Monitoring luminAl Breast Cancer Through the Evaluation of Mutational and epiGeNEtic alteraTIons of Circulating ESR1 DNA

Breast Neoplasms Clinical Trial

— MAGNETIC1  

Official title:

Monitoring luminAl Breast Cancer Through the Evaluation of Mutational and epiGeNEtic alteraTIons of Circulating ESR1 DNA

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05814224
• Other study ID #: 2018.016
• Status: Recruiting
• Phase: N/A
• Start date: May 22, 2018
• Est. completion date: December 2024

Study information

• Verified date: March 2023
• Source: Centro di Riferimento Oncologico - Aviano
• Contact: Fabio Puglisi, MD
• Phone: 0434 659310
• Email: fabio.puglisi[@]cro.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of the study is to determine the diagnostic role of ctDNA when used to monitor metastatic breast cancer (MBC) during first-line endocrine therapy.

Description:

Patients with hormone receptor-positive MBC are eligible for endocrine therapy (ET) as first line treatment which is based on strategies aimed to either block signaling pathways depending on the estrogen receptor (ESR1) or using ESR1 antagonists. Only a few accepted predictive factors are associated with treatment benefit for MBC (i.e., hormone receptor status and HER2 status). Furthermore, a standardized assessment evaluation for MBC is still lacking. Because of these unmet needs, ET is continued until disease progression, or if toxicity requiring discontinuation occurs. Resistance is frequent in the treatment of early BC and unavoidable in MBC. Recently, mutations in ESR1 have been described in MBC that had been previously exposed to aromatase inhibitors (AIs) and are rarely detectable in primary BC. Besides that, resistance phenomena have been also linked to ESR1 cisregulatory elements (CRE, i.e. enhancers and promoters) hypermethylation, both related to ESR1 silencing.

According to the literature, the aim of the study is to detect tumor response with liquid biopsy technique compared to conventional clinical pratice algorithms.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 164
• Est. completion date: December 2024
• Est. primary completion date: December 31, 2023
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically proven diagnosis of adenocarcinoma of the breast with evidence of metastatic disease.

• ER positive tumor = 1%

• HER2 negative breast cancer by FISH or IHC (IHC 0,1+, 2+ and/or FISH HER2: CEP17 ratio < 2.0)

• Females, 18 years of age or older

• Candidate to first-line endocrine therapy (LH-RH analogue for premenopausal women is allowed)

• Signed and dated informed consent document indicating that the subject (or legally acceptable representative) has been informed of all the pertinent aspects of the trial prior to enrollment.

• Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.

Exclusion Criteria:

• Diagnosis of any secondary malignancy within the last 3 years, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix.

• Prior endocrine therapy for metastatic disease

Related Conditions & MeSH terms

• Antineoplastic Agents
• Aromatase Inhibitors
• Breast Diseases
• Breast Neoplasms
• ESR1 Gene Mutation
• Hormone Receptor Positive Breast Carcinoma
• Neoplasms
• Neoplasms, Breast

Intervention

Diagnostic Test:
• Liquid biopsy and CT scan
CT scan and liquid biopsy blood sample are performed at baseline, after 8 weeks from baseline and, then, every 12 weeks. Between two subsequent CT scan another liquid biopsy blood sample is performed. CEA and CA 15.3 will be performed at baseline and then concomitantly to the radiological evaluation

Locations

Country	Name	City	State
Italy	Centro di Riferimento Oncologico - Aviano	Aviano	Pordenone
Italy	Asst Papa Giovanni Xxiii- Bergamo	Bergame	Bergamo
Italy	Asst Ospedali Civili Di Brescia	Brescia
Italy	Azienda Ospedaliero Universitaria Policlinico G. Rodolico- San Marco-Catania	Catania
Italy	Universita' Degli Studi Di Napoli Federico Ii	Napoli
Italy	azienda sanitaria universitaria friuli centrale- Udine	Udine
Italy	Ospedale San Bortolo- Azienda Ulss8 Berica	Vicenza

Sponsors (1)

Lead Sponsor	Collaborator
Centro di Riferimento Oncologico - Aviano

Country where clinical trial is conducted

Italy, 

References & Publications (14)

Bonotto M, Gerratana L, Di Maio M, De Angelis C, Cinausero M, Moroso S, Milano M, Stanzione B, Gargiulo P, Iacono D, Minisini AM, Mansutti M, Fasola G, De Placido S, Arpino G, Puglisi F. Chemotherapy versus endocrine therapy as first-line treatment in patients with luminal-like HER2-negative metastatic breast cancer: A propensity score analysis. Breast. 2017 Feb;31:114-120. doi: 10.1016/j.breast.2016.10.021. Epub 2016 Nov 9. — View Citation

Bonotto M, Gerratana L, Iacono D, Minisini AM, Rihawi K, Fasola G, Puglisi F. Treatment of Metastatic Breast Cancer in a Real-World Scenario: Is Progression-Free Survival With First Line Predictive of Benefit From Second and Later Lines? Oncologist. 2015 Jul;20(7):719-24. doi: 10.1634/theoncologist.2015-0002. Epub 2015 May 27. — View Citation

Bonotto M, Gerratana L, Poletto E, Driol P, Giangreco M, Russo S, Minisini AM, Andreetta C, Mansutti M, Pisa FE, Fasola G, Puglisi F. Measures of outcome in metastatic breast cancer: insights from a real-world scenario. Oncologist. 2014 Jun;19(6):608-15. doi: 10.1634/theoncologist.2014-0002. Epub 2014 May 2. — View Citation

Fribbens C, O'Leary B, Kilburn L, Hrebien S, Garcia-Murillas I, Beaney M, Cristofanilli M, Andre F, Loi S, Loibl S, Jiang J, Bartlett CH, Koehler M, Dowsett M, Bliss JM, Johnston SR, Turner NC. Plasma ESR1 Mutations and the Treatment of Estrogen Receptor-Positive Advanced Breast Cancer. J Clin Oncol. 2016 Sep 1;34(25):2961-8. doi: 10.1200/JCO.2016.67.3061. Epub 2016 Jun 6. — View Citation

Jansen MP, Martens JW, Helmijr JC, Beaufort CM, van Marion R, Krol NM, Monkhorst K, Trapman-Jansen AM, Meijer-van Gelder ME, Weerts MJ, Ramirez-Ardila DE, Dubbink HJ, Foekens JA, Sleijfer S, Berns EM. Cell-free DNA mutations as biomarkers in breast cancer patients receiving tamoxifen. Oncotarget. 2016 Jul 12;7(28):43412-43418. doi: 10.18632/oncotarget.9727. — View Citation

Jeselsohn R, Yelensky R, Buchwalter G, Frampton G, Meric-Bernstam F, Gonzalez-Angulo AM, Ferrer-Lozano J, Perez-Fidalgo JA, Cristofanilli M, Gomez H, Arteaga CL, Giltnane J, Balko JM, Cronin MT, Jarosz M, Sun J, Hawryluk M, Lipson D, Otto G, Ross JS, Dvir A, Soussan-Gutman L, Wolf I, Rubinek T, Gilmore L, Schnitt S, Come SE, Pusztai L, Stephens P, Brown M, Miller VA. Emergence of constitutively active estrogen receptor-alpha mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res. 2014 Apr 1;20(7):1757-1767. doi: 10.1158/1078-0432.CCR-13-2332. Epub 2014 Jan 7. — View Citation

Manavalan TT, Teng Y, Appana SN, Datta S, Kalbfleisch TS, Li Y, Klinge CM. Differential expression of microRNA expression in tamoxifen-sensitive MCF-7 versus tamoxifen-resistant LY2 human breast cancer cells. Cancer Lett. 2011 Dec 26;313(1):26-43. doi: 10.1016/j.canlet.2011.08.018. Epub 2011 Sep 10. — View Citation

Martinez-Galan J, Torres-Torres B, Nunez MI, Lopez-Penalver J, Del Moral R, Ruiz De Almodovar JM, Menjon S, Concha A, Chamorro C, Rios S, Delgado JR. ESR1 gene promoter region methylation in free circulating DNA and its correlation with estrogen receptor protein expression in tumor tissue in breast cancer patients. BMC Cancer. 2014 Feb 4;14:59. doi: 10.1186/1471-2407-14-59. — View Citation

Miller TE, Ghoshal K, Ramaswamy B, Roy S, Datta J, Shapiro CL, Jacob S, Majumder S. MicroRNA-221/222 confers tamoxifen resistance in breast cancer by targeting p27Kip1. J Biol Chem. 2008 Oct 31;283(44):29897-903. doi: 10.1074/jbc.M804612200. Epub 2008 Aug 15. — View Citation

Panageas KS, Ben-Porat L, Dickler MN, Chapman PB, Schrag D. When you look matters: the effect of assessment schedule on progression-free survival. J Natl Cancer Inst. 2007 Mar 21;99(6):428-32. doi: 10.1093/jnci/djk091. — View Citation

Sasaki M, Tanaka Y, Perinchery G, Dharia A, Kotcherguina I, Fujimoto Si, Dahiya R. Methylation and inactivation of estrogen, progesterone, and androgen receptors in prostate cancer. J Natl Cancer Inst. 2002 Mar 6;94(5):384-90. doi: 10.1093/jnci/94.5.384. — View Citation

Schiavon G, Hrebien S, Garcia-Murillas I, Cutts RJ, Pearson A, Tarazona N, Fenwick K, Kozarewa I, Lopez-Knowles E, Ribas R, Nerurkar A, Osin P, Chandarlapaty S, Martin LA, Dowsett M, Smith IE, Turner NC. Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer. Sci Transl Med. 2015 Nov 11;7(313):313ra182. doi: 10.1126/scitranslmed.aac7551. — View Citation

Stone A, Zotenko E, Locke WJ, Korbie D, Millar EK, Pidsley R, Stirzaker C, Graham P, Trau M, Musgrove EA, Nicholson RI, Gee JM, Clark SJ. DNA methylation of oestrogen-regulated enhancers defines endocrine sensitivity in breast cancer. Nat Commun. 2015 Jul 14;6:7758. doi: 10.1038/ncomms8758. — View Citation

Toy W, Shen Y, Won H, Green B, Sakr RA, Will M, Li Z, Gala K, Fanning S, King TA, Hudis C, Chen D, Taran T, Hortobagyi G, Greene G, Berger M, Baselga J, Chandarlapaty S. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet. 2013 Dec;45(12):1439-45. doi: 10.1038/ng.2822. Epub 2013 Nov 3. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Liquid-biopsy in monitoring treatment response in luminal breast cancer	The primary objective of this study is to evaluate whether liquid-biopsy technique is able to detect treatment response in luminal breast cancer through the quantification of ESR1 ctDNA mutations	3 years
Secondary	ctDNA/miRNA based follow-up	To characterize the clinical implications of deploying a ctDNA/miRNA based follow-up both in terms of outcome and health systems management.	3 years
Secondary	Treatment resistance mechanisms	To investigate treatment resistance mechanisms and their detectability through ctDNA/miRNA analysis.	3 years
Secondary	Specificity	The proportion of patients correctly classified with a stable or response disease through the genetic and epigenetic analysis of ESR1 ctDNA among those without clinicoradiological relapse.	From baseline until disease progression
Secondary	Positive predictive value	The proportion of patients correctly classified with a progressive disease through the genetic and epigenetic analysis of ESR1 ctDNA (i.e. those patients with molecular progression that is confirmed by clinic-radiological progression) among all patients with molecular progression (i.e. patients who show molecular progression irrespectively of clinic-radiological progression).	3 years
Secondary	Negative predictive value	The proportion of patients correctly classified with a stable or response among those without clinico-radiological relapse.	3 years
Secondary	Accuracy	Accuracy of the ESR1 ctDNA test in respect to correctly classify the patients with clinicoradiological relapse and without clinico-radiological relapse at 6 months.	6 months
Secondary	Lead time (for PFS)	The time elapsed between the molecular detected progression and the imaging assessed one.	3 years
Secondary	Number of futile diagnostic imaging	The number of imaging evaluations negative for progression and that could be avoided with the liquid biopsy technique.	3 years
Secondary	Time to Progression (TTP)	The time from first biomarker assessment until objective tumor progression.	3 years
Secondary	Progression Free Survival (PFS)	The time from first biomarker assessment until objective tumor progression or death for any cause, whichever comes first.	3 years
Secondary	Overall Survival (OS)	The time from first biomarker assessment until death from any cause.	3 years
Secondary	Overall Response Rate (ORR)	The sum of partial responses (PR) and complete responses (CR) evaluated from the time of first biomarker assessment to documented disease progression.	3 years