Trial of Retifanlimab With Trastuzumab and Pertuzumab Combination in HER2-Addicted Breast Cancer

Inclusion Criteria: Patients are eligible to be included in the trial only if all of the following criteria apply: 1. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form and in this protocol. Written informed consent and any locally required authorization (e.g., Health Insurance Portability and Accountability Act) will be obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations. 2. Male and female aged \>18 years at the time of study entry. HR-positive patients are eligible because eligibility is driven by the biologic enrichment criteria above; HR status will be recorded and analyzed as a prespecified subgroup. 3. All breast cancers must be HER2+ (IHC 3+ or FISH \>=2) and HER2- addicted(Low Relapse score on HER2Dx assay or PDL \>10%. ER+ HER2+ cancers are allowed. Patients who are progesterone receptor positive or negative will be eligible to participate in the study. 4. Primary tumor greater than 1 cm diameter and \<=5cm, measured by clinical examination and mammography or echography. 5. T1-T2, N0-N1 tumors 6. Bilateral breast cancers that individually meet eligibility criteria are allowed. 7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 as of consent date . 8. Life expectancy \>6 months. 9. Adequate organ and marrow function as defined below: * Hemoglobin ≥10.0 g/dL with no blood transfusion in the past 28 days * Absolute neutrophil count ≥1.5 × 109/L * Platelet count ≥100 × 109/L * Serum total bilirubin ≤1 × institutional upper limit of normal (ULN; In the case of known Gilbert's syndrome, a higher serum total bilirubin \[\< 1.5 × ULN\] is allowed), * Aspartate transaminase/alanine transaminase ≤2.5 × institutional ULN * Alkaline phosphatase ≤1.5 × institutional ULN * Creatinine ≤1.5 mg/dL 10. Baseline left ventricular ejection fraction ≥50%, as measured by multigated acquisition (MUGA) scan or echocardiogram (ECHO). 11. Evidence of postmenopausal status or negative serum pregnancy test for premenopausal female patients. Negative serum β-human chorionic gonadotropin pregnancy test within 7 days prior to the first dose of study treatment for premenopausal patients. Women will be considered postmenopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: * Women \<50 years of age would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the postmenopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy). * Women ≥50 years of age would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \>1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy). 12. Willing to provide biopsy tissues as required by the study. - Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow-up. Exclusion Criteria: Patients are excluded from the trial if any of the following criteria apply: 1. Participation in another clinical study with an investigational product within 28 days prior to the first dose of study treatment. 2. Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study. 3. Unresolved or unstable adverse events (AEs) Grade 3 from prior administration of another investigational drug. 4. Any concurrent chemotherapy, radiation therapy, immunotherapy, or biologic therapy for cancer treatment. 5. Major surgical procedure (as defined by the investigator) within 28 days prior to the first dose of study treatment. 6. History of allogeneic bone marrow/stem, cell or solid organ transplantation. 7. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.\]). The following are exceptions to this criterion: * Patients with vitiligo or alopecia * Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement * Any chronic skin condition that does not require systemic therapy * Patients without active disease in the last 5 years may be included but only after consultation with the study physician 8. History of active primary immunodeficiency. 9. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical exam and radiographic findings, and tuberculosis testing in line with local practice), hepatitis B (known positive HBV surface antigen \[HBsAg\] result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of hepatitis B surface antigen \[HBsAg\]) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. 10. Current or prior use of immunosuppressive medication within 14 days prior to the first dose of study treatment. The following are exceptions to this criterion: * Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra-articular injection) * Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent * Steroids as premedication for hypersensitivity reactions 11. Female patients who are pregnant or breastfeeding or patients of reproductive potential who are not willing to employ effective birth control from screening to 7 months after the last dose of study treatment. 12. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients. 13. Patients with a mean QT interval of greater than or equal to 470ms calculated from 3 screening EKGs. 14. Patients with underlying cardiovascular conditions that have recently undergone interventions including: cardiac ventricular arrhythmia requiring medication, history of second or third degree AV blocks, myocardial infarction with the previous year, congestive heart failure, and unstable angina. 15. Evidence of interstitial lung disease, history of interstitial lung disease, or active, noninfectious pneumonitis at the time of consent. 16. Palliative radiation therapy administered within 1 week before the first dose of study treatment or radiation therapy in the thoracic region that is \> 30 Gy within 6 months before the first dose of study treatment. Note: Participants must have recovered from all radiation-related toxicities (to Grade ≤ 1 or baseline), must not require corticosteroids for this purpose, and must not have had radiation pneumonitis. 17. Has received a live vaccine within 28 days before the planned start of study treatment Note: Examples of live vaccines include but are not limited to measles, mumps, rubella, varicella-zoster (chickenpox), yellow fever, rabies, BCG, and typhoid vaccines. Seasonal influenza vaccines for injection are generally killed-virus vaccines and are allowed; however, intranasal influenza vaccines are live, attenuated vaccines and are not allowed. COVID vaccines are allowed.