Risk of early progression according to circulating ESR1 mutation, CA-15.3 and cfDNA increases under first-line anti-aromatase treatment in metastatic breast cancer

Florian Clatot, Anne Perdrix, Ludivine Beaussire, Justine Lequesne, Christelle Lévy, George Emile, Michael Bubenheim, Sigrid Lacaille, Céline Calbrix, Laetitia Augusto, Cécile Guillemet, Cristina Alexandru, Maxime Fontanilles, David Sefrioui, Lucie Burel, Sabine Guénot, Doriane Richard, Nasrin Sarafan-Vasseur, Frédéric Di Fiore, Florian Clatot, Anne Perdrix, Ludivine Beaussire, Justine Lequesne, Christelle Lévy, George Emile, Michael Bubenheim, Sigrid Lacaille, Céline Calbrix, Laetitia Augusto, Cécile Guillemet, Cristina Alexandru, Maxime Fontanilles, David Sefrioui, Lucie Burel, Sabine Guénot, Doriane Richard, Nasrin Sarafan-Vasseur, Frédéric Di Fiore

Abstract

Background: Endocrine therapy is recommended as a first-line treatment for hormone receptor-positive metastatic breast cancer (HR+MBC) patients. No biomarker has been validated to predict tumor progression in that setting. We aimed to prospectively compare the risk of early progression according to circulating ESR1 mutations, CA-15.3, and circulating cell-free DNA in MBC patients treated with a first-line aromatase inhibitor (AI).

Methods: Patients with MBC treated with a first-line AI were prospectively included. Circulating biomarker assessment was performed every 3 months. The primary objective was to determine the risk of progression or death at the next follow-up visit (after 3 months) in case of circulating ESR1 mutation detection among patients treated with a first-line AI for HR+MBC.

Results: Overall, 103 patients were included, and 70 (68%) had progressive disease (PD). Circulating ESR1 mutations were detected in 22/70 patients with PD and in 0/33 patients without progression (p < 0.001). Among the ESR1-mutated patients, 18/22 had a detectable mutation prior to progression, with a median delay of 110 days from first detection to PD. The detection of circulating ESR1 mutations was associated with a 4.9-fold (95% CI 3.0-8.0) increase in the risk of PD at 3 months. Using a threshold value of 25% or 100%, a CA-15.3 increase was also correlated with progression (p < 0.001 and p = 0.003, respectively). In contrast to ESR1, the CA-15.3 increase occurred concomitantly with PD in most cases, in 27/47 (57%) with a 25% threshold and in 21/25 (84%) with a 100% threshold. Using a threshold value of either 25% or 100%, cfDNA increase was not correlated with progression.

Conclusion: The emergence of circulating ESR1 mutations is associated with a 4.9-fold increase in the risk of early PD during AI treatment in HR+MBC. Our results also highlighted that tracking circulating ESR1 mutations is more relevant than tracking CA-15.3 or cfDNA increase to predict progression in this setting.

Trial registration: ClinicalTrials.gov, NCT02473120. Registered 16 June 2015-retrospectively registered after one inclusion (first inclusion 1 June 2015).

Keywords: Aromatase inhibitor; Breast cancer; CA-15.3; Cell-free DNA; Circulating DNA; ESR1 mutation.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Correlation between biomarker variations and time to progression. For each biomarker, the number of patients with a biomarker event (biomarker increase or mutation emergence) according to the time of progression (PD) is reported
Fig. 2
Fig. 2
Overall survival according to ESR1 mutation status at progression disease. p value was determined using a log-rank test
Fig. 3
Fig. 3
Overall survival according to CA-15.3 level at progression disease. p value was determined using a log-rank test or a Cox model
Fig. 4
Fig. 4
Overall survival according to cfDNA level at progression disease. p value was determined using a log-rank test or a Cox model

References

    1. Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2007;25:5287–5312. doi: 10.1200/JCO.2007.14.2364.
    1. Bidard F-C, Peeters DJ, Fehm T, Nolé F, Gisbert-Criado R, Mavroudis D, et al. Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data. Lancet Oncol. 2014;15:406–414. doi: 10.1016/S1470-2045(14)70069-5.
    1. Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6:224ra24. doi: 10.1126/scitranslmed.3007094.
    1. Cheng J, Holland-Letz T, Wallwiener M, Surowy H, Cuk K, Schott S, et al. Circulating free DNA integrity and concentration as independent prognostic markers in metastatic breast cancer. Breast Cancer Res Treat. 2018;169:69–82. doi: 10.1007/s10549-018-4666-5.
    1. Finn RS, Martin M, Rugo HS, Jones S, Im S-A, Gelmon K, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375:1925–1936. doi: 10.1056/NEJMoa1607303.
    1. Chandarlapaty S, Chen D, He W, Sung P, Samoila A, You D, et al. Prevalence of ESR1 mutations in cell-free DNA and outcomes in metastatic breast cancer: a secondary analysis of the BOLERO-2 clinical trial. JAMA Oncol. 2016;2:1310–1315. doi: 10.1001/jamaoncol.2016.1279.
    1. Gyanchandani R, Kota KJ, Jonnalagadda AR, Minteer T, Knapick BA, Oesterreich S, et al. Detection of ESR1 mutations in circulating cell-free DNA from patients with metastatic breast cancer treated with palbociclib and letrozole. Oncotarget. 2017;8:66901–66911. doi: 10.18632/oncotarget.11383.
    1. Clatot F, Perdrix A, Augusto L, Beaussire L, Delacour J, Calbrix C, et al. Kinetics, prognostic and predictive values of ESR1 circulating mutations in metastatic breast cancer patients progressing on aromatase inhibitor. Oncotarget. 2016;7:74448–74459. doi: 10.18632/oncotarget.12950.
    1. Chu D, Paoletti C, Gersch C, VanDenBerg DA, Zabransky DJ, Cochran RL, et al. ESR1 mutations in circulating plasma tumor DNA from metastatic breast cancer patients. Clin Cancer Res Off J Am Assoc Cancer Res. 2016;22:993–999. doi: 10.1158/1078-0432.CCR-15-0943.
    1. Sefrioui D, Perdrix A, Sarafan-Vasseur N, Dolfus C, Dujon A, Picquenot J-M, et al. Short report: monitoring ESR1 mutations by circulating tumor DNA in aromatase inhibitor resistant metastatic breast cancer. Int J Cancer J Int Cancer. 2015;137:2513–2519. doi: 10.1002/ijc.29612.
    1. Schiavon G, Hrebien S, Garcia-Murillas I, Cutts RJ, Pearson A, Tarazona N, et al. Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer. Sci Transl Med. 2015;7:313ra182. doi: 10.1126/scitranslmed.aac7551.
    1. Guttery DS, Page K, Hills A, Woodley L, Marchese SD, Rghebi B, et al. Noninvasive detection of activating estrogen receptor 1 (ESR1) mutations in estrogen receptor-positive metastatic breast cancer. Clin Chem. 2015;61:974–982. doi: 10.1373/clinchem.2015.238717.
    1. Yanagawa T, Kagara N, Miyake T, Tanei T, Naoi Y, Shimoda M, et al. Detection of ESR1 mutations in plasma and tumors from metastatic breast cancer patients using next-generation sequencing. Breast Cancer Res Treat. 2017;163:231–240. doi: 10.1007/s10549-017-4190-z.
    1. Fribbens C, Garcia Murillas I, Beaney M, Hrebien S, O’Leary B, Kilburn L, et al. Tracking evolution of aromatase inhibitor resistance with circulating tumour DNA analysis in metastatic breast cancer. Ann Oncol Off J Eur Soc Med Oncol. 2018;29:145–153. doi: 10.1093/annonc/mdx483.
    1. Dawson S-J, Tsui DWY, Murtaza M, Biggs H, Rueda OM, Chin S-F, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013;368:1199–1209. doi: 10.1056/NEJMoa1213261.
    1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer Oxf Engl 1990. 2009;45:228–247.
    1. O’Leary B, Hrebien S, Morden JP, Beaney M, Fribbens C, Huang X, et al. Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer. Nat Commun. 2018;9:896. doi: 10.1038/s41467-018-03215-x.
    1. Gilson P. Enrichment and analysis of ctDNA. Recent Results Cancer Res Fortschritte Krebsforsch Progres Dans Rech Sur Cancer. 2020;215:181–211. doi: 10.1007/978-3-030-26439-0_10.
    1. Martoni A, Zamagni C, Bellanova B, Zanichelli L, Vecchi F, Cacciari N, et al. CEA, MCA, CA 15.3 and CA 549 and their combinations in expressing and monitoring metastatic breast cancer: a prospective comparative study. Eur J Cancer Oxf Engl 1990. 1995;31A:1615–1621.
    1. Kurebayashi J, Yamamoto Y, Tanaka K, Kohno N, Kurosumi M, Moriya T, et al. Significance of serum carcinoembryonic antigen and CA 15-3 in monitoring advanced breast cancer patients treated with systemic therapy: a large-scale retrospective study. Breast Cancer Tokyo Jpn. 2003;10:38–44. doi: 10.1007/BF02967624.
    1. Tampellini M, Berruti A, Bitossi R, Gorzegno G, Alabiso I, Bottini A, et al. Prognostic significance of changes in CA 15-3 serum levels during chemotherapy in metastatic breast cancer patients. Breast Cancer Res Treat. 2006;98:241–248. doi: 10.1007/s10549-005-9155-y.
    1. Laessig D, Nagel D, Heinemann V, Untch M, Kahlert S, Bauerfeind I, et al. Importance of CEA and CA 15-3 during disease progression in metastatic breast cancer patients. Anticancer Res. 2007;27:1963–1968.
    1. Sölétormos G, Nielsen D, Schiøler V, Mouridsen H, Dombernowsky P. Monitoring different stages of breast cancer using tumour markers CA 15-3, CEA and TPA. Eur J Cancer Oxf Engl 1990. 2004;40:481–486.
    1. Kurebayashi J, Nishimura R, Tanaka K, Kohno N, Kurosumi M, Moriya T, et al. Significance of serum tumor markers in monitoring advanced breast cancer patients treated with systemic therapy: a prospective study. Breast Cancer Tokyo Jpn. 2004;11:389–395. doi: 10.1007/BF02968047.
    1. Perrier A, Boelle P-Y, Chrétien Y, Gligorov J, Lotz J-P, Brault D, et al. An updated evaluation of serum sHER2, CA15.3, and CEA levels as biomarkers for the response of patients with metastatic breast cancer to trastuzumab-based therapies. PloS One. 2020;15:e0227356. doi: 10.1371/journal.pone.0227356.
    1. Shaw JA, Guttery DS, Hills A, Fernandez-Garcia D, Page K, Rosales BM, et al. Mutation analysis of cell-free DNA and single circulating tumor cells in metastatic breast cancer patients with high circulating tumor cell counts. Clin Cancer Res Off J Am Assoc Cancer Res. 2017;23:88–96. doi: 10.1158/1078-0432.CCR-16-0825.
    1. Ye Z, Wang C, Wan S, Mu Z, Zhang Z, Abu-Khalaf MM, et al. Association of clinical outcomes in metastatic breast cancer patients with circulating tumour cell and circulating cell-free DNA. Eur J Cancer Oxf Engl 1990. 2019;106:133–143.
    1. Thierry AR, El Messaoudi S, Gahan PB, Anker P, Stroun M. Origins, structures, and functions of circulating DNA in oncology. Cancer Metastasis Rev. 2016;35:347–376. doi: 10.1007/s10555-016-9629-x.
    1. Fernandez-Garcia D, Hills A, Page K, Hastings RK, Toghill B, Goddard KS, et al. Plasma cell-free DNA (cfDNA) as a predictive and prognostic marker in patients with metastatic breast cancer. Breast Cancer Res BCR. 2019;21:149. doi: 10.1186/s13058-019-1235-8.
    1. O’Leary B, Cutts RJ, Liu Y, Hrebien S, Huang X, Fenwick K, et al. The genetic landscape and clonal evolution of breast cancer resistance to palbociclib plus fulvestrant in the PALOMA-3 trial. Cancer Discov. 2018;8:1390–1403. doi: 10.1158/-18-0264.
    1. Garcia-Murillas Isaac, Chopra Neha, Comino-Méndez Iñaki, Beaney Matthew, Tovey Holly, Cutts Rosalind J., Swift Claire, Kriplani Divya, Afentakis Maria, Hrebien Sarah, Walsh-Crestani Giselle, Barry Peter, Johnston Stephen R. D., Ring Alistair, Bliss Judith, Russell Simon, Evans Abigail, Skene Anthony, Wheatley Duncan, Dowsett Mitch, Smith Ian E., Turner Nicholas C. Assessment of Molecular Relapse Detection in Early-Stage Breast Cancer. JAMA Oncology. 2019;5(10):1473. doi: 10.1001/jamaoncol.2019.1838.
    1. Coombes RC, Page K, Salari R, Hastings RK, Armstrong A, Ahmed S, et al. Personalized detection of circulating tumor DNA antedates breast cancer metastatic recurrence. Clin Cancer Res Off J Am Assoc Cancer Res. 2019;25:4255–4263. doi: 10.1158/1078-0432.CCR-18-3663.

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