Clinical trial NCT05297617: Deescalation of Endocrine Therapy Duration in Women With HR+ HER2- Breast Cancer at Very Low Risk
Official title: Single-arm Study to De-escalate Adjuvant Endocrine Therapy Duration in Women With HR+ HER2- Breast Cancer at Very Low Risk of Metastasis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Breast Cancer
Lead sponsor: UNICANCER
Sponsor class: OTHER
Collaborators: name: Agendia
First posted: 2022-03-28
Enrollment: 696
Sex: FEMALE
Minimum age (years): 51
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: This is a prospective, national, multicenter, single-arm, interventional, non-threshold crossing phase II study evaluating a therapeutic de-escalation that limits adjuvant hormone therapy to 2 years of aromatase inhibitor
Primary purpose: TREATMENT

Brief summary: Hormone therapy is recommended for five years in all patients with hormone receptor-positive breast cancer, but there is no consensus on its duration in low-risk tumours and especially in postmenopausal women. Adjuvant endocrine therapy (ET) is associated with substantial side effects and long-term decreased quality of life.

Moreover, while it has been shown that ET provides a real benefit in reducing the relapse rate over time, the deterioration in quality of life may also have a negative effect on patient adherence to treatment. It is therefore important to offer treatment to women with low-risk cancer less intensive treatment strategies. If recent trials tested longer durations as compared to 5 years for high-risk cancers, older trials have tested shorter durations. The 5-year duration appeared at that time as the gold standard because of optimal benefit-risk ratios of tamoxifen among high-risk patients. However shorter treatments of 2-3 years were already associated with substantial benefits and may be enough for very low risk patients.

Detailed description: Adjuvant ET is the cornerstone treatment of localized hormone-receptor positive breast cancer, with demonstrated benefits on overall survival (30-40% relative decrease in mortality) but also on the risk of local and contralateral relapse (43-50% relative decrease). While the relative benefit of 5 years ET is identical for small tumors as compared to larger ones, the absolute benefit is much lower, and the risk-benefit ratio may therefore become very questionable given the frequent and impactful side effects of ET. If recent trials tested longer durations as compared to 5 years for high-risk cancers, older trials have tested shorter durations. Five years appeared at that time as the gold standard because of optimal benefit-risk ratios of tamoxifen among rather high-risk patients. However shorter treatments of 2-3 years were already associated with substantial benefits and may be enough for very low risk patients. The purpose of this study is to demonstrate that adjuvant hormone therapy limited to 2 years of antiaromatase in postmenopausal women with a good prognosis can ensure very high survival without metastatic relapse and allows a reduction of side effects and a better quality of life. The 5-year DMFS was excellent in patients with low risk Luminal A tumors who received endocrine therapy.

Eligibility criteria: Inclusion Criteria:

1. Postmenopausal women: Postmenopausal status is defined by any of the following:

   * Prior bilateral oophorectomy
   * Age ≥60 years
   * Age \>50 and \<60 years and amenorrheic for at least 12 months, and follicle-stimulating hormone (FSH) and estradiol in the postmenopausal range
2. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
3. Women with histologically proven invasive unilateral breast cancer Note: In case of a multifocal invasive tumor, all lesions (maximum 3 infiltrating lesions allowed) must be of identical phenotype and low biological risk
4. M0: Not clinically nor radiologically detectable metastases at time of inclusion
5. Primary tumor completely resected and adequate axillary surgery performed, according to current standards
6. IHC expression of the estrogen receptor and/or progesterone receptor ≥50%
7. HER2 negative according to ASCO criteria in immunohistochemistry and/or genomic analysis (HER2 negativity is defined as IHC 0-1+, or \[IHC 2+ and FISH or CISH nonamplified\])
8. No indication of adjuvant chemotherapy
9. pT1 (tumor ≤20 mm), pN0, Grade 1 or Grade 2 OR pT2 (tumor ≤30 mm) and pN0, Grade 1 or Grade 2

   Note 1: patient with Grade 2 pT2pN0 tumor must be aged under 70 years of age and should receive a genomic test as part of standard care (RIHN reimbursement)
10. Patient considered has having a luminal A ultralow risk of metastatic recurrence (i.e.less than 5% risk of metastatic relapse at 10 years) according to MammaPrint® and Blueprint® tests.

    Note 1: To be eligible, MammaPrint index score should be \> +0.355
11. Patients eligible to receive or have recently started (with a maximum of 4 months of adjuvant hormone therapy prior to enrollment) an adjuvant hormone therapy (letrozole, anastrozole, or exemestane)
12. Patient is willing and able to comply with the protocol for the duration of the study including scheduled visits, treatment plan, laboratory tests and other study procedures
13. Patients must be affiliated to a Social Security System (or equivalent)
14. Patient must have signed a written informed consent form prior to any trial specific procedures. When the patient is physically unable to give their written consent, a trusted person of their choice, independent from the investigator or the sponsor, can confirm in writing the patient's consent.

Exclusion Criteria:

1. Patients who received a neo-adjuvant hormone therapy, a neo-adjuvant or adjuvant chemotherapy or preoperative medical treatment
2. Any local or regional recurrence or metastatic disease
3. Non-invasive carcinoma
4. Bilateral breast cancer (except in case of contralateral DCIS), or history of other invasive ipsi- or contralateral breast cancer
5. Patients with a history of another malignancy, except for properly treated cervical carcinoma in situ, and non-melanoma cancer of the skin
6. Women with high-risk breast cancer predisposing deleterious germline mutations
7. Contra-indications to the administration of anti-aromatase inhibitors
8. Patients enrolled in another therapeutic study within 30 days prior to inclusion
9. Patients with any other disease or illness, which requires hospitalization or is incompatible with the trial treatment
10. Patients unwilling or unable to comply with trial obligations for geographic, social, physical or psychological reasons, or who are unable to understand the purpose and procedures of the trial
11. Persons deprived of their liberty or under protective custody or guardianship

Primary outcomes:
measure: Distant relapse-free interval (DRFI)
timeFrame: From date of beginning of hormonotherapy to onset of metastases or death, up to 5-years.
Secondary outcomes:
measure: Distant Disease-Free Survival (DDFS)
timeFrame: From date of beginning of hormonotherapy to the date of first event of distant recurrence, death from any cause or secondary non-breast cancer up to 10 years
measure: Invasive disease free survival (iDFS)
timeFrame: From date of beginning of hormonotherapy to onset of invasive event, second cancer, or death, up to 10 years.
measure: Invasive breast cancer-free survival (iBCFS)
timeFrame: From date of beginning of hormonotherapy to onset of invasive event or death, up to 10 years.
measure: Breast cancer-specific survival (BCSS)
timeFrame: From date of beginning of hormonotherapy to death from breast cancer, up to 10 years.
measure: Overall survival (OS)
timeFrame: From date of beginning of hormonotherapy to death from any cause, up to 10 years.
measure: Quality of life (QoL) questionnaire - Core 30 (QLQ-C30)
timeFrame: At baseline, 1 year, 2 years, 3 years, 4 years, 5 years
measure: Quality of life (QoL) questionnaire - EORTC QLQ-BR23/QLQ-BR45
timeFrame: At baseline, 1 year, 2 years, 3 years, 4 years, 5 years
measure: Quality of life (QoL) questionnaire - Cancer related fatigue (QLQ-FA12)
timeFrame: At baseline, 1 year, 2 years, 3 years, 4 years, 5 years
measure: Hospital anxiety and depression scale (HADS)
timeFrame: At baseline, 1 year, 2 years, 3 years, 4 years, 5 years
measure: Functional Assessment of Cancer Therapy - Cognitive Function (FACT-Cog)
timeFrame: At baseline, 1 year, 2 years, 3 years, 4 years, 5 years
measure: Impact of Cancer (including fear of recidivism)
timeFrame: At baseline, 1 year, 2 years, 3 years, 4 years, 5 years
measure: Geriatric Core Dataset (G-CODE)
timeFrame: At baseline, 1 year, 2 years, 3 years, 4 years, 5 years
measure: Evaluate the safety of the treatment in the study population
timeFrame: Throughout study completion, up to 10 years.
Other outcomes:
Locations:
city: Limoges
country: France
facility: Centre Hospitalier Universitaire de Limoges
city: Villejuif
country: France
facility: Institute Gustave Roussy
Study officials:
affiliation: CHU Limoges
name: Elise DELUCHE, MD
role: STUDY_CHAIR
affiliation: Gustave Roussy, Cancer Campus, Grand Paris
name: Fabrice André, MD
role: STUDY_CHAIR
References: