Overview

Rationale

Around 70 to 80% of breast cancers are so-called "hormone-dependent" (HR+)/HER2-. For more than 50 years, studies have shown that chemotherapy and optimised hormonal treatments (hormone therapy), including a drug associated with ovarian suppression (OFS), improve survival in patients with these cancers, which are characterised by a high risk of relapse. However, younger patients suffer more side effects than older women, particularly from chemotherapy. This can affect their quality of life and reduce their ability to work.

For post-menopausal women, genetic tests exist to assess whether chemotherapy is really necessary in addition to hormonal treatment. However, for high-risk premenopausal patients, chemotherapy is still systematically recommended, as no study has proved that it can be safely avoided. Clinical trials based on risk stratification using genetic tests have not been conclusive, but the majority of premenopausal women included had not received optimal hormone treatment. It is possible that the beneficial effect of chemotherapy is partly due to the artificial menopause it induces. Some experts believe that, for patients with a high clinical risk but a low genetic risk, an optimised hormonal treatment (drug + OFS) could suffice, without the need for chemotherapy.

Objectives

Main objective: The aim of the study is to determine whether the use of a genetic test (Prosigna®) to decide whether or not to administer chemotherapy produces results as good as standard treatment (systematic chemotherapy) in premenopausal women with hormone-dependent (HR+) breast cancer/HER2-, by assessing their risk of cancer recurrence.

The secondary objectives include verifying whether, in patients with a low Prosigna® score (around 70% of cases), optimised hormonal treatment (including suppression of ovarian function) is as effective as chemotherapy combined with hormonal in treatment preventing cancer recurrence. The study also seeks to compare the efficacy of treatment Prosigna®-guided versus systematic chemotherapy in terms of recurrence and quality of life, as well as economic aspects. Finally, the aim is to understand patients' concerns about the concept of reducing treatment (therapeutic de-escalation) and the way in which this information is communicated to them.

The primary endpoint of the study is to measure the time elapsed between the start of participation in the study and the appearance of an event indicating a return of the cancer. This includes the return of cancer in the same breast or neighbouring areas, the spread of cancer to other parts of the body, the appearance of new cancer in the other breast or death from any cause.

Trial Population:

The study includes women major premenopausal diagnosed with invasive, hormone receptor-positive (ER+) and HER2-negative breast cancer. Patients must have undergone breast and axillary surgery recent and have a tumour sample suitable for analysis by the testProsigna® . They must be able to receive the study treatments Postmenopausal women, women with stage IV breast cancer, women who have already received adjuvant systemic treatment (except short neoadjuvant hormone therapy), women with a recent history of invasive cancer, pregnant women or women who are breast-feeding will not be able to take part in the study.

Interventions

After agreeing to take part, patients will enter the pre-inclusion period (up to 28 days before randomisation), during which the investigator will carry out all the necessary tests to assess their eligibility. The investigator will then randomise the patients to find out which treatment they have been assigned, no more than 2 weeks later: the experimental group will receive a treatment decided on the basis of the results of a genomic test: either chemotherapy and hormone therapy, or hormone therapy alone. The control group will receive the standard treatment. The treatment and follow-up phases are the same as for standard care. Information on the quality of life patient's will and other information (associated costs, perception of their participation in the study, etc.) also be collected by means of questionnaires completed by the patients during the 5 years following randomisation.

Eligibility

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:

<!-- -->

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.