Anti-HER2 Therapy + Fulvestrant/Capecitabine in Women With HR+, HER2+, Non-visceral Metastases Stage IV Breast Cancer

Inclusion Criteria:

1. Patients provided written informed consent

2. Postmenopausal or premenopausal or perimenopausal women aged 18-75 years:

3. ≥60 years, or bilateral ovariectomy was previously performed, or

4. <60 years, natural postmenopausal status (defined as a continuous period of atleast 12 months following spontaneous cessation without other pathological orphysiological causes), estrogen (E2) and follicle-stimulating hormone (FSH) arepresent at postmenopausal levels

5. Premenopausal or perimenopausal women, willing to receive luteinizing hormone (LHRH) stimulation during the study

6. Histologically or cytologically confirmed HR-positive (ER/PR≥10%), HER2-positive (IHC 3+ or ISH+) breast cancer

7. At least one measurable non-visceral metastatic lesion (liver, lung, pleura,pericardium, peritoneum, kidney, adrenal, brain or leptomeningeal metastases areexcluded), HR-positive (ER/PR≥10%), HER2-positive (IHC 3+ or ISH+), (≥10 mm onT1-weighted, gadolinium-enhanced MRI) (RECIST v1.1)

8. Previous treatment with HER2 inhibitors to be discontinued prior to first studytreatment administration (at least 14 days for trastuzumab and other antibodies, atleast 7 days for lapatinib)

9. Previous chemotherapy, biological or target therapy to recurrent or metastatic diseaseare not allowed; Previous radiotherapy allowed, but radiotherapy must have beendiscontinued at least 14 days prior to first study treatment administration.

10. Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 2

11. Life expectancy > 24 weeks

12. left ventricular ejection fraction (LVEF) of 50% or higher at baseline (within 42 daysbefore randomization)

13. Previous adjuvant chemotherapy treatment is allowed

14. Previous adjuvant trastuzumab treatment is allowed

15. Hormone therapy must have been discontinued at least 1 month prior to recruitment

16. Patients with good compliance

17. Patients must have recovered to baseline condition or to Common Terminology Criteriafor Adverse Events (CTCAE) version 5.0 grade = 1 from any acute CTCAE v. 5.0 grade =2side effects of previous treatments

18. Without infection of human immunodeficiency virus (HIV) on central laboratory assayresults prior to randomization

19. Alanine aminotransferase (ALT) </= 2.5 × the upper limit of normal (ULN), Aspartateaminotransferase (AST) </= 2.5 × ULN prior to randomization

20. Total bilirubin (TBIL) </= 1.25 × ULN

21. Alkaline phosphatase (ALK) </= 2.5 × ULN

22. Gamma glutamyl transpeptidase (GGT) </= 2.5 × ULN

23. Serum total bilirubin (TBil) </= 1.5 × ULN

24. Serum creatinine (Scr) </= 1.5 × ULN

25. WBC >/= 3×109/L, Blood neutrophil count >/= 1×109/L, Platelet count >/= 100×109/L, HB >/= 9 g/dL

26. Albumin >/= 30g/L

27. Women of child-bearing age who had a negative serum pregnancy test (within 14 daysbefore randomization) should take effective contraceptive measures

Exclusion Criteria:

1. Primary and metastatic lesion lack of histological or cytological confirmation ofHR-positive (ER/PR≥10%), HER2-positive (IHC 3+ or ISH+)

2. Breast cancer with visceral metastases (liver, lung, pleura, pericardium, peritoneum,kidney, adrenal, brain or leptomeningeal metastases)

3. Inflammatory breast cancer

4. Having a life-threatening metastatic visceral disease, defined as extensive liverdamage or brain or leptomeninges damage (past or present) or symptomatic pulmonarylymphatic diffusion. Patients with discrete pulmonary parenchyma metastasis wereeligible if the investigators determined that their respiratory function was notsignificantly impaired by the disease.

5. Disease progression or recurrence within 12 months after neo/adjuvant endocrinetherapy

6. Unable to tolerate endocrine therapy, including those who with symptoms, who havespread to the viscera, and who are at risk for short-term life-threateningcomplications (including uncontrolled thorax, pericardium, or abdominal cavityexudation, pulmonary lymphangitis, and more than 50% liver damage).

7. CT or MRI confirmed the presence of brain or leptomeningeal metastases.

8. Any other current malignancy or malignancy diagnosed within the past five years (otherthan breast cancer, carcinoma in situ of the cervix, skin basal cell carcinoma orsquamous cell carcinoma), unless radical treatment is performed and there is noevidence of recurrence or metastasis within the last 5 years.

9. Non- visceral metastatic lesions cannot be evaluated by RECIST v1.1

10. Active infection with human immunodeficiency virus (HIV) prior to first studytreatment administration.

11. History of participating any other clinical trials within 30 days prior torandomization

12. Known hypersensitivity (Grade 3 or 4) to Pertuzumab, Trastuzumab, Fulvestrant orCapecitabine or the excipients of any of the trial drugs

13. Pregnancy or lactation

14. Uncontrolled illnesses including symptomatic congestive heart failure, unstable anginapectoris, cardiac arrhythmia requiring therapy, myocardial infarction within the past 6 months, or active infection

15. severe pulmonary and renal disease

16. Patients with GI tract disease resulting in an inability to take oral medication,malabsorption syndrome, a requirement for IV alimentation, prior surgical proceduresaffecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's, ulcerativecolitis)

17. Legal incompetence or limitation.

18. Considered unable to complete the study or sign the informed consent due to a medicalor mental disorder by the investigator.