Assessment of Genomic Test Impact on Shared Decision of Adjuvant Chemotherapy in ER-positive, Her2-negative Early Breast Cancer (OPTIGEN)

Prospective Multicenter Randomized Study Assessing Genomic Test Impact on Shared Decision of Adjuvant Chemotherapy in Patients With ER-positive, Her2-negative Early Breast Cancer With Uncertainty on the Indication of Chemotherapy Using Standard Assessments.

The need/benefit of adjuvant chemotherapy could be negligible for a certain category of patient with newly diagnosed unilateral non metastatic breast cancer. Physicians are sometimes divided between the administration of adjuvant treatment and no administration when the risk of distant relapse at 10 years is around 10% with uncertainty and a theoretical benefit of chemotherapy is less than 5% at 10 years according to guidelines in use in the center.

Several genomic tests have been developed this last decade. These tests use a sample of breast cancer tissue to analyze the activity of a group of genes. Knowing whether certain genes are present or absent, overly active or not active enough, can help physicians predict the risk of recurrence.

In addition to standard pathological characteristics, a genomic test could be helpful in making treatment decisions, such as whether or not chemotherapy should be part of the treatment plan. First generation prognostic tests are currently widely used worldwide to guide decision making regarding adjuvant chemotherapy (OncotypeDX™ Mammaprint®). Prognostic tests have reached a level of evidence 1A, with the results of the prospective randomized trial "Mindact". In the "Mindact" trial, among women with early-stage breast cancer who were at high clinical risk and low genomic risk for recurrence, the receipt of no chemotherapy on the basis of the 70-gene signature led to a 5-year rate of survival without distant metastasis that was 1.5 percentage points lower than the rate with chemotherapy. Given these findings, approximately 46% of women with breast cancer who are at high clinical risk might not require chemotherapy. The health-economic value of such signatures in the general population of patients with localized breast cancer appears very low at current costs.

Meanwhile, next generation prognostic signatures have been developed that have integrated clinical parameters and suggest high added value beyond all standard and traditional characteristics including tumor burden, grade, Estrogen Receptor (ER) and Progesterone Receptor (PR), Her2, age and also standard assessment of proliferation.

In this study, the clinical utility of genomic tests (Endopredict®, Prosigna®, OncotypeDX®, Mammaprint® assay) defined as impact on chemotherapy decision in the adjuvant setting in patients with ER-positive, Her2-negative early breast cancer with uncertainty on the indication of chemotherapy using standard assessments will be compared.

Study Overview

• Status: Withdrawn
• Conditions: ER-positive Her2-negative Early Breast Cancer
• Intervention / Treatment: Diagnostic test: Genomic test

• Study Type: Interventional
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Woman, Age ≥ 18 years;
2. Performance status 0 or 1 (according to World Health Organization criteria);
3. Patient with newly diagnosed, unilateral, localized, histologically confirmed, invasive breast cancer; Note: Multicentric/multifocal tumors are allowed provided a maximum of 3 lesions are present, and all are ER > 10% or Allred ≥ 4, Her2-negative (genomic test will be performed on the lesion considered the most pertinent by the multidisciplinary team)
4. Fully operated breast cancer including complete resection of breast tumor and adequate axillary surgery;
5. Available surgical material (formalin-fixed, paraffin-embedded) for genomic test evaluation;
6. ER-positive by immuno-histochemical (>10% cells stained or Allred Score≥4);
7. HER2-negative by IHC (score 0 or 1+) and/or fluorescence in situ hybridization/silver in situ hybridization/chemiluminescent in situ hybridization ;

8. Uncertainty regarding the toxicity/benefit of adjuvant chemotherapy, outlined in the following situations:

   • Grade 1: pT3 or 1-3 node positive
   • Grade 2: pT1 pN0 but high proliferation (Ki67 >20%) or lympho-vascular emboli, or 1-3 node positive
   • Grade 2 : pT2 pN0
   • Grade 3: pT1 pN0
9. Adequate renal, hepatic, cardiac and hematopoietic functions for a chemotherapy administration;
10. Willingness and ability to comply with scheduled visits as well as with test results and chemotherapy decision according to the latest;
11. Signed informed consent and Health insurance coverage.

Exclusion Criteria:

1. Non operable, bilateral, locally advanced, T4 or metastatic breast cancer;
2. HER2 Overexpression, as assessed by 3+ IHC or FISH/SISH/CISH amplification;
3. Diagnosis of any previous malignancy within the last 5 years, except for adequately treated basal cell carcinoma, or squamous cell skin carcinoma, or in situ cervical carcinoma;
4. Any previous systemic or locoregional treatment for the present breast cancer;
5. Documented inherited predisposition with BRCA1/2 or TP53 mutation;
6. Previous hormone replacement therapy (HRT) stopped less than 2 weeks before surgery;
7. Previous treatment for the present breast cancer;
8. Person unable to give informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: DIAGNOSTIC
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Endopredict®; genomic test Endopredict® realized on surgery tumour samples	Diagnostic test: Genomic test; genomic test realized on surgery block or formalin-fixed paraffin-embedded slides
ACTIVE_COMPARATOR: Prosigna®; genomic test Prosigna® realized on surgery tumour samples	Diagnostic test: Genomic test; genomic test realized on surgery block or formalin-fixed paraffin-embedded slides
ACTIVE_COMPARATOR: OncotypeDX®; genomic test OncotypeDX® realized on surgery tumour samples	Diagnostic test: Genomic test; genomic test realized on surgery block or formalin-fixed paraffin-embedded slides
ACTIVE_COMPARATOR: Mammaprint® assay; genomic test Mammaprint® assay realized on surgery tumour samples	Diagnostic test: Genomic test; genomic test realized on surgery block or formalin-fixed paraffin-embedded slides

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of genomic tests clinical utility	Pairwise comparisons between genomic tests in terms of percentage of changes between initial adjuvant chemotherapy decision and final receipt of chemotherapy (yes/no)	At the end of the inclusion period: 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Distant disease-free survival in patients who do not receive chemotherapy	5-year distant disease-free survival among the pooled cohort of patients who did not receive chemotherapy	5 years
Distant disease-free survival in patients who do not receive chemotherapy based on genomic test result.	5-year distant disease-free survival in patients who did not receive chemotherapy based on genomic test result	5 years
Reason for discordant final decision when they occur	Number of decision changes according to the test results. Physicians' and patients' reasons for "non-compliance" with the test's results will be recorded (a threshold at 10% 10 year distant recurrence risk will be chosen)	12 months
Feasibility of test in terms of time interval.	Time interval between prescription and result of the test (% < 10 days)	12 months
differences in results between local and central reading of ER, PR, Her2 and Ki67	A comparison with local evaluation of HR, Her2, and ki-67 will be made	12 months
Change of therapy based on the genomic test findings in a virtual tumour board	Choice of therapy in a virtual tumour board based on the genomic test findings	12 months
Evaluation of the cost effectiveness of genomic tests	Medico-economic impact based on results of the "Optisoin 01" study	5 years

Collaborators and Investigators

• Sponsor: UNICANCER
• Investigators: Principal Investigator: Roman Rouzier, MD, Institut Curie

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): May 1, 2017
• Primary Completion (ANTICIPATED): June 1, 2018
• Study Completion (ANTICIPATED): May 1, 2023

Study Registration Dates

• First Submitted: March 9, 2017
• First Submitted That Met QC Criteria: March 9, 2017
• First Posted (ACTUAL): March 15, 2017

Study Record Updates

• Last Update Posted (ACTUAL): August 28, 2017
• Last Update Submitted That Met QC Criteria: August 25, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: Breast cancer; ER-positive; Her-2 negative; genomic test
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms
• Other Study ID Numbers: UC-0140/1620; 2016-A01731-50 (OTHER: Id-RCB); UCBG 2-15 (OTHER: UNICANCER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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