Immunogenomic profiling and pathological response results from a clinical trial of docetaxel and carboplatin in triple-negative breast cancer

Abstract

Purpose: Patients with triple negative breast cancer (TNBC) who do not achieve pathological complete response (pCR) following neoadjuvant chemotherapy have a high risk of recurrence and death. Molecular characterization may identify patients unlikely to achieve pCR. This neoadjuvant trial was conducted to determine the pCR rate with docetaxel and carboplatin, and to identify molecular alterations and/or immune gene signatures predicting pCR.Experimental Design: Patients with clinical stages II/III TNBC received 6 cycles of docetaxel and carboplatin. The primary objective was to determine if neoadjuvant docetaxel and carboplatin would increase the pCR rate in TNBC compared to historical expectations. We performed whole exome sequencing (WES) and immune pro ling on pre-treatment tumor samples to identify alterations that may predict pCR. Thirteen matching on-treatment samples were also analyzed to assess changes in molecular pro les.Results: Fifty-eight of 127 (45.7%) patients achieved pCR. There was a non-signi cant trend towards higher mutation burden for patients with residual cancer burden (RCB) 0/I versus RCB II/III (median 80, versus 68 variants, p 0.88). TP53 was the most frequently mutated gene, observed in 85.7% of tumors. EGFR, RB1, RAD51AP2, SDK2, L1CAM, KPRP, PCDHA1, CACNA1S, CFAP58, COL22A1, and COL4A5 mutations were observed almost exclusively in pre-treatment samples from patients who achieved pCR.Seven mutations in PCDHA1 were observed in pre-treatment samples from patients who did not achieve pCR. Several immune gene signatures including IDO1, PD-L1, interferon gamma signaling, CTLA4, cytotoxicity, tumor in ammation signature, in ammatory chemokines, cytotoxic cells, lymphoid, PD-L2, exhausted CD8, Tregs, and immunoproteosome were upregulated in pre-treatment samples from patients who achieved pCR.Conclusions: Neoadjuvant docetaxel and carboplatin resulted in a pCR of 45.7%. WES and immune pro ling differentiated patients with and without pCR.

Identification of Pyroptosis-Related Gene Signatures and Construction of the Risk Model to Predict BCR in Prostate Cancer

“…On the one hand, the release of a large number of inflammatory factors caused by pyroptosis will promote the transformation of normal cells into tumor cells ( Karki and Kanneganti, 2019 ); on the other hand, pyroptosis can induce the death of tumor cells ( Xia et al, 2019 ). Il7R and COL22A1 are related to the TME of lung cancer ( Fan et al, 2021 ) and breast cancer ( Ademuyiwa et al, 2021 ), respectively. Zinc finger protein 185 (ZNF185) is a novel LIM domain gene and is rarely expressed in most human tissues of the body; however, it is most abundantly expressed in the prostate ( Heiss et al, 1997 ; Zhang et al, 2007 ).…”

Triple negative breast cancer: approved treatment options and their mechanisms of action

“…Currently, docetaxel is administered in 60-100 mg/m 2 doses every 3 weeks (there appears to be no discernable difference between weekly and 3-weekly treatment cycles) in both neoadjuvant and adjuvant settings (Mauri et al 2010). An ongoing clinical trial is testing the effectiveness of combining 75 mg/m 2 docetaxel doses with carboplatin, a platinumbased chemotherapeutic, every 3 weeks (Ademuyiwa et al 2021).…”

Immunostimulatory Properties of Chemotherapy in Breast Cancer: From Immunogenic Modulation Mechanisms to Clinical Practice

“…A case report described that level of CD8 and PD-L1 expression on immune cells were increased after capecitabine and gemcitabine-carboplatin-iniparib therapy ( 132 ). A clinical trial aimed to identify molecular alterations of immune gene signatures following neoadjuvant chemotherapy of TNBC and they found several immune checkpoints including IDO1, PD-L1 and CTLA4 were upregulated in pre-treatment samples who achieved pCR ( 133 ). Collectively, the absence of unifying PD-L1 protocols makes it hard to draw a convincing conclusions from these studies.…”