Reverse Luminal Immune Resistant Breast Cancer

This is a Phase II, open-label study evaluating the efficacy and safety of combined treatment (retinoic acid) with immune checkpoint inhibitor in luminal breast cancer patients who progressed during previous immune checkpoint inhibitors.

This is a Phase II, open-label study evaluating the efficacy and safety of combined treatment (retinoic acid) with immune checkpoint inhibitors in metastatic luminal breast cancer patients who progressed during or following previous immune checkpoint inhibitors. Current clinical studies on immunotherapy for luminal breast cancer are limited, with inconsistent results across trials. The KEYNOTE-028 study reported an objective response rate (ORR) of only 12% for pembrolizumab in PD-L1-positive, previously treated advanced luminal breast cancer patients, demonstrating limited efficacy. The GIADA phase II trial revealed a pathological complete response (pCR) rate of 16.3% with neoadjuvant chemotherapy followed by immunotherapy in luminal breast cancer. Additionally, trials such as NCT02779751 and NCT03051659 also indicated limited clinical benefits from immunotherapy. However, the I-SPY2 platform showed that combinations like olaparib, paclitaxel, and immunotherapy or wP-AC chemotherapy with immunotherapy could improve pCR rates in high-risk patients. Despite advancements, immunotherapy benefits are limited in luminal breast cancer compared to other cancers, with advanced-stage patients more likely to develop resistance. Thus, strategies to overcome immunotherapy resistance or increase the sensitivity of immunotherapy efficacy are urgently needed for this population. The preclinical results of our center show that retinoic acid can enhance the anti-tumor immune response by promoting the peroxidation of macrophages, increasing the infiltration and function of cytotoxic CD8+ T cells, inhibiting the growth of tumors in mice. Based on the preclinical study, the investigators designed this study to enroll metastatic luminal breast cancer patients who have progressed during or following immunotherapy, and to explore the efficacy of retinoic acid combined with immunotherapy at a clinical level, providing new strategies of combined treatment for luminal breast cancer patients.

Eligibility Criteria:
Inclusion Criteria:

* ECOG Performance Status of 0, 1, or 2
* Metastatic or locally advanced, histologically documented luminal breast cancer (presence of ER and/or PR expression, and absent or low HER2 expression)
* Radiologic/objective evidence of recurrence or disease progression after immunotherapy(combined with targeted therapy or chemo ) for metastatic breast cancer(MBC)
* Adequate hematologic and end-organ function, laboratory test results, obtained within 14 days prior to initiation of study treatment.

For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures as outlined for each specific treatment arm

* Measurable disease according to Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1)
* have the cognitive ability to understand the protocol and be willing to participate and to be followed up.

Exclusion Criteria:

* Symptomatic, untreated, or actively progressing CNS metastases
* Active or history of autoimmune disease or immune deficiency
* Significant cardiovascular disease
* History of malignancy other than breast cancer within 5 years prior to screening, with the exception of those with a negligible risk of metastasis or death
* Treatment with chemotherapy, radiotherapy, immunotherapy or surgery (outpatient clinic surgery excluded) within 3 weeks prior to initiation of study treatment.
* Pregnancy or breastfeeding, or intention of becoming pregnant during the study
* History of allergies to the drug components of this trial
* History of eosinophilosis or mastocytosis
* Patients who have been using oral steroid hormones for a long time will need to stop for 4 weeks if they have used them occasionally in the past