Adjuvant Systemic Treatment for (ER)-Positive HER2-negative Breast Carcinoma in Women Over 70 According to Genomic Grade (GG): Chemotherapy + Endocrine Treatment Versus Endocrine Treatment

Phase 3Active Not RecruitingNCT01564056

UNICANCER1,989 enrolled

Overview

The purpose of the study is to evaluate the benefit of adjuvant chemotherapy on overall survival for elderly patients with breast cancer, in a sub group with a high risk of relapse according to Genomic Grade test.

The purpose of this trial is to address the question of the added value of adjuvant chemotherapy on survival in 70+ BC patients with ER+ disease, deemed "at risk of relapse" (pN+ or pN0 with a high prognostic classifier, namely GG by RT-PCR) and planned to receive as well adjuvant endocrine treatment. This benefit will be weighed with the competition exerted by comorbidities on mortality. As in many recently developed trials evaluating specific strategies for the elderly (e.g. CALGB 49907 (8); bevacizumab and colorectal cancer in the PRODIGE 20 elderly program supported by the PHRC 2010), the choice of chemotherapy regimen will be left to the investigator between 3 "standard" ones: TC x 4 (no anthracyclines), AC x 4 or MC x 4 (better cardiac tolerance), in order to obtain enrolment of a less highly selected population, more representative of the general population to the difference of the high selection classically observed in standard oncology trials. In parallel, patients not included in the randomized part (whatever reason) and treated with adjuvant endocrine treatment only will be followed up as a separate observational cohort. 1. Screening All women 70+ having undergone surgery for invasive pN0 or pN+, ER+ HER2- BC, will be screened and invited to participate. Pre-selection will be possible pre-operatively. 2. Prognostic signature After having signed a written informed consent, the prognostic signature Genomic Grade (GG) will be assessed by RT-PCR. 3. Randomization (Group I) Only the patients with a Genomic Grade (GG) considered as high will be randomized (1:1): endocrine treatment only (Arm A) versus endocrine treatment + adjuvant chemotherapy (Arm B). Randomization1:1 between arm A and B will be done using minimization stratified according to pN status (pN+ vs pN0), G8 (≤ vs \> 14), and center. Given (i) the high potential of less cardiotoxic regimen including liposomal formulations for anthracyclines or excluding anthracyclines and (ii) the wish to capture the whole population to depict the heterogeneity of ageing from 70, adjuvant chemotherapy (Arm B) will be left to the choice of investigator amongst 3 standard regimen of same duration, 4 cycles given every 3 weeks + primary prophylactic GCSF: * AC = doxorubicin 60 mg/m² + cyclophosphamide 600 mg/m² * TC = docetaxel 75 mg/m² + cyclophosphamide 600 mg/m² * MC = liposomal non pegylated doxorubicin (Myocet) 60 mg/m² + cyclophosphamide 600 mg/m² 4. Patients not randomized (Group II) Patients not randomized for any reason (low GG, randomization refusal or treatment refusal, etc.) will enter a surveillance program and will be able to participate to other specific geriatric studies (GERICO project to evaluate the impact of comprehensive geriatric assessment on quality of life, treatment administered and BC survival after 75 years; EORTC study to validate the scale specifically developed for elderly ELD15). The Group II will present a triple interest and will participate, together with randomized patients, to achieve the following objectives: * validation of the prognostic value of Genomic Grade and performance of the test in the elderly BC population, as compared to standardized routine histopathological parameters, * translational studies to identify molecular signatures, * collection of descriptive data including comorbidities and polymedication. 5. Endocrine treatment and radiotherapy In both Groups (I and II), the endocrine treatment will be left to the choice of the investigator (tamoxifen, aromatase inhibitor or sequential) and radiotherapy will follow standard guidelines.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

1,989

Conditions

Breast Cancer

Interventions

HORMONOTHERAPYDRUG

Hormonotherapy will be administered during 5 years following chemotherapy when allocated. (Tamoxifen, aromatase inhibitor or sequential hormonotherapy) is left to the investigator judgement in both groups (I and II).

CHEMOTHERAPY then HORMONOTHERAPYDRUG

CHEMOTHERAPY regimen will be chosen amongst the following ones: i) 4 cycles of TC (docetaxel + cyclophosphamide) * Docetaxel 75 mg/m² IV infusion at hospital every 21 days * Cyclophosphamide 600 mg/m² IV infusion at hospital every 21 days ii) 4 cycles of AC (doxorubicin + cyclophosphamide) * Doxorubicin 60 mg/m² IV infusion at hospital every 21 days * Cyclophosphamide 600 mg/m² IV infusion at hospital every 21 days iii) 4 cycles of MC (liposomal non pegylated doxorubicin \[Myocet®\]+ cyclophosphamide) * Myocet® 60 mg/m² IV infusion at hospital every 21 days * Cyclophosphamide 600 mg/m² IV infusion at hospital every 21 days HORMONOTHERAPY (Tamoxifen, aromatase inhibitor or sequential hormonotherapy) is left to the investigator judgement in both groups (I and II).

Eligibility

Sex: FEMALEMin age: 70 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Women aged ≥ 70 yo, * Histologically proven invasive breast cancer (regardless of the type), * Complete surgery performed before enrolment: radical modified mastectomy or breast conservative surgery, with either a sentinel lymph node procedure or axillary lymph node dissection, * Any N status (pN+ or pN0), * No clinically or radiologically detectable metastases (M0), * Oestrogen receptor (ER)-positive, as defined by a ≥ 10% tumor stained cells by immunohistochemistry (IHC), * HER2 negative status (i.e. IHC score 0 or 1+, or IHC score 2+ and FISH/SISH/CISH negative), * Normal haematological function: ANC ≥ 1,500/mm3; platelets count ≥ 100,000/mm3; haemoglobin \> 9 g/dl, * Normal hepatic function: total bilirubin ≤ 1.25 ULN; ASAT and ALAT ≤ 1.5 ULN; alkaline phosphatases ≤ 3 ULN, * Creatinine clearance (MDRD formula) ≥ 40 mL/min, * PS (ECOG) ≤ 2, * Patient able to comply with the protocol, * Patients must have signed a written informed consent form prior to any study specific procedures, including the agreement for the use of archived tumoral material for genomic screening and data collection, * Patients must be affiliated to a Social Health Insurance. Exclusion Criteria: * Any metastatic impairment, including homolateral sub-clavicular node involvement, regardless of its type, * Any tumor ≥ T4a (UICC1987) (cutaneous invasion, deep adherence, inflammatory breast cancer), * ER-negative breast cancer (i.e. \<10% tumor stained cells by IHC), * HER2 overexpression, defined as IHC score 3+ or score 2+ and FISH/SISH/CISH positive, * Any chemotherapy, hormonal therapy or radiotherapy for breast cancer before surgery, * PS (ECOG) ≥ 3, * Any specific contra-indication to the study drugs (including but not limited to hypersensitivity to the study drugs or their components), * Patient deprived of freedom or under tutelage, * Patient unable to comply with the required medical follow-up for geographic, social or psychological reasons.

Locations (84)

Outcomes

Primary Outcomes

Overall survival

The OS is defined as the interval between the date of randomization and the date of death from any cause.

Time frame: Median follow-up = 4 years

Secondary Outcomes

Specific overall survival

The specific OS is defined as the interval between the date of randomization and the date of death due to cancer. Alive patients or dead patients from another cause will be censored at the last follow-up

Time frame: median follow-up = 4 years

Disease-free survival (DFS)

The DFS is defined as the interval between the date of randomization and the date of breast cancer relapse (local, regional or distant) or the date of invasive contralateral breast cancer or death from any cause, whichever occurs first.

Time frame: median follow-up = 4 years

Event-free survival (ESF)

The EFS is defined as the interval between the date of randomization and the date of breast cancer relapse (local, regional or distant) or the date of invasive contralateral breast cancer or the date of second neoplasia, or the date of death from any cause, whichever occurs first.

Time frame: median follow-up = 4 years

Acute and late toxicity during the study

The National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.0 (NCI-CTCAE v4.0) is widely accepted in the community of oncology research as the leading rating scale for adverse events. This scale, divided into 5 grades (1 = "mild", 2 = "moderate", 3 = "severe", 4 = "life-threatening", and 5 = "death") determined by the investigator, will make it possible to assess the severity of the disorders.

Time frame: Throughout treatment completion, up to 4 years

Geriatric Assessment

Data from ClinicalTrials.gov

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