Basal biomarkers nestin and INPP4B predict gemcitabine benefit in metastatic breast cancer: Samples from the phase III SBG0102 clinical trial

Abstract

In a formal prospective‐retrospective analysis of the phase III SBG0102 clinical trial randomizing metastatic breast cancer patients to gemcitabine‐docetaxel or to single agent docetaxel, patients with basal‐like tumors by PAM50 gene expression had significantly better overall survival in the gemcitabine arm. By immunohistochemistry (IHC), triple negative status was not predictive, but more specific biomarkers have since become available defining basal‐like by nestin positivity or loss of inositol‐polyphosphate‐4‐phosphate (INPP4B). Here, we evaluate their capacity to identify which patients benefit from gemcitabine in the metastatic setting. Nestin and INPP4B staining and interpretation followed published methods. A prespecified statistical plan evaluated the primary hypothesis that patients with basal‐like breast cancer, defined as “nestin+ or INPP4B−”, would have superior overall survival on gemcitabine‐docetaxel when compared to docetaxel. Interaction tests, Kaplan–Meier curves and forest plots were used to assess prognostic and predictive capacities of biomarkers relative to treatment. Among 239 cases evaluable for our study, 36 (15%) had been classified as basal‐like by PAM50. “Nestin+ or INPP4B−” was observed in 41 (17%) of the total cases and was significantly associated with PAM50 basal‐like subtype. Within an estimated median follow‐up of 13 years, patients assigned as IHC basal “nestin+ or INPP4B‐” had significantly better overall survival on gemcitabine‐docetaxel versus docetaxel monotherapy (HR = 0.31, 95%CI: 0.16–0.60), whereas no differences were observed for other patients (HR = 0.99), p‐interaction < 0.01. In the metastatic setting, women with IHC basal breast cancers defined as “nestin+ or INPP4B‐” have superior overall survival when randomized to gemcitabine‐containing chemotherapy compared to docetaxel alone. These findings need to be validated using larger prospective‐retrospective phase III clinical trials series.

Comprehensive profiling identifies a novel signature with robust predictive value and reveals the potential drug resistance mechanism in glioma

“…The hyperactivation of IL6/STAT3 pathway was reported to be essential for CSC self-renewal and tumorigenic [31,32]. While other biomarkers, such as CD44 and Nestin, were correlated with tumor staging, tumor size and lymph node metastasis [33,34]. The correlations between risk signature and cancer cell stemness and drug resistance have been confirmed by IHC assay.…”

LncRNA ENST869 Targeting Nestin Transcriptional Region to Affect the Pharmacological Effects of Chidamide in Breast Cancer Cells

“…Anti-cell death is an important feature of tumor cell survival ( 35 ). It enables tumor cells to withstand various challenges, including chemotherapeutic drugs ( 36 ). Nestin plays an essential role in the resistance against conventional chemotherapy of tumor stem cells ( 37 – 39 ).…”

The immune microenvironment and relation to outcome in patients with advanced breast cancer treated with docetaxel with or without gemcitabine

“…The TMAs contain two 2 mm cores of primary breast cancer tissue per patient, as previously described. 40 Immunohistochemical (IHC) staining for CD8 (clone C8/ 144B, Dako), PD-1 (clone NAT105, CellMarque), LAG3 (clone 17B4, Abcam), FOXP3 (clone 236A/E7, Abcam) and CD163 (clone 10D6, Leica Biosystems) was performed as per manufacturer's protocol using the Ventana Discovery Ultra staining platform at the Genetic Pathology Evaluation Center (Vancouver, Canada). PD-L1 staining using the SP142 clone (Roche) was performed following manufacturer's instructions at the Victoria Deeley Research Center (Victoria, Canada).…”

“…Staining and scoring of the standard breast cancer biomarkers ER, PR, and HER2 had been performed in connection with previous publications following published methods at the Genetic Pathology Evaluation Center, Vancouver, Canada. [40][41][42][43] Slides were scanned and digitized on the Aperio AT2 scanner at 20X magnification. Representative photomicrographs are shown in supplementary Figure S1.…”