Locoregional Treatment and Palbociclib in de Novo, Treatment Naive, Stage IV ER+, HER2- Breast Cancer Patients

Study Overview
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Brief Summary
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Approximately 3.5% to 6% of newly diagnosed breast cancer patients are stage IV metastatic. De novo metastatic breast cancer accounts for 20% to 25% of these cases. Despite a decrease in mortality in Europe and North America due to early detection and access to treatment, breast cancer remains the 2ⁿᵈ leading cause of cancer deaths in developed countries after lung cancer and the world's leading cause. In the ESME French national retrospective cohort (NCT03275311), the newly diagnosed estrogen receptor (ER)-positive and HER2-negative (luminal) metastatic patients had a 59.1 months overall survival (OS) for pre-menopausal women and 44.7 months for postmenopausal women. In the same cohort, the median OS was 47.4 months for de novo metastatic patients with hormone receptor (HR)-positive / HER2-negative breast cancer. The most important current treatment for metastatic breast cancer remains systemic therapy. Surgery and radiation are mainly used to treat symptoms. However, more than 15 retrospective studies have assessed the impact of locoregional treatment on relapse and OS. These studies suggested an improvement of the OS in patients with de novo metastatic breast cancer thanks to the addition of locoregional treatment to systemic therapy. Recent data from the ESME cohort suggest that patients with de novo luminal or HER2-positive metastatic breast cancer may benefit from local treatment of the primary tumor. Several prospective trials have attempted to demonstrate the benefit of locoregional treatment with mixed results. This can be explained by a limited power of statistical analysis, on the recruitment of patients with breast cancer of all types, and on a limited access to effective systemic therapies in some cases and all before the area of anti CD4/6 which is the current standard treatment in patients with HR-positive / HER2-negative luminal metastatic disease. However, guidelines indicate that a multimodal approach, including curative locoregional treatments, should be considered. As a result, many clinicians offer locoregional treatment of the primary tumor, especially if there is a good response to the first line of systematic treatment. Taken together, these data underscore the need for an evaluation of the value of combined therapy - endocrine therapy - CDK4/6 inhibitor and locoregional treatment - in this population of patients with newly diagnosed HR-positive / HER2-negative breast cancer.

Official Title
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PALbociclib in Advanced Breast Cancer: Therapy INtegrating locorEgional Treatment and Palbociclib in de Novo, Treatment Naive, Stage IV ER+, HER2- Breast Cancer Patients

Conditions
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Breast Cancer Stage IV, Radiotherapy, Surgery

Intervention / Treatment
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* Drug: Palbociclib
* Other: locoregional treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women with newly diagnosed and histologically proven de novo adenocarcinoma of the breast, Any T, any N, with at least one metastatic site measurable and/or non-measurable according to Response Evaluation Criteria In Solid Tumours (RECIST) v1.1 and/or PET Response Criteria in Solid Tumours (PERCIST) v1.0 and/or MD Anderson bone response criteria (MDA criteria). For patients with only bone metastases, at least one lytic and non-irradiated lesion must be present NB: Bilateral breast cancer is allowed only if tumours present similar histological criteria (morphological subtype, ER and HER2 status). Estrogen Receptor (ER)-positive and HER2-negative breast cancer. To be considered as ER-positive, the biopsy of the primary tumour must display at least 10% of cancer cells with positive ER staining. HER2-positive is defined as IHC3+ or FISH/CISH amplified according to 2018 criteria Age ≥18 years Eastern Cooperative Oncology Group (ECOG) ≤2 Indication for treatment with palbociclib and letrozole (with or without ovarian suppression) Diagnostic FFPE tumour sample and/or frozen primary breast tumour sample available Women of childbearing potential must have a negative serum or urine pregnancy test done within 14 days before inclusion Patients must agree to use adequate contraception methods for the duration of the study and for within 21 days after completing treatment Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and any protocol-related procedures including absence of co-morbidities preventing surgery and or radiotherapy and any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. Those conditions should be discussed with the patient before registration in the trial Patient affiliated to a social security system Written informed consent obtained prior to performing any protocol-related procedures including screening evaluations Exclusion Criteria: Patients with advanced, symptomatic, visceral spread at a risk for short-term, life-threatening complications according to investigator judgement and at risk for visceral crisis as defined by ABC4* Women with previously diagnosed and treated ipsilateral adenocarcinoma of the breast Women with previously treated or concomitant contralateral breast cancer except for Ductal carcinoma in situ (DCIS) treated with curative intent Patients with another concomitant cancer Concurrent enrolment in another clinical trial in which investigational therapies are administered or administration of an investigational drug within 30 days before inclusion Pregnant women or women who are breast-feeding Inability or willingness to swallow oral medication HIV, hepatitis (B and C) Active infection Prior therapy for metastatic breast cancer (systemic or local) Persons deprived of their freedom or under guardianship or incapable of giving consent Visceral crisis is defined as severe organ dysfunction as assessed by signs and symptoms, laboratory studies and rapid progression of disease. Visceral crisis is not the mere presence of visceral metastases but implies important visceral compromise leading to a clinical indication for a more rapidly efficacious therapy, particularly since another treatment option at progression will probably not be possible.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Palbociclib + locoregional treatment<br>All patients will receive the standard of care treatment ie Palbociclib + letrozole for 24-26 weeks (a delay of +/- 2 weeks to initiate the locoregional treatment is authorized after the day 1 of cycle 1 of palbociclib plus letrozole). After this period, patient will have the most adapted locoregional treatment ie surgery (conservative or mastectomy) with or without radiotherapy, or radiotherapy. The palbociclib will be continued until progression | Drug: Palbociclib<br>* The included patients will first receive the following systemic treatment according standard of care: Non-steroidal aromatase inhibitor (letrozole) Palbociclib Monthly Luteinizing hormone-releasing hormone (LHRH) analogue for non-menopausal patients only. Surgical bilateral oophorectomy is an acceptable option.<br>Other: locoregional treatment<br>* After normally 6 courses of systemic treatment initiation, the loco-regional treatment of the primary tumour will be performed: surgery (conservative or mastectomy) with or without radiotherapy, or radiotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival rate in patients receiving the letrozole plus palbociclib combination plus locoregional treatment | Overall survival | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical response rate on both primary tumour and metastasis disease | Follow-up of the disease status by imaging exams until surgery | 24 months | 
| Pathological response rate in primary tumour | Pathological response (tumour size, cellularity... ) evaluated at the surgery or at the biopsy | 26 weeks | 
| Conversion rate of breast surgery (conservative-radical) | Rate of modification of indication of mastectomy | 26 weeks | 
| Locoregional control rate | Rate of locoregional recurrence after surgery and/or radiotherapy | 60 months | 
| Progression-free survival (PFS) | Follow-up of the disease status by imaging exams | 60 months | 
| Overall survival |  | 60 months | 
| Incidence of combined therapies in terms of adverse events | Will be evaluated using the National Cancer Institute - common terminology criteria for adverse events (NCI-CTCAE) v5.0 | 60 months | 
| Registration of post letrozole-CDKi therapies | Records of cancer treatments prescribed to patients after disease progression | 60 months | 
| Evolution of quality of life during treatment | self-administered questionnaire of quality of life EORTC QLQ-C30 taking into account the patient's activity and his/her physical and psychological state | 60 months | 
| Evolution of quality of life during treatment | self-administered questionnaire of quality of life EORTC QLQ-BR23, complementary module to QLQ C30 questionnaire, is more specifically interested in patients with se cancer and the impact of treatment on their lives | 60 months | 
| Evolution of quality of life during treatment | self-administered questionnaire of quality of life Euroquol EQ-5D-5L consists of a descriptive system and a visual scale | 60 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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therapies combination