038/s41586-019-1056-z
pubmed: 31118521
Razavi P, Dickler MN, Shah PD, Toy W, Brown DN, Won HH, et al. Alterations in PTEN and ESR1 promote clinical resistance to Alpelisib plus aromatase inhibitors. Nat Cancer. 2020;1:382–93.
doi: 10.1038/s43018-020-0047-1
pubmed: 32864625
pmcid: 7450824
Bidard FC, Hardy-Bessard AC, Dalenc F, Bachelot T, Pierga JY, de la Motte Rouge T, et al. 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.
doi: 10.1016/S1470-2045(22)00555-1
pubmed: 36183733
Razavi P, Chang MT, Xu G, Bandlamudi C, Ross DS, Vasan N, et al. The genomic landscape of endocrine-resistant advanced breast cancers. Cancer Cell. 2018;34:427–38.e6.
doi: 10.1016/j.ccell.2018.08.008
pubmed: 30205045
pmcid: 6327853
Prat A, Brase JC, Cheng Y, Nuciforo P, Paré L, Pascual T, et al. Everolimus plus Exemestane for hormone receptor-positive advanced breast cancer: A PAM50 intrinsic subtype analysis of BOLERO-2. Oncologist. 2019;24:893–900.
doi: 10.1634/theoncologist.2018-0407
pubmed: 30679318
pmcid: 6656445
Bera K, Schalper KA, Rimm DL, Velcheti V, Madabhushi A. Artificial intelligence in digital pathology—new tools for diagnosis and precision oncology. Nat Rev Clin Oncol. 2019;16:703–15.
doi: 10.1038/s41571-019-0252-y
pubmed: 31399699
pmcid: 6880861
Espina V, Edmiston KH, Heiby M, Pierobon M, Sciro M, Merritt B, et al. A portrait of tissue Phosphoprotein stability in the clinical tissue procurement process. Mol Cell Proteom. 2008;7:1998–2018.
doi: 10.1074/mcp.M700596-MCP200
O’Hurley G, Sjöstedt E, Rahman A, Li B, Kampf C, Pontén F, et al. Garbage in, garbage out: A critical evaluation of strategies used for validation of immunohistochemical biomarkers. Mol Oncol. 2014;8:783–98.
doi: 10.1016/j.molonc.2014.03.008
pubmed: 24725481
pmcid: 5528533