Clinical trial NCT01564056: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Breast Cancer
Keywords: Adjuvant systemic treatment
Breast cancer
Elderly patients
Lead sponsor: UNICANCER
Sponsor class: OTHER
First posted: 2012-03-27
Enrollment: 1989
Sex: FEMALE
Minimum age (years): 70
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Overall survival
timeFrame: Median follow-up = 4 years
Secondary outcomes:
measure: Specific overall survival
timeFrame: median follow-up = 4 years
measure: Disease-free survival (DFS)
timeFrame: median follow-up = 4 years
measure: Event-free survival (ESF)
timeFrame: median follow-up = 4 years
measure: Acute and late toxicity during the study
timeFrame: Throughout treatment completion, up to 4 years
measure: Geriatric Assessment
timeFrame: 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
measure: Four-Year Mortality Index for Older Adults(Lee Score)
timeFrame: At the inclusion
measure: Quality of life questionnaire - Core 30 (QLQ-C30)
timeFrame: At baseline, week 16, 5 months, 6 months, 1 year, 2 years, 3 years, and 4 years
measure: Quality of life questionnaire - Elderly cancer patients (QLQ-ELD15)
timeFrame: At baseline, week 16, 5 months, 6 months, 1 year, 2 years, 3 years, and 4 years
measure: Usefulness of GG by RT-PCR
timeFrame: two weeks after surgery (local histo. and GG test) then after inclusions are performed (central histo.)
measure: Cost-effectiveness analysis
timeFrame: 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.
Other outcomes:
Locations:
city: Arlon
country: Belgium
facility: Clinique du Sud Luxembourg
city: Bruxelles
country: Belgium
facility: Cliniques universitaires Saint-Luc - UCL
city: Charleroi
country: Belgium
facility: Grand Hopital de Charleroi (GHdC)
city: Haine-Saint-Paul
country: Belgium
facility: Hôpital INDC entité Jolimontoise
city: Libramont
country: Belgium
facility: Centre Hospitalier de l'Ardenne
city: Liege
country: Belgium
facility: CHC - Les Cliniques Saint-Joseph
city: Mons
country: Belgium
facility: CHU Ambroise Paré
city: Namur
country: Belgium
facility: Clinique et Maternité Sainte-Elisabeth
city: Ottignies
country: Belgium
facility: Cliniques Saint-Pierre Ottignies
city: Tournai
country: Belgium
facility: Centre Hôspitalier de Wallonie Picarde (CHWAPI)
city: Verviers
country: Belgium
facility: CHPLT Verviers
city: Yvoir
country: Belgium
facility: CHU Mont-Godinne
city: Albi
country: France
facility: Clinique Claude Bernard
city: Angers
country: France
facility: Centre Paul Papin
city: Aubenas
country: France
facility: CH d'Ardèche méridionale
city: Avignon
country: France
facility: Institut Sainte Catherine
city: Avignon
country: France
facility: Polyclinique Urbain V
city: Bobigny
country: France
facility: Hôpital Avicenne
city: Bordeaux
country: France
facility: Institut Bergonié
city: Brest
country: France
facility: CHU de Brest
city: Caen Cedex 05
country: France
facility: Centre François Baclesse
city: Cergy -pontoise
country: France
facility: Centre Hospitalier René Dubos
city: Cholet
country: France
facility: CH de Cholet
city: Clamart
country: France
facility: Hôpital Antoine Béclère
city: Clermont Ferrand
country: France
facility: Centre Jean Perrin
city: Contamine Sur Arve
country: France
facility: Centre Hospitalier Alpes Léman
city: Creil
country: France
facility: Groupement Hospitalier Public du Sud de l'Oise - site de Creil
city: Creteil
country: France
facility: CHI de Créteil
city: Creteil
country: France
facility: Hôpital Henri Mondor
city: DAX
country: France
facility: CH de Dax
city: Dijon
country: France
facility: Centre d'oncologie et de radiothérapie du Parc
city: Dijon
country: France
facility: Centre Georges-François Leclerc
city: Epinal
country: France
facility: CH Jean Monnet
city: Hyeres
country: France
facility: Clinique Sainte Marguerite
city: La Roche Sur Yon
country: France
facility: CHD de Vendée
city: Lagny Sur Marne
country: France
facility: CH de Lagny sur Marne
city: Le Mans
country: France
facility: CH du Mans
city: Le Mans
country: France
facility: Clinique Victor Hugo
city: Levallois-perret
country: France
facility: Clinique Hartmann
city: Lille
country: France
facility: Centre Oscar Lambret
city: Limoges
country: France
facility: CHU de Limoges
city: Lorient
country: France
facility: Centre Hospitalier de Bretagne Sud
city: Lyon
country: France
facility: Centre Léon Bérard
city: Marseille
country: France
facility: Institut Paoli-Calmettes
city: Meulan-en-Yvelines
country: France
facility: Centre Hospitalier Intercommunal de Meulan - Les Mureaux
city: Mont de Marsan
country: France
facility: CH Layné
city: Montauban
country: France
facility: Clinique du Pont de Chaume
city: Montpellier
country: France
facility: Centre Val d'Aurelle - Paul Lamarque
city: Mâcon
country: France
facility: CH de Mâcon - Les Chanaux
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Orleans
country: France
facility: CHR d'Orléans
city: Paris
country: France
facility: Groupe Hospitalier Paris St Joseph
city: Paris
country: France
facility: Groupe Hospitalier des Diaconesses - Croix Saint Simon
city: Paris
country: France
facility: Institut Curie - Hôpital Claudius Regaud
city: Perigueux
country: France
facility: Polyclinique de Francheville
city: Pierre Benite
country: France
facility: Centre Hospitalier Lyon Sud
city: Poitiers
country: France
facility: CHU de Poitiers
city: Pringy
country: France
facility: CH de la Région d'Annecy
city: Reims
country: France
facility: Institut du Cancer Courlancy
city: Reims
country: France
facility: Institut Jean Godinot
city: Rennes
country: France
facility: Centre Eugène Marquis
city: Rodez
country: France
facility: CH de Rodez
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Rouen
country: France
facility: Clinique Mathilde
city: Saint Germain En Laye
country: France
facility: CHI Poissy Saint Germain
city: Saint Gregoire
country: France
facility: CHP Saint Grégoire
city: Saint Priest En Jarez
country: France
facility: Institut de Cancérologie de la Loire
city: Saint-cloud
country: France
facility: Institut Curie - Hôpital René Huguenin
city: Saint-Herblain
country: France
facility: ICO -Centre René Gauducheau
city: Saint-nazaire
country: France
facility: Clinique Mutualiste de l'Estuaire
city: Sarcelles
country: France
facility: RISSA Sarcelles (GCS Recherche & Innovation Santé Sarcelles)
city: Senlis
country: France
facility: CH de Senlis
city: Strasbourg
country: France
facility: Centre Paul Strauss
city: Strasbourg
country: France
facility: Hôpitaux Universitaires de Strasbourg
city: Strasbourg
country: France
facility: Strasbourg Oncologie Libérale
city: Thonon-les-bains
country: France
facility: Hopitaux du Léman
city: Toulon
country: France
facility: CHI de Toulon - Hopital Sainte Musse
city: Toulouse
country: France
facility: Clinique Pasteur
city: Toulouse
country: France
facility: Clinique Saint Jean du Languedoc
city: Toulouse
country: France
facility: Institut Claudius Regaud
city: Vandoeuvre Les Nancy
country: France
facility: Centre Alexis Vautrin
city: Vannes
country: France
facility: Centre Saint Yves
city: Vannes
country: France
facility: CH Bretagne Atlantique
city: Villejuif
country: France
facility: Institut Gustave Roussy
Study officials:
affiliation: Institut Curie, Saint Cloud
name: Etienne Brain
role: PRINCIPAL_INVESTIGATOR
References: