Studio di fase 3 sull'uso di test genomici per decidere la chemioterapia dopo l'intervento nelle donne giovani con tumore della mammella ormonosensibile

Inclusion Criteria:

1. Patient must have signed a written informed consent 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 signing the patient's consent;
2. . Premenopausal defined by patient that are not post-menopaused
3. Female
4. Age ≥ 35 years
5. Diagnosis of invasive HR-positive (ER≥10% of tumour cells stained positive and any PR expression) HER2-negative (IHC score 0-1+ or 2+ with negative/non-amplified ISH) invasive breast cancer; ER and HER2 determination will be assessed according to latest ASCO/CAP or national guidelines;
6. Breast and axillary surgery completed ≤ 12 weeks from study entry and randomization;
7. Availability of a Formalin-Fixed Paraffin-Embedded (FFPE) tumour sample from surgery to perform Prosigna® analysis or slides.

   Note: in case of receipt of neoadjuvant endocrine therapy the Prosigna® test must be done on the baseline biopsy. Performing the test on the surgical piece or on on-treatment biopsy is not permitted.
8. Tumour size and axillary lymph node status. One of the following must apply:

   1. 1-3 lymph nodes involved AND any invasive tumour size.
   2. node negative (including micrometastases in at least 1 node [i.e. deposit >0.2-2mm diameter]) AND invasive tumour size ≥ 50mm.
9. Multiple ipsilateral breast cancers are permitted provided that at least one tumour meets the tumour size and axillary lymph node entry criteria, and none meet any of the exclusion criteria.
10. Bilateral breast cancers are permitted provided the tumour(s) in one breast meets the eligibility criteria and the other, contralateral tumour is not ER negative and/or HER2 positive and not clinically significant, defined by both of the following:

    1. The contralateral tumour does not fulfil the tumour size and lymph node eligibility criteria required for trial entry; i.e. the following are not acceptable:

       .i. presence of lymph node macro-metastases; .ii. tumour size ≥50mm when there is no lymph node involvement.
    2. The treating physician does not consider that the characteristics of the contralateral tumour alone justify consideration of adjuvant chemotherapy.
11. Fitness to receive adjuvant chemotherapy, as judged by the treating physician;
12. Short term pre-surgical treatment with endocrine therapy, including in combination with non-cytotoxic agents, is allowed providing that the duration of treatment did not exceed 8 weeks;
13. Patients affiliated with or a beneficiary of the local social security system, health social security system, or other local regulatory requirements
14. Patients must agree to use adequate contraception methods for the duration of study treatment and for the duration specified in the SmPC after completing the treatment, unless agreed with the treatment physician the safety of attempt a pregnancy, which could be possible after at least 18 months of endocrine therapy.

Note : patient with extracapsular nodular transgression are eligible. NOTE: If neoadjuvant endocrine therapy was received, the Prosigna® test must be realized on the baseline biopsy. Performing the test on the surgical specimen or on biopsy taken during treatment is not permitted.

NOTE: Re-excision or complementary mastectomy for close/positive surgical margins should be postponed after chemotherapy completion, if chemotherapy is given; breast reconstruction is allowed after trial entry.

NOTE: The use of approved adjuvant targeted agents (abemaciclib, ribociclib and olaparib) combined to adjuvant endocrine therapy is allowed according to local practice recommendations and availability.

Exclusion Criteria:

* 1. Postmenopausal women. Women who fulfil the following criteria at trial entry will be considered postmenopausal:

  1. Age >45 and natural amenorrhoea of at least 1 year's duration.
  2. Bilateral surgical oophorectomy.
  3. For amenorrhoea not fulfilling the above criteria the diagnosis of postmenopausal status should be supported by hormone measurement: FSH levels must be > 25IU/L with low oestradiol (i.e. within the locally defined postmenopausal range), in the event of doubt measured on 2 occasions preferably 4-6 weeks apart. This applies to women who have undergone hysterectomy without bilateral surgical oophorectomy and are age <60; those ≥60 may be considered postmenopausal.

     NOTE: Hormonal contraception will suppress FSH and oestradiol levels. In those taking oral contraception, levels will recover rapidly on discontinuation. Depo-Provera injectable contraception lasts many months: all women receiving this agent should be considered premenopausal.

     2. Stage IV breast cancer; 3. Start of adjuvant systemic treatment (except for neoadjuvant endocrine therapy for a duration ≤ 8 weeks) before trial entry*; 4. Previous diagnosis of malignancy except:

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  1. Previous ductal carcinoma in situ (DCIS) or pleomorphic lobular carcinoma in situ (LCIS) of the breast managed by local treatment only;
  2. Previous in situ carcinoma as defined by the International Classification of Diseases for Oncology (ICD-O) including basal cell carcinoma of skin and cervical intraepithelial neoplasia;
  3. Previous invasive malignancy managed by local treatment only AND disease-free for at least 10 years.

     5. Patients enrolled in another therapeutic trial within 30 days of inclusion; 6. Presence of concomitant medical and/or psychiatric comorbidities and/or social problems that might prevent informed consent, treatment compliance or follow up; 7. Person deprived of their liberty or under protective custody or guardianship.

     8. Pregnant women or women who are breast-feeding at inclusion. 9. Patients unwilling or unable to comply with the protocol for the duration of the study including scheduled visits, treatment plan, laboratory tests and other study procedures because of geographic, familial, social, or psychological reasons.

     *Trial entry is dated from of the date the participant signs the consent form or provides remote verbal consent, whichever is earlier.