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Aromatase Inhibitors

Ribociclib (400 mg/day; 3 weeks ON and 1 week OFF) in the adjuvant setting for 33 cycles. Letrozole or other aromatase inhibitor treatment duration must be of at least 5 years

Adjuvant chemotherapy. 3 regimens are permitted.

Regimen 1:

- Doxorubicin 60 mg/m2 IV day 1 (or Epirubicin 75-100 mg/m2) and Cyclophosphamide 600-830 mg/m2 day 1 every 14/21 days for 4 cycles, followed by Paclitaxel 80 mg/m2 every week for 12 weeks or Docetaxel 75-100 mg/m2 every 3 weeks for 12 weeks.

Regimen 2:

- Docetaxel 75-100 mg/m2 IV day 1 and Cyclophosphamide 600-830 mg/m2 day 1 every 21 days for 4-6 cycles.

Regimen 3:

- Paclitaxel 80 mg/m2 every week for 12 weeks or Docetaxel 75-100 mg/m2 every 3 weeks for 12 weeks followed by Doxorubicin 60 mg/m2 IV day 1 (or Epirubicin 75-100 mg/m2) and Cyclophosphamide 600-830 mg/m2 day 1 every 14/21 days for 4 cycles.

Then, patients will receive ribociclib (400 mg/day; 3 weeks ON and 1 week OFF) in the adjuvant setting for 33 cycles. Letrozole or other aromatase inhibitor treatment duration must be of at least 5 years

Ribociclib 600 mg/day + letrozole during neoadjuvant phase.

Ribociclib (neoadjuvant)

Adjuvant chemotherapy. 3 regimens are permitted.

Chemotherapy (adjuvant)

Ribociclib 400 mg/day + letrozole (or other aromatase inhibitor) during adjuvant phase.

Ribociclib (adjuvant)

Fernando Salvador, PhD

Ana Bargues

Julien GRENIER

Thomas Grellety

Laura MANSI

Olivier ARSENE

George EMILE

Victor SIMMET

Marie-Ange OURET-REYNIER

Sylvain Ladoire

Emmanuelle JACQUET

Nathalie PEREZ STAUB

Audrey MAILLIEZ

Elise DELUCHE

Thomas BACHELOT

Olfa DERBEL

Frederic VIRET

Dorothée CHOCTEAU-BOUJU

Paul Cottu

Nicolas ISAMBERT

Léa Muzellec

Amélie LEMOINE

Thibault DE LA MOTTE ROUGE

Romuald LE SCODAN

Valérie DELECROIX

Youssef TAZI

Thierry PETIT

Francesco DEL PIANO

Chantal BERNARD-MARTY

Florence DALENC

Géraldine LAURIDANT

Maria RIOS

Camille POIRIER

Barbara PISTILLI

Eudald Felip, 'MD

Sonia Pernas, MD

Antonia Perelló, MD

Maria Vidal, MD

Meritxell Bellet, MD

Isabel Blancas, MD

Ana López González, MD

Yann Izarzugaza

Ana M Luna, MD

Eva M Ciruelos, MD

Elena López, MD

Cesar Rodriguez, MD

Javier Salvador, MD

Cristina Hernando, MD

Joaquín Gavilá, MD

Aleix Prat, MD

Paul Cottu, MD

Thibault de La Motte Rouge, MD

This is an open-label, multicenter international trial in men and women with primary operable HR+/HER2-, ki67≥20%, grade 2 or 3 and stage II breast cancer to evaluate safety and long-term efficacy of a non-chemo treatment in patients biologically responders to neoadjuvant ribociclib and letrozole.

This study aims to evaluate whether chemotherapy could be avoided for initial high-risk clinicopathological breast cancer patients that are converted to low genomic risk assessed by Risk of Recurrence-low (ROR-low) at 6 months of letrozole - ribociclib neoadjuvant treatment by continuing with this treatment in adjuvant setting.

All patients will receive letrozole plus ribociclib as neoadjuvant therapy. Treatment will consist of six 28-days cycles of daily letrozole (2.5mg; continuous) and ribociclib (600 mg/day; 3 weeks ON and 1 week OFF). In pre-menopausal and men patients, monthly LHRH agonists will be added to letrozole and ribociclib, beginning at least two weeks before starting letrozole and ribociclib.

After finalization of neoadjuvant treatment, patients will undergo surgery. Surgery samples of the residual tumor tissue (or tumor bed if pathological complete response \[pCR\] is achieved) will be collected regardless of whether they completed full neoadjuvant treatment.

This is not a randomized study; therefore, adjuvant treatment will be decided according to centrally assessed ROR and pathological stage after surgery. Patients are considered responders if they achieve a pCR or have ypN0 and ROR ≤ 30 or ypN1mi (cancer the lymph node is \> 0.2 mm but \< 2 mm) and ROR ≤ 20 or ypN1 and ROR ≤ 10. All patients with ypN0 and ROR \> 30, ypN1mi and ROR \> 20, ypN1 and ROR \> 10 or ypN2-3 are considered non-responders. Patients who progress during neoadjuvant treatment with ribociclib will be considered non-responders.

If indicated, adjuvant radiotherapy will be performed after surgery in the responder group and after adjuvant chemotherapy in the non-responders group.

Patients considered as responders will continue on treatment after optimal recovery of surgery and radiotherapy if indicated. Treatment with ribociclib (400 mg/day; 3 weeks ON and 1 week OFF) in the adjuvant setting will be maintained for 30 months approximately corresponding to 33 cycles. Letrozole treatment duration must be of at least 5 years. Visits during ribociclib treatment will be scheduled every three cycles. At the end of ribociclib treatment, visits will be every 6 months until 5 years from last patient's surgery.

Patients considered as non-responders will be treated with standard chemotherapy regimens. Patients will continue treatment with ribociclib and letrozole after optimal recovery of adjuvant chemotherapy and radiotherapy if indicated. Treatment with ribociclib (400 mg/day; 3 weeks ON and 1 week OFF) in the adjuvant setting will be maintained for 30 months approximately corresponding to 33 cycles after adjuvant chemotherapy. Endocrine therapy treatment duration must be of at least 5 years. Visits during ribociclib treatment will be scheduled every three cycles. At the end of ribociclib treatment, visits will be every 6 months until 5 years from last patient's surgery.

During adjuvant treatment (both responders and non-responders), letrozole can be switched to another aromatase inhibirtor (AI). Tamoxifen is only permitted after the 30-day post ribociclib visit, according to investigator criteria. Maintaining suppression of ovarian function by luteinizing hormone releasing hormone (LHRH) agonists during adjuvant treatment is mandatory (if AI are taken)/ recommended (if tamoxifen is taken) in premenopausal and men patients unless there is unmanageable toxicity.

Adjuvant hormonal treatment of patients who progress during neoadjuvant Ribociclib will be at the investigator's discretion.

Blood samples for ctDNA will be collected at screening, C2D1, pre-surgery, post-surgery, and every 6 months during the adjuvant period. Blood samples will be also collected in case of recurrence.

The global end of the study is defined as the date when the last patient accomplishes 5 years of follow up after surgery. The total duration of the study is expected to be 32 months for enrollment, 3 years of adjuvant treatment (including 2.5 years of ribociclib treatment), and additional 2.5 years of follow-up.

Neoadjuvant and Adjuvant Ribociclib and ET for Clinically High-risk ER+ and HER2- Breast Cancer

Neoadjuvant and Adjuvant Ribociclib and Endocrine Therapy for Clinically High-risk Estrogen Receptor-positive (ER+) and HER2-negative (HER2-) Breast Cancer

Correlation between DMFS and pCR in ROR-low cohort, in ROR-medium/high cohort, and in all patients

Correlation between DMFS and ROR score (as a continuous variable) in ROR-low cohort, in ROR-medium/high cohort, and in all patients.

Correlation between DMFS and RCB at surgery in ROR-low cohort, in ROR-medium/high cohort, and in all patients

Correlation between DMFS and PAM50 intrinsic breast cancer subtype at surgery in ROR-low cohort, in ROR-medium/high cohort, and in all patients

Correlation between DMFS and PAM50 intrinsic breast cancer subtype at baseline in ROR-low cohort, in ROR-medium/high cohort, and in all patients

* To evaluate the predictive value of early dynamic changes in ctDNA between baseline and after 1 cycle of ribociclib + letrozole.
* Correlation of clinical benefit endpoints and specific baseline genomic alterations or patterns in ctDNA.
* To explore the value of ctDNA to detect a later clinical recurrence during the adjuvant phase.
* To explore alterations or patterns related to drug resistance.

To correlate TKa dynamics with DMFS, IDFS, pCR and RCB0/1.

DMFS is defined as the time from date of surgery to date of first event of distant metastatic recurrence or death (any cause).

iDFS is defined as the time from surgery until the date of the first occurrence of one of the following events: recurrence of ipsilateral invasive breast tumor, recurrence of ipsilateral locoregional invasive disease, a distant disease recurrence, contralateral invasive breast cancer, second primary or death from any cause.

pCRBL after completion of study treatment, defined as the complete absence of invasive carcinoma in the breast and axillary lymph nodes on histological examination at the time of definitive surgery, irrespective of in situ carcinoma in the breast.

RCB0/1 after neoadjuvant treatment, according to the MD Anderson Cancer Center procedures, as per local assessment.

Rate of ROR-low (at surgery) after neoadjuvant treatment, according to Prosigna test.

Incidence, duration and severity of Adverse Events (AEs) assessed by the National Cancer Instirute (NCI) Common Terminology for Classification of Adverse Events (CTCAE) version 4.03, including dose reductions, delays and treatment discontinuations.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Neoadjuvant and Adjuvant Ribociclib and ET for Clinically High-risk ER+ and HER2- Breast Cancer	NCT05296746	Breast Cancer S...	Ribociclib (neo... Chemotherapy (a... Ribociclib (adj...	18 Years -	SOLTI Breast Cancer Research Group
Neoadjuvant and Adjuvant Ribociclib and ET for Clinically High-risk ER+ and HER2- Breast Cancer	NCT05296746	Breast Cancer S...	Ribociclib (neo... Chemotherapy (a... Ribociclib (adj...	18 Years -	SOLTI Breast Cancer Research Group

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