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

Adjuvant Systemic Treatment for Oestrogen-receptor (ER)-Positive HER2-negative Breast Carcinoma in Women Over 70 According to Genomic Grade (GG): Chemotherapy + Endocrine Treatment Versus Endocrine Treatment. A French UNICANCER Geriatric Oncology Group (GERICO) and Breast Group (UCBG) Multicentre Phase III Trial

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.

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.