Clinical Trials /

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

NCT03900637

Description:

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)

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: PersonaLized neoAdjuvant Strategy ER Positive and HER2 Negative Breast Cancer TO Increase BCS Rate
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: PLATO study
  • NCT ID: NCT03900637

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
Leuprorelin acetateLeuplinArm I
LetrozoleLenara, BretraArm I

Purpose

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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm IExperimentalMammaPrint 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)
  • Leuprorelin acetate
  • Letrozole

Eligibility Criteria

        Inclusion Criteria:

          1. Histopathologically and immunohistochemically confirmed ER+ and HER2- BC patients

          2. Stage I-IIIA BC patients with detectable tumor sizes

          3. BC patients for whom BCS is not feasible due to tumor sizes or locations (two surgeons
             at each institution evaluate the infeasibility of BCS)

          4. Patients without distant metastasis which were identified pathologically or
             radiologically

          5. Female patients ≥ 19 years

               -  Diagnosis of menopause is defined as no menstruation for 1-year or both ovaries
                  removed surgically

          6. ECOG 0-2

          7. Patients with adequate bone marrow function

               -  Hemoglobin 10 g/dL, ANC 1,500/mm3, Plt 100,000/mm3

          8. Patients with adequate kidney function

               -  serum Cr ≤ 1.5 mg/dL

          9. 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

         10. Patients who decided to voluntarily participate in this trial with written informed
             consent

        Exclusion Criteria:

          1. History of treatment for ipsilateral BC or breast carcinoma in situ

          2. Confirmed distant metastasis of BC

          3. History of cancer other than BC

          4. Pregnant (positive pregnancy test within a week of enrollment) or breast-feeding
             patients

          5. Uncontrolled severe infection

          6. Psychiatric illness or epilepsy

          7. Male BC patients

          8. Inability to understand and willingness to sign a written informed consent

          9. Mammographic extensive microcalcification

         10. Multicentral, Bilateral BC

         11. History of chemotherapy or endocrine therapy on contralateral BC for the past 2 years

         12. ER-

         13. HER2+

         14. Undetectable and unmeasurable primary tumor size
      
Maximum Eligible Age:N/A
Minimum Eligible Age:19 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

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

Secondary Outcome Measures

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

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Seoul National University Hospital

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