Complete Response of Triple-Negative Metaplastic Carcinoma of the Breast Using Pembrolizumab

Ladwa, Amrita; Elghawy, Omar; Schroen, Anneke; Abernathy, Kristan; Schlefman, Jenna; Dillon, Patrick

doi:10.1159/000534146

Cited by 4 publications

(3 citation statements)

References 13 publications

(42 reference statements)

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Section: Resultsmentioning

confidence: 99%

“…Cyclophosphamide is a neo-adjuvant chemotherapy used with success in association with pembrolizumab in metaplastic triple-negative breast cancer [45], but cyclophosphamide is also known as a ferroptosis inducer because cyclophosphamideinduced GPX4 degradation triggers parthanatos by activating AIFM1 [46] and also acts on Heme Oxygenase-1 [47]. The single cell transcriptome of the microenvironment infiltrating in 4T1-transplanted tumors was investigated with or without Cyclophosphamide is a neo-adjuvant chemotherapy used with success in association with pembrolizumab in metaplastic triple-negative breast cancer [45], but cyclophosphamide is also known as a ferroptosis inducer because cyclophosphamide-induced GPX4 degradation triggers parthanatos by activating AIFM1 [46] and also acts on Heme Oxygenase-1 [47]. The single cell transcriptome of the microenvironment infiltrating in 4T1-transplanted tumors was investigated with or without cyclophosphamide pretreatment [18].…”

Section: Cd274 Ferroptosis-driver Score Predicts Recurrence Of Breast...mentioning

confidence: 99%

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Ferroptosis Inducers Upregulate PD-L1 in Recurrent Triple-Negative Breast Cancer

Desterke,

Xiang,

Elhage

et al. 2023

Cancers

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(1) Background: Triple-negative breast cancer (TNBC) is a distinct subgroup of breast cancer presenting a high level of recurrence, and neo-adjuvant chemotherapy is beneficial in its therapy management. Anti-PD-L1 immunotherapy improves the effect of neo-adjuvant therapy in TNBC. (2) Methods: Immune-modulation and ferroptosis-related R-packages were developed for integrative omics analyses under ferroptosis-inducer treatments: TNBC cells stimulated with ferroptosis inducers (GSE173905, GSE154425), single cell data (GSE191246) and mass spectrometry on breast cancer stem cells. Clinical association analyses were carried out with breast tumors (TCGA and METABRIC cohorts). Protein-level validation was investigated through protein atlas proteome experiments. (3) Results: Erastin/RSL3 ferroptosis inducers upregulate CD274 in TNBC cells (MDA-MB-231 and HCC38). In breast cancer, CD274 expression is associated with overall survival. Breast tumors presenting high expression of CD274 upregulated some ferroptosis drivers associated with prognosis: IDO1, IFNG and TNFAIP3. At the protein level, the induction of Cd274 and Tnfaip3 was confirmed in breast cancer stem cells under salinomycin treatment. In a 4T1 tumor treated with cyclophosphamide, the single cell expression of Cd274 was found to increase both in myeloid- and lymphoid-infiltrated cells, independently of its receptor Pdcd1. The CD274 ferroptosis-driver score computed on a breast tumor transcriptome stratified patients on their prognosis: low score was observed in the basal subgroup, with a higher level of recurrent risk scores (oncotypeDx, ggi and gene70 scores). In the METABRIC cohort, CD274, IDO1, IFNG and TNFAIP3 were found to be overexpressed in the TNBC subgroup. The CD274 ferroptosis-driver score was found to be associated with overall survival, independently of TNM classification and age diagnosis. The tumor expression of CD274, TNFAIP3, IFNG and IDO1, in a biopsy of breast ductal carcinoma, was confirmed at the protein level (4) Conclusions: Ferroptosis inducers upregulate PD-L1 in TNBC cells, known to be an effective target of immunotherapy in high-risk early TNBC patients who received neo-adjuvant therapy. Basal and TNBC tumors highly expressed CD274 and ferroptosis drivers: IFNG, TNFAIP3 and IDO1. The CD274 ferroptosis-driver score is associated with prognosis and to the risk of recurrence in breast cancer. A potential synergy of ferroptosis inducers with anti-PD-L1 immunotherapy is suggested for recurrent TNBC.

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Section: Resultsmentioning

confidence: 99%

Section: Cd274 Ferroptosis-driver Score Predicts Recurrence Of Breast...mentioning

confidence: 99%

Ferroptosis Inducers Upregulate PD-L1 in Recurrent Triple-Negative Breast Cancer

Desterke,

Xiang,

Elhage

et al. 2023

Cancers

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“…This suggests a potential for enhanced effectiveness of immunotherapy-based treatments within this subgroup. Case reports have illustrated positive responses and clinical benefits with immunotherapy in patients diagnosed with BC-Mp ( 47 – 50 ). In the present study, one patient received pembrolizumab with chemotherapy within a clinical trial, achieving a PFS of 20 months (the longest in the cohort) and an OS of 21 months.…”

Section: Discussionmentioning

confidence: 99%

Clinical analysis of metaplastic breast carcinoma with distant metastases: A multi‑centre experience

Püsküllüoğlu,

Swiderska,

Konieczna

et al. 2024

Oncol Lett

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Metaplastic breast cancer (BC-Mp), which includes a range of epithelial and mixed epithelial-mesenchymal tumours, are rare malignancies with an unfavourable prognosis. The limited literature on BC-Mp focuses mainly on retrospective data for radically treated patients. Notably absent are studies dedicated to the palliative treatment of BC-Mp with distant metastases. The present retrospective study investigated treatment modalities and prognosis in a multi-centre cohort of 31 female participants diagnosed with distant metastatic BC-Mp, including 7 patients with de novo metastatic disease. The median age of the patients was 61 years (range, 33–87 years), with 38.7% presenting local lymph node involvement. Lungs were the most common site for the metastatic disease (61.3%). Median Ki-67 index was 50% (range, 35–70%), and 80.7% of cases were classified as grade 3. Human epidermal growth factor receptor 2 (HER2) + and estrogen receptor + were detected in 12.9 and 6.5% of cases, respectively. A total of 62.4% of patients received first-line palliative systemic treatment. The 1- and 2-year overall survival (OS) were 38.5 and 19.2%, respectively. Receiving ≥1 line of palliative treatment was significantly associated with improved OS (P<0.001). Factors such as age, Ki-67 index, HER2 or hormonal status, presence of specific epithelial or mesenchymal components, location of metastases or chemotherapy regimen type did not influence OS. The present study provided insights into the clinicopathological profile, systemic treatment experience, prognostic factors and OS data of BC-Mp with distant metastases, emphasizing the imperative for clinical trials in this population.

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Carboplatin/Paclitaxel/Pembrolizumab

2023

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Complete Response of Triple-Negative Metaplastic Carcinoma of the Breast Using Pembrolizumab

Cited by 4 publications

References 13 publications

Ferroptosis Inducers Upregulate PD-L1 in Recurrent Triple-Negative Breast Cancer

Ferroptosis Inducers Upregulate PD-L1 in Recurrent Triple-Negative Breast Cancer

Clinical analysis of metaplastic breast carcinoma with distant metastases: A multi‑centre experience

Carboplatin/Paclitaxel/Pembrolizumab

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