PersonaLized neoAdjuvant Strategy ER Positive and HER2 Negative Breast Cancer TO Increase BCS Rate

Study Overview
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Brief Summary
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In ER+ and HER2- breast cancer(BC) patients for whom BCS is not feasible, we investigate the rate of BCS can be increased while decreasing unnecessary chemotherapy thru selective neoadjuvant chemotherapy or neoadjuvant endocrine therapy using tools of nodal status, Ki-67, and multigene assay(Mammaprint)

Detailed Description
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In patients with resectable BC, the neoadjuvant chemotherapy is recognized as one of the standard therapy in order to control and prevent the micrometastasis. Conducting neoadjuvant chemotherapy can lead to increased numbers of BCS compared with adjuvant chemotherapy and the prognosis of BC patients is known to be improved when there is pathological complete response (pCR) after neoadjuvant chemotherapy compared with no pCR. The effect of neoadjuvant chemotherapy is different in breast cancer subtypes. The quasi-pCR in HR- HER2+ BC is reported as 67% while 37% and 13% in triple negative and HR+ HER2- BC, respectively and it indicates that neoadjuvant chemotherapy has only limited effect in HR+ BC and the declined quality of life and the fecundity loss due to chemotherapy is a serious socioeconomic loss, especially in young patients. According to the SOFT trial, for high risk, pre-menopausal women, use of exmestane (AI, Aromatase Inhibitors) and ovarian suppression as adjuvant systemic therapy did improve the PFD compared with the use of tamoxifen and ovarian suppression. Neoadjuvant hormonal therapy as well as neoadjuvant chemotherapy has benefits in making inoperable BC to operable BC and improving the possibility of BCS by reducing the tumor size with complete response or partial response. Although these neoadjuvant systemic therapies have an ultimate objective to reduce the recurrence rate and improve the survival rate, the overall survival and disease-free survival has been reported similar to adjuvant systemic therapies. The clinical response rate of neoadjuvant hormonal therapy ranged from 13.5% to 100%, the radiologic response rate by ultrasound ranged from 20% to 91.7%, and these are statistically similar to the response rate of the neoadjuvant chemotherapy in ER+ patients. Most studies where letrozole was tested among AIs showed that letrozole has a similar or a little better effect on clinical or radiological response rate over tamoxifen and there were statistically more patients who became operable or eligible for BCS after neoadjuvant chemotherapy. Comparison studies among AIs showed that the response rates have been best achieved in letrozole over anastrozole and exemestane and the BCS rate was lowest in letrozole without statistical significance. According to the standard treatment guideline suggesting the selective use of ovarian suppression along with tamoxifen in HR+, premenopausal patients, a study investigated the combined treatment of letrozole with reversible ovarian ablation using goserelin (luteinizing hormone-releasing hormone: LHRH). The results showed that the response rate of the combination treatment of goserelin and anastrozole for 24 weeks as neoadjuvant hormonal therapy was statistically superior to goserelin and tamoxifen in premenopausal BC patients and this was not observed in the adjuvant setting. The most commonly used agents in BC are goserelin and leuprorelin(Leuplin) and their mechanism of action is to desensitize the hypothalamus and suppress the ovarian function by reducing the secretion of LH and FSH. MammaPrint, which analyses 70-gene expressed in breast cancer, can identify low risk patients who may safely forgo chemotherapy and high risk patients who can benefit from chemotherapy. Recent results from MINDACT trial have proved that 46.2% of HR+ and clinical high risk patients were classified into MammaPrint low risk and they could avoid unnecessary chemotherapy. In 2017 San Antonio breast cancer symposium, Dubsky et al. reported the analysis of correlation between neoadjuvant chemotherapy and score of Endopredict(EP) multigene assay in ER+ and HER2- patients treated on ABCSG 34. In neoadjuvant chemotherapy group, reduction of tumor size in patients with low EP score(Endopredict low risk group) was significantly low(NPV 100%). Meanwhile, in neoadjuvant hormonal therapy group, reduction of tumor size in patients with high EP score(Endopredict high risk group) was significantly low(NPV 92%). These results support the evidence that response of neoadjuvant chemotherapy or hormonal therapy can be predicted by the molecular score of tumor and selective treatment can maximize the effect. Accordingly, in this study, patients with MammaPrint test is performed, neoadjuvant chemotherapy is conducted to genomic High Risk patients, and neoadjuvant endocrine therapy is conducted to Low Risk patients. Although adjuvant therapy is conducted after the completion of this study, in case there is progressive disease (PD) after neoadjuvant endocrine therapy, adjuvant chemotherapy is conducted.

Official Title
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Multi-institutional Study to Increase Breast Conserving Surgery (BCS) Rate With Personalized Neoadjuvant Strategy in ER Positive and HER2 Negative Breast Cancer Patients for Whom BCS is Not Feasible

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Leuprorelin acetate
* Drug: Letrozole
* Genetic: MammaPrint


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histopathologically and immunohistochemically confirmed ER+ and HER2- BC patients Stage I-IIIA BC patients with detectable tumor sizes BC patients for whom BCS is not feasible due to tumor sizes or locations (two surgeons at each institution evaluate the infeasibility of BCS) Patients without distant metastasis which were identified pathologically or radiologically Female patients ≥ 19 years Diagnosis of menopause is defined as no menstruation for 1-year or both ovaries removed surgically ECOG 0-2 Patients with adequate bone marrow function Hemoglobin 10 g/dL, ANC 1,500/mm3, Plt 100,000/mm3 Patients with adequate kidney function serum Cr ≤ 1.5 mg/dL Patients with adequate liver function Bilirubin: ≤ 1.5 times of upper normal limit AST/ALT: ≤ 1.5 times of upper normal limit Alkaline phosphatase: ≤ 1.5 times of upper normal limit Patients who decided to voluntarily participate in this trial with written informed consent Exclusion Criteria: History of treatment for ipsilateral BC or breast carcinoma in situ Confirmed distant metastasis of BC History of cancer other than BC Pregnant (positive pregnancy test within a week of enrollment) or breast-feeding patients Uncontrolled severe infection Psychiatric illness or epilepsy Male BC patients Inability to understand and willingness to sign a written informed consent Mammographic extensive microcalcification Multicentral, Bilateral BC History of chemotherapy or endocrine therapy on contralateral BC for the past 2 years ER- HER2+ Undetectable and unmeasurable primary tumor size

Ages Eligible for Study
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Minimum Age: 19 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 |
| --- | --- |
| Experimental: Arm I<br>MammaPrint high risk : Neoadjuvant chemotherapy : Adriamycin/Cyclophosphamide #4 followed by Docetaxel #4 MammaPrint low risk : Premenopausal women : Letrozole 2.5mg PO QD + leuprorelin acetate 3.6mg SQ every 4weeks during 16 weeks (if needed, maximum for 24 weeks) Postmenopausal women : Letrozole 2.5mg PO QD during 16 weeks (if needed, maximum for 24 weeks) | Drug: Leuprorelin acetate<br>* In premenopausal women, 3.75mg of leuprorelin acetate is subcutaneously administered once every 4 weeks for 16 weeks. (if needed, maximum for 24 weeks)<br>* Other names: Leuplin;Drug: Letrozole<br>* 2.5 mg tablet is orally administered once a day, without regard to meals, for 16 weeks (if needed, maximum for 24 weeks)<br>* Other names: Bretra;Genetic: MammaPrint<br>* In this study, patients with MammaPrint test is performed, neoadjuvant chemotherapy is conducted to genomic High Risk patients, and neoadjuvant endocrine therapy is conducted to Low Risk patients.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Conversion Rate | Evaluate the conversion rate from BCS-ineligible to BCS-eligible patients | 4 months(maximum 6 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Actual Conversion Rate | Evaluate the actual performance rate of BCS | 4 months(maximum 6 months) | 
| pCR | Evaluate pathological complete response | 4 months(maximum 6 months) | 
| cCR | Evaluate clinical response rate | 4 months(maximum 6 months) | 
| Tumor Size Reduction Rate | Evaluate the accomplished rate of targeted tumor size reduction which enable to make BCS possible at presentation | 4 months(maximum 6 months) |