Objectives To examine tumor infiltrating lymphocytes (TILs) and their prognostic value in patients with pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant therapy. Methods Intra-tumoral CD4+, CD8+, and FOXP3+ lymphocytes was examined by immunohistochemistry using a computer-assisted quantitative analysis in 136 PDAC patients who received neoadjuvant therapy and pancreaticoduodenectomy. The results were correlated with clinicopathologic parameters and survival. Results High CD4+ TILs in treated PDAC were associated with high CD8+ TILs (P = 0.003), differentiation (P = 0.04) and a lower frequency of recurrence (P = 0.02). Patients with high CD4+ TILs had longer disease-free survival (DFS) and overall survival (OS) than did patients with low CD4+ TILs (P < 0.01). The median OS of patients with a high CD8+/FOXP3+ lymphocyte ratio (39.5 [standard deviation, 6.1] months) was longer than that of patients with a low CD8+/FOXP3+ lymphocyte ratio (28.3 [standard deviation, 2.3] months; P=0.01). In multivariate analysis, high CD4+ TILs were an independent prognostic factor for DFS [Hazard ratio (HR): 0.49, 95% CI, 0.30–0.81; P = 0.005] and OS (HR, 0.54; 95% CI, 0.33–0.89; P = 0.02). Conclusions High CD4+ lymphocytes is associated with tumor differentiation, lower recurrence and is an independent prognostic factor for survival in PDAC patients treated with neoadjuvant therapy.
Purpose Determination of microsatellite instability (MSI) by PCR is the gold standard; however, immunohistochemistry (IHC) of mismatch repair (MMR) proteins is frequently performed instead. The reliability of these methods on post-neoadjuvant-therapy specimens is unknown. We examined the effect of neoadjuvant therapy on MSI results by PCR and IHC. Experimental design A total of 239 colorectal cancers resected after neoadjuvant therapy were assessed for MSI with PCR and IHC. PCR and IHC results for matched paired pre- and post-treatment specimens were compared. In parallel, two isogenic cell lines conditioned for MMR functioning and two different patient-derived xenografts (PDX) were exposed to chemotherapy, radiation or both. We also examined whether establishment of PDXs induced MSI changes in five tumors. IHC and MSI were tested after treatment to assess for changes. Results We identified paired pre- and post-treatment specimens for 37 patients: 2 with PCR only, 34 with IHC only, and 1 with both. All three patients with PCR had microsatellite stable pre- and post-treatment specimens. Of the 35 patients with IHC, 30 had intact MMR proteins in pre- and post-treatment specimens, 1 had equivocal MLH1 staining in the pre-treatment and loss in the post-treatment specimen, and 4 had intact pre-treatment MSH6 but variable post-treatment staining. In the experimental setting, no changes in MSI status were detected after treatment or tumor implantation in animals. Conclusions Our findings show that expression of MMR proteins, commonly MSH6, can change after neoadjuvant therapy and confirm PCR as the gold-standard test for MSI after neoadjuvant therapy.
Purpose: Family history of BRCA-related tumors may correlate with response to chemotherapy and overall survival (OS) in pancreatic cancer. The frequency of germline mutations has been reported in patients predominantly under the age of 60 or with strong family history. We examine the incidence of deleterious germline mutations and compare the chemotherapy responses and OS in an unselected group of patients with metastatic pancreatic cancer.Experimental Design: Patients with metastatic pancreatic cancer, who were seen at a single cancer center between 2010 and 2016, were included. Germline DNA was sequenced using a 263-gene panel to identify novel mutations (N ¼ 133 MD Anderson cohort, N ¼ 127 TCGA cohort). Chemotherapy response and OS were determined by review of medical records.Results: Deleterious germline mutations were identified in 26 of 133 patients (19.5%). Patients with DNA damage repair (DDR) gene mutations (ATM, BRCA1/2, CDKN2A, CHEK2, ERCC4, PALB2, n ¼ 15) had an improved OS as compared with patients without (16.8 vs. 9.1 months, P ¼ 0.03). Conversely, patients with other deleterious mutations had a trend toward worse OS. However, survival in the latter group was longer (P ¼ NS) in those mutants initially treated with gemcitabine/nab-paclitaxel. A family history of multiple breast, ovarian, and pancreatic cancers was associated with DDR gene mutations and better survival.Conclusions: We have identified novel germline mutations that are prognostic for survival in patients with pancreatic cancer. We observe improved survival in patients with DDR gene mutations and worsened survival in patients with deleterious mutations in non-DDR genes.
Introduction: We aimed to determine the prevalence and landscape of germline mutations among patients with young onset pancreatic ductal adenocarcinoma (PDAC) as well as their influence in prognosis. Methods: Patients from two cohorts were studied, the High Risk Cohort (HRC) which included 584 PDAC patients who received genetic counseling at MD Anderson Cancer Center and a General Cohort (GC) with 233 metastatic PDAC patients. We defined germline DNA sequencing on 13 known pancreatic cancer susceptibility genes. The prevalence and landscape of mutations was determined and clinical characteristics including survival were analyzed. Results: A total of 409 patients underwent genetic testing (277 from HRC and 132 from GC). As expected, the HRC had higher prevalence of germline mutations compared to the GC: 17.3% vs 6.81%. The most common mutations in both cohorts were in BRCA1/2 and mismatch repair (MMR) genes. Patients younger than 60 years old had significantly higher prevalence of germline mutations in both the HRC (OR: 1.93 +/−1.03–3.70, P: 0.039) and GC (4.78 +/−1.10–32.95, P: 0.036). Furthermore, PDAC patients with germline mutations in the GC had better overall survival than patients without mutations (HR= 0.44, 95% CI of HR: 0.25–0.76, p: 0.030). Discussion Germline mutations are highly prevalent in patients with PDAC of early-onset and can be predictive of better outcomes. Considering emerging screening strategies for relatives carrying susceptibility genes as well as impact on therapy choices, genetic counseling and testing should be encouraged in PDAC patients, particularly those of young onset.
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