reverse her2-negative immune resistant breast cancer

Conditions: HER2 Negative Breast Cancer

Summary: this is a phase ii, open-label study evaluating the efficacy and safety of combined treatment (retinoic acid) with immune checkpoint inhibitor in her2-negative 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 her2-negative breast cancer patients who progressed during or following previous immune checkpoint inhibitors. her2-negative breast cancers include luminal breast cancers and triple-negative breast cancers. 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. recent clinical studies on advanced triple-negative breast cancer have shown that immunotherapy combined with chemotherapy demonstrates superior clinical efficacy compared to traditional chemotherapy alone. phase iii trials such as impassion130 and keynote-522 have confirmed that pd-1/pd-l1 inhibitors used with chemotherapy significantly improve progression-free survival, overall survival, and pathological complete response rates. however, compared to other malignancies, triple-negative breast cancer patients still show relatively low overall response rates to immunotherapy: treatment-naïve patients achieve objective response rates of only 10-20% with immunotherapy monotherapy, though this improves to 56% when combined with chemotherapy, extending median progression-free survival to 7.2 months. unfortunately, efficacy decreases significantly in later treatment lines, with objective response rates falling to just 10.6-15.9% after multiple previous treatments. thus, strategies to overcome immunotherapy resistance or increase the sensitivity of immunotherapy efficacy are urgently needed for her2-negative breast cancer patients. 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 her2-negative 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 her2-negative breast cancer patients.

Eligibility criteria:
inclusion criteria: * ecog performance status of 0, 1, or 2 * metastatic or locally advanced, histologically confirmed luminal breast cancer (defined as: er positive when immunohistochemistry shows \>1% positive tumor cells, pr positive when \>1% tumor cells are positive, and her2 negative when scored as 0-1+ or when her2 2+ shows no amplification by fish or cish) or triple negative breast cancer (defined as: er negative when immunohistochemistry shows \<1% positive tumor cells, pr negative when \<1% tumor cells are positive, and her2 negative when scored as 0-1+ or when her2 2+ shows no amplification by fish or cish). * 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

Keywords: immunotherapy retinoic acid her2 negative breast cancer