CIrCuLAting Dna ESr1 Gene Mutations Analysis (CICLADES)

Monitoring of ESR1, PIK3CA and AKT ctDNA Mutations During Real-life Followup of Patients With Metastatic Breast Cancer Treated With Aromatase Inhibitors

The estrogen-dependent nature of breast cancer was first reported in 1896 with the publication of George Beatson's observations on the regression of breast cancer following oophorectomy. Endocrine therapy, targeting ER either directly by selective estrogen receptor modulators (SERMs) and pure antagonists or indirectly by aromatase inhibitors (AIs) that block estrogen production, remains the mainstay of treatment of hormone-sensitive breast cancer in the adjuvant and metastatic settings.

Intrinsic (de novo) and acquired endocrine resistance constitutes an important clinical challenge in the treatment of breast cancer and multiple mechanisms are suspected to underlie the emergence of endocrine resistance.

The role of the estrogen receptor (ER), encoded by the ESR1 gene, in normal mammary gland development and the progression of breast cancer is well established. ESR1 mutations, occurring in 10 to 30% of ER-positive metastatic breast cancer resistant to AIs, lead to ligand-independent activation of the ER.

For patients treated with AIs, monitoring of circulating tumour DNA (ctDNA) for ESR1, PIK3CA and AKT1 mutations could permit early detection of resistance to AIs as recently reported during 2016 American Society of Clinical Oncology (ASCO) meeting.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Diagnostic test: next-generation sequencing (NGS)

• Study Type: Interventional
• Enrollment (Actual): 146
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Metz, France, 57070
    • Hôpital Claude Bernard
  • Metz, France, 57085
    • CHR Metz-Thionville
  • Nancy, France
    • Centre d'oncologie Gentilly
  • Reims, France, 51100
    • Institut Jean Godinot
  • Reims, France, 51100
    • Polyclinique de Courlancy
  • Rouen, France, 76038
    • Centre Henri Becquerel
  • Strasbourg, France, 67091
    • CHU Strasbourg
  • Strasbourg, France, 67000
    • Polyclinique de l'Orangerie
  • Strasbourg, France, 67085
    • Clinique Saint Anne
  • Vandœuvre-lès-Nancy, France, 54509
    • Institut de Cancerologie de Lorraine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Female patient aged 18 and older
2. Histologically confirmed estrogen-receptor-positive, HER2-negative breast cancer
3. Proven metastatic (AJCC stage IV) or loco-regionally advanced (AJCC stage III) breast cancer, not amenable to surgery or radiation with curative intent.

4. Indication to treat with first-line endocrine therapy for palliative care.

   • Patients already receiving first-line endocrine therapy can be enrolled up to 6 weeks after start of endocrine therapy.
   • Endocrine therapy can be prescribed in combination with a CDK4/6 inhibitor.
   • One prior regimen of chemotherapy for the treatment of advanced disease is allowed.
   • Prior (neo)adjuvant chemotherapy and/or (neo)adjuvant endocrine therapy is/are allowed; patients with recurrence while on adjuvant endocrine therapy can be enrolled.
5. Patients who can benefit from an additional blood sample of 10ml. The total volume of each sample meets with the indications of the Order in force establishing the list of researches mentioned in 2 ° of Article L. 1121-1 of the Public Health Code.
6. Informed consent explained to, understood by and signed by patient. Patient must be given a copy of informed consent.
7. Patients affiliated to a social security scheme or benefit from a social regime

The prescription of medicinal product(s) is clearly separated from the decision to include the subject in this ISMRC.

Exclusion Criteria:

1. Pregnant or breast-feeding woman.
2. Patient who received any prior systemic hormonal therapy for advanced breast cancer; no more than one prior regimen of chemotherapy for the treatment of advanced disease is allowed.
3. Chemotherapy in combination with endocrine therapy.
4. Targeted therapy, except CDK 4/6 inhibitor, in combination with endocrine therapy.
5. Planned surgery or radiation with curative intent.
6. Other active malignancy.
7. Any concurrent severe and/or uncontrolled medical condition(s) which could compromise participation in the study.
8. Patient whose general state and / or conditions do not permit the collection of the additional blood sample.
9. Patients under guardianship, under curatorship or deprived of liberty.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: experimental

Diagnostic test: next-generation sequencing (NGS); ESR1, PI3KCA and AKT extensive exon sequencing will be performed using NGS (Miseq Illumina) at the Biopathology department, Institut de Cancérologie de Lorraine (ISO15189 certified lab). Samples taken at baseline (t0), at progression (tp) and 3 months before progression (tp-3) will be systematically analyzed. The intermediate samples will be stored and kept for additional studies. Follow up assessment will be performed according to prescriber's directions.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
incidence of ESR1 mutations	1 day

Secondary Outcome Measures

Outcome Measure	Time Frame
incidence of PIK3CA and AKT1 mutations	1 day
prevalence of ESR1, PIK3CA and AKT1 mutations in patients with and without endocrine resistance at enrolment	1 day
prevalence of ESR1, PIK3CA and AKT1 mutations in patients according to mono vs combo therapy.	1 day
prevalence of mutations of other genes of interest included in the panel from the start of treatment to progression or end of follow-up	1 day
ESR1, PIK3CA and AKT1 mutations predictor of progression free survival	1 day

Collaborators and Investigators

• Sponsor: Institut de Cancérologie de Lorraine
• Investigators: Principal Investigator: MASSARD VINCENT, MD, Institut de Cancerologie de Lorraine

Study record dates

Study Major Dates

• Study Start (Actual): December 7, 2017
• Primary Completion (Actual): December 22, 2022
• Study Completion (Actual): December 22, 2022

Study Registration Dates

• First Submitted: October 18, 2017
• First Submitted That Met QC Criteria: October 18, 2017
• First Posted (Actual): October 23, 2017

Study Record Updates

• Last Update Posted (Actual): August 4, 2023
• Last Update Submitted That Met QC Criteria: August 3, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: PIK3CA; circulating tumor DNA; Estrogen-receptor-positive breast cancer; aromatase inhibitor,; ESR1,; AKT; endocrine resistance
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms
• Other Study ID Numbers: 2017-A01767-46

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No