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Triple‐negative breast cancer (TNBC) is the most aggressive breast cancer subtype and lacks specific targeted therapeutic agents. The current mechanistic evidence from cell‐based studies suggests that the matricellular protein SPARC has a tumor‐promoting role in TNBC; however, data on the clinical relevance of SPARC expression/secretion by tumor and stromal cells in TNBC are limited. Here, we analyzed by immunohistochemistry the prognostic value of tumor and stromal cell SPARC expression in 148 patients with non‐metastatic TNBC and long follow‐up (median: 5.4 years). We also quantified PD‐L1 and PD‐1 expression. We detected SPARC expression in tumor cells (42.4%), cancer‐associated fibroblasts (CAFs; 88.1%), tumor‐associated macrophages (77.1%), endothelial cells (75.2%) and tumor‐infiltrating lymphocytes (9.8%). Recurrence‐free survival was significantly lower in patients with SPARC‐expressing CAFs. Multivariate analysis showed that SPARC expression in CAFs was an independent prognostic factor. We also detected tumor and stromal cell SPARC expression in TNBC cytosols, and in patient‐derived xenografts and cell lines. Furthermore, we analyzed publicly available single‐cell mRNA sequencing data and found that in TNBC, SPARC is expressed by different CAF subpopulations, including myofibroblasts and inflammatory fibroblasts that are involved in tumor‐related processes. We then showed that fibroblast‐secreted SPARC had a tumor‐promoting role by inhibiting TNBC cell adhesion and stimulating their motility and invasiveness. Overall, our study demonstrates that SPARC expression in CAFs is an independent prognostic marker of poor outcome in TNBC. Patients with SPARC‐expressing CAFs could be eligible for anti‐SPARC targeted therapy. [ABSTRACT FROM AUTHOR]

In a previous phase II study (THERAPY), cetuximab and trastuzumab combination, as second‐line after progression with gemcitabine, showed disease stabilization in 27% of 33 patients with pancreatic carcinoma. In the present phase II multicenter study, we assessed the efficacy and tolerance of gemcitabine, trastuzumab plus erlotinib as first‐line treatment of metastatic pancreatic cancer. The primary endpoint was disease control rate (DCR, RECIST v.1); secondary endpoints were progression‐free (PFS), overall (OS) survival and toxicity (NCI‐CTCAE v3.0). Ancillary study addressed the predictive value of both EGFR/HER2 expression and KRAS mutational status. Sixty‐three patients from four centers were included (62 evaluable for toxicity, 59 for efficacy), median age was 62 years (35‐77), 59.7% men. The median treatment duration was 16.1 weeks (2.1‐61). Eleven patients (19%) reported a partial tumor response, and 33 (56%) disease stabilization. DCR was 74.6% (95%CI: 61.8‐85.0; 44/59 patients). After a median follow‐up of 23.3 months (0.6‐23.6), median PFS was 3.5 months (95%CI: 2.4‐3.8) and median OS 7.9 months (95%CI: 5.1‐10.2). PFS was significantly longer in patients with grade ≥ 2 cutaneous toxicities vs patients with grade 0‐1 toxicities (HR = 0.55, 95%CI: 0.33‐0.92, P =.020). Expression of EGFR and HER2 was correlated with PFS and OS in multivariate analysis; HER2 expression was correlated with the tumor response. Main severe toxicities were neutropenia (32%), cutaneous rash (37%) and thrombosis/embolisms (35.5%). This triplet combination is effective in terms of disease control, PFS and OS, and acceptable for safety. A larger study to investigate this combination compared to the standard regimen should be discussed. What's new? Despite extensive investigation into gemcitabine‐based combination therapies for pancreatic cancer, significant need remains for novel strategies with improved clinical benefit. A promising approach is the triplet combination gemcitabine, trastuzumab, and erlotinib, which the present pilot multicenter phase II trial identifies as an effective strategy for disease control and survival when used as a first‐line regimen. In particular, pancreatic cancer patients with grade 2 or worse cutaneous toxicity showed superior progression‐free survival compared to patients with grade 0‐1 cutaneous toxicities. In multivariate analyses, progression‐free and overall survival were correlated EGFR and HER2, while HER2 expression was linked to tumor response. [ABSTRACT FROM AUTHOR]