Adjuvant Intensification for LAR

Standard Chemotherapy Plus Oral Everolimus as Adjuvant Therapy for LAR Breast Cancer Patients: A Randomized, Open-Label, Phase III Trial （POLARIS）

This study enrolled patients with early-stage triple-negative breast cancer who had undergone radical surgery. The postoperative pathology met the TNM staging criteria of pT1c-3N0-3M0, and immunohistochemistry (IHC) results confirmed ER-negative status (IHC showed <1% of tumor cells positive for ER), PR-negative status (IHC showed <1% of tumor cells positive for PR), and HER2-negative status (IHC intensity of 0 or 1+; or IHC intensity of 2+ but with negative in situ hybridization results). Additionally, patients either exhibited high AR expression (IHC showing AR ≥10%) or were classified as the LAR subtype based on digital pathology.

This study plans to prospectively enroll 904 subjects, who will be randomized in a 1:1 ratio after completing standard chemotherapy. They will be allocated to either the standard-of-care (SOC) chemotherapy followed by everolimus group or the SOC-alone group. The study aims to evaluate the efficacy of SOC chemotherapy followed by everolimus versus SOC chemotherapy alone as adjuvant therapy for patients with early-stage radically resected triple-negative breast cancer of the LAR subtype, with the primary endpoint being 3-year invasive disease-free survival (iDFS).

Inclusion Criteria:

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Patients must meet **all** of the following inclusion criteria to be enrolled in this study:

1. Female, aged ≥18 years and ≤70 years.

2. ECOG performance status 0-1.

3. Histologically confirmed invasive triple-negative breast cancer (**definition**: breast cancer with estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) all confirmed negative by pathology. Specifically: **ER-negative**: IHC <1%; **PR-negative**: IHC <1%; **HER2-negative**: IHC 0/1+ or IHC 2+ but FISH/CISH negative. Additionally, histology must confirm **high AR expression**: AR IHC ≥10%, **or** digital pathology indicates the LAR subtype.

4. Underwent radical surgery for early-stage breast cancer, with postoperative pathology meeting TNM staging **pT1c-3N0-3M0**.

5. Patients with early-stage breast cancer who have received **at least 4 cycles of neoadjuvant chemotherapy containing anthracycline or taxane agents**, **did not achieve pathological complete response (pCR)**, and **do not carry pathogenic/likely pathogenic germline BRCA1/2 mutations**.

6. Adequate organ function, meeting the following criteria:

   • **Hematology**: HB ≥ 90 g/L (no transfusion within 14 days); ANC ≥ 1.5 × 10⁹/L; PLT ≥ 75 × 10⁹/L.

     • **Biochemistry**: TBIL ≤ 1.5 × ULN; ALT and AST ≤ 3 × ULN; serum Cr ≤ 1 × ULN, with creatinine clearance >50 mL/min (Cockcroft-Gault formula).

7. Surgical wound fully healed before study initiation.

8. Females of childbearing potential must use a medically approved contraceptive method during the study treatment and for at least 3 months after the last dose of study drug.

9. The patient voluntarily agrees to participate, signs the informed consent form, demonstrates good compliance, and agrees to follow-up.

Exclusion Criteria:

• Patients who meet **any** of the following criteria will be excluded from this study:

  1. Bilateral breast cancer.
  2. Metastatic disease at any site.
  3. Patients with cT > 2 cm or positive lymph nodes **and** carrying pathogenic/likely pathogenic germline BRCA1/2 mutations.
  4. History of clinically significant or uncontrolled cardiac disease, including congestive heart failure, angina, myocardial infarction within the past 6 months, or ventricular arrhythmia.
  5. History of clinically significant pulmonary disease, including but not limited to interstitial pneumonia, pneumonia, pulmonary fibrosis, and radiation pneumonitis (except for asymptomatic radiation changes not requiring intervention); or suspected such disease based on screening examinations.
  6. History of other malignancies within the past 5 years, excluding cured carcinoma in situ of the cervix, basal cell carcinoma of the skin, or squamous cell carcinoma of the skin.
  7. Pregnant or lactating women; women of childbearing potential who cannot practice effective contraception.
  8. Patients concurrently participating in other clinical trials.
  9. Patients with a history of hypersensitivity or known allergy to any component of the study drugs; or patients with a history of allergy to other monoclonal antibodies.
  10. Severe or uncontrolled infection.
  11. Hypertension that cannot be adequately controlled with antihypertensive medication (systolic blood pressure > 140 mmHg, diastolic blood pressure > 90 mmHg).
  12. History of gastrointestinal bleeding within the past 6 months, or clear tendency for gastrointestinal bleeding, such as esophageal varices at risk of bleeding, locally active ulcerative lesions, or fecal occult blood ≥ (++). Patients with fecal occult blood (+) must undergo gastroscopy for further evaluation.
  13. Known active HBV or HCV infection (HBV-DNA ≥ 500 IU/mL), or chronic infection with abnormal liver function.
  14. Urinalysis showing urine protein ≥ ++, or 24-hour urine protein quantification > 1.0 g.
  15. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to study enrollment.
  16. History of drug abuse (psychoactive substances) with inability to abstain, or history of psychiatric disorders.
  17. Patients deemed unsuitable for participation by the investigator's judgment.