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
- Conditions
- Breast Cancer
- Interventions
- Drug: HORMONOTHERAPYDrug: CHEMOTHERAPY then HORMONOTHERAPY
- Registration Number
- NCT01564056
- Lead Sponsor
- UNICANCER
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- Female
- Target Recruitment
- 1989
- 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.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm A: ENDOCRINE TREATMENT HORMONOTHERAPY HORMONOTHERAPY (Tamoxifen, aromatase inhibitor or sequential hormonotherapy) is left to the investigator judgement in both groups (I and II). Arm B: CHEMOTHERAPY + ENDOCRINE TREATMENT CHEMOTHERAPY then HORMONOTHERAPY HORMONOTHERAPY (Tamoxifen, aromatase inhibitor or sequential hormonotherapy) is left to the investigator judgement in both groups (I and II). CHEMOTHERAPY regimen will be chosen amongst the following ones: * TC (docetaxel + cyclophosphamide) * AC (doxorubicin + cyclophosphamide) * MC (liposomal non pegylated doxorubicin \[Myocet®\]+ cyclophosphamide)
- Primary Outcome Measures
Name Time Method Overall survival Median follow-up = 4 years The OS is defined as the interval between the date of randomization and the date of death from any cause.
- Secondary Outcome Measures
Name Time Method Four-Year Mortality Index for Older Adults(Lee Score) At the inclusion A 4-year mortality score including items depicting functional status, nutritional status and comorbidities, three key issues in elderly, will be systematically calculated.
Event-free survival (ESF) median follow-up = 4 years 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.
Acute and late toxicity during the study Throughout treatment completion, up to 4 years 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.
Quality of life questionnaire - Elderly cancer patients (QLQ-ELD15) At baseline, week 16, 5 months, 6 months, 1 year, 2 years, 3 years, and 4 years The EORTC QLQ-ELD15, a validated HRQOL questionnaire for cancer patients aged greater than or equal to 70 years, is intended to supplement the QLQ-C30.
The QLQ-ELD15 contains 15 items incorporating five scales to assess mobility, family support, worries about future, autonomy and maintaining purpose, and burden of illness. All items are rated on a four-point Likert-type scale (1 = "not at all", 2 = "a little", 3 = "quite a bit", and 4 = "very much"), and are linearly transformed to a 0-100 scale. High scores indicate poor mobility, good family support, less worried about the future, poor autonomy and maintaining purpose, and high burden of illness.Usefulness of GG by RT-PCR two weeks after surgery (local histo. and GG test) then after inclusions are performed (central histo.) The prognostic signature of the GG test will be evaluated in an elderly population by comparison to standardized routine histopathological criteria and to the results obtained in the general non elderly population. In the whole cohort (n=2000) results of the GG will be compared to routine histopathological characteristics (pN, histological grade, mitotic count, Ki67 index, determination of Elston and Ellis histological grade) as determined locally or centrally for assessment of patient prognosis.
Specific overall survival median follow-up = 4 years 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
Disease-free survival (DFS) median follow-up = 4 years 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.
Geriatric Assessment at the end of the chemotherapy in arm B or 16 weeks after the randomization in arm A (endocrine treatment only), and then each year during a 4-year follow-up period, for both arms the geriatric questionnaires (CCI \& listing comedications, G8, IADL or MMSE) will be completed by a geriatrician or a person trained to geriatric assessment before randomization, at the end of the chemotherapy in arm B or 16 weeks after the randomization in arm A (endocrine treatment only), and then each year during a 4-year follow-up period, for both arms.
Quality of life questionnaire - Core 30 (QLQ-C30) At baseline, week 16, 5 months, 6 months, 1 year, 2 years, 3 years, and 4 years Developed by the EORTC, this self-reported questionnaire assesses the health-related quality of life of cancer patients in clinical trials.
The questionnaire includes five functional scales (physical, everyday activity, cognitive, emotional, and social), three symptom scales (fatigue, pain, nausea and vomiting), a health/quality of life overall scale, and a number of additional elements assessing common symptoms (including dyspnea, loss of appetite, insomnia, constipation, and diarrhea), as well as, the perceived financial impact of the disease.
All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.Cost-effectiveness analysis at the end of the chemotherapy in arm B or 16 weeks after randomization in arm A, and then each year during a 4-year follow-up period, for both arms of the group I. In parallel with efficacy analysis, measured by an objective clinical result indicator of state of health, such as the number of year gained (overall survival), costs for the two treatment strategies (endocrine treatment only or endocrine treatment and chemotherapy) in adjuvant systematic treatment will be also estimated. This study should provide information for decision-makers about the incremental efficacy obtained in relation to the incremental cost.
Trial Locations
- Locations (84)
Centre Jean Perrin
🇫🇷Clermont Ferrand, France
Grand Hopital de Charleroi (GHdC)
🇧🇪Charleroi, Belgium
CHU Ambroise Paré
🇧🇪Mons, Belgium
CH d'Ardèche méridionale
🇫🇷Aubenas, France
Centre Paul Papin
🇫🇷Angers, France
Clinique du Sud Luxembourg
🇧🇪Arlon, Belgium
Cliniques universitaires Saint-Luc - UCL
🇧🇪Bruxelles, Belgium
Centre Hospitalier de l'Ardenne
🇧🇪Libramont, Belgium
CHU Mont-Godinne
🇧🇪Yvoir, Belgium
Centre Hôspitalier de Wallonie Picarde (CHWAPI)
🇧🇪Tournai, Belgium
Institut Sainte Catherine
🇫🇷Avignon, France
CHPLT Verviers
🇧🇪Verviers, Belgium
Hôpital INDC entité Jolimontoise
🇧🇪Haine-Saint-Paul, Belgium
CHC - Les Cliniques Saint-Joseph
🇧🇪Liege, Belgium
Clinique et Maternité Sainte-Elisabeth
🇧🇪Namur, Belgium
Centre Hospitalier Alpes Léman
🇫🇷Contamine Sur Arve, France
Hôpital Henri Mondor
🇫🇷Creteil, France
CH du Mans
🇫🇷Le Mans, France
Groupe Hospitalier Paris St Joseph
🇫🇷Paris, France
Centre Hospitalier de Bretagne Sud
🇫🇷Lorient, France
Centre Antoine Lacassagne
🇫🇷Nice, France
CHR d'Orléans
🇫🇷Orleans, France
Centre Val d'Aurelle - Paul Lamarque
🇫🇷Montpellier, France
Groupe Hospitalier des Diaconesses - Croix Saint Simon
🇫🇷Paris, France
Polyclinique de Francheville
🇫🇷Perigueux, France
Clinique Saint Jean du Languedoc
🇫🇷Toulouse, France
Centre Alexis Vautrin
🇫🇷Vandoeuvre Les Nancy, France
Institut Claudius Regaud
🇫🇷Toulouse, France
CH Bretagne Atlantique
🇫🇷Vannes, France
CH de Cholet
🇫🇷Cholet, France
Centre Oscar Lambret
🇫🇷Lille, France
Clinique Victor Hugo
🇫🇷Le Mans, France
Centre Léon Bérard
🇫🇷Lyon, France
CH Layné
🇫🇷Mont de Marsan, France
Clinique du Pont de Chaume
🇫🇷Montauban, France
Institut du Cancer Courlancy
🇫🇷Reims, France
Centre Henri Becquerel
🇫🇷Rouen, France
Centre Eugène Marquis
🇫🇷Rennes, France
CH de Rodez
🇫🇷Rodez, France
ICO -Centre René Gauducheau
🇫🇷Saint-Herblain, France
Clinique Sainte Marguerite
🇫🇷Hyeres, France
Cliniques Saint-Pierre Ottignies
🇧🇪Ottignies, Belgium
Clinique Claude Bernard
🇫🇷Albi, France
Hôpital Avicenne
🇫🇷Bobigny, France
Polyclinique Urbain V
🇫🇷Avignon, France
Centre François Baclesse
🇫🇷Caen Cedex 05, France
Centre Hospitalier René Dubos
🇫🇷Cergy -pontoise, France
Institut Bergonié
🇫🇷Bordeaux, France
CHU de Brest
🇫🇷Brest, France
Groupement Hospitalier Public du Sud de l'Oise - site de Creil
🇫🇷Creil, France
Hôpital Antoine Béclère
🇫🇷Clamart, France
Centre d'oncologie et de radiothérapie du Parc
🇫🇷Dijon, France
CH Jean Monnet
🇫🇷Epinal, France
CH de Dax
🇫🇷DAX, France
CHI de Créteil
🇫🇷Creteil, France
Centre Georges-François Leclerc
🇫🇷Dijon, France
Clinique Hartmann
🇫🇷Levallois-perret, France
CHD de Vendée
🇫🇷La Roche Sur Yon, France
CHU de Limoges
🇫🇷Limoges, France
CH de Lagny sur Marne
🇫🇷Lagny Sur Marne, France
Centre Hospitalier Intercommunal de Meulan - Les Mureaux
🇫🇷Meulan-en-Yvelines, France
Institut Paoli-Calmettes
🇫🇷Marseille, France
CH de Mâcon - Les Chanaux
🇫🇷Mâcon, France
Institut Jean Godinot
🇫🇷Reims, France
Institut Curie - Hôpital Claudius Regaud
🇫🇷Paris, France
CHI Poissy Saint Germain
🇫🇷Saint Germain En Laye, France
CHU de Poitiers
🇫🇷Poitiers, France
Centre Hospitalier Lyon Sud
🇫🇷Pierre Benite, France
CH de la Région d'Annecy
🇫🇷Pringy, France
Clinique Mathilde
🇫🇷Rouen, France
Clinique Mutualiste de l'Estuaire
🇫🇷Saint-nazaire, France
CHP Saint Grégoire
🇫🇷Saint Gregoire, France
Institut de Cancérologie de la Loire
🇫🇷Saint Priest En Jarez, France
Institut Curie - Hôpital René Huguenin
🇫🇷Saint-cloud, France
CH de Senlis
🇫🇷Senlis, France
RISSA Sarcelles (GCS Recherche & Innovation Santé Sarcelles)
🇫🇷Sarcelles, France
Centre Paul Strauss
🇫🇷Strasbourg, France
Hôpitaux Universitaires de Strasbourg
🇫🇷Strasbourg, France
Strasbourg Oncologie Libérale
🇫🇷Strasbourg, France
Clinique Pasteur
🇫🇷Toulouse, France
Hopitaux du Léman
🇫🇷Thonon-les-bains, France
CHI de Toulon - Hopital Sainte Musse
🇫🇷Toulon, France
Centre Saint Yves
🇫🇷Vannes, France
Institut Gustave Roussy
🇫🇷Villejuif, France