Despite improvements in cancer management, most pancreatic cancers are still diagnosed at an advanced stage. We have recently identified promoter DNA methylation of the genes ADAMTS1 and BNC1 as potential blood biomarkers of pancreas cancer. In this study, we validate this biomarker panel in peripheral cell-free tumor DNA of patients with pancreatic cancer. Sensitivity and specificity for each gene are as follows: ADAMTS1 87.2% and 95.8% (AUC = 0.91; 95% CI 0.71–0.86) and BNC1 64.1% and 93.7% (AUC = 0.79; 95% CI 0.63–0.78). When using methylation of either gene as a combination panel, sensitivity increases to 97.3% and specificity to 91.6% (AUC = 0.95; 95% CI 0.77–0.90). Adding pre-operative CA 19-9 values to the combined two-gene methylation panel did not improve sensitivity. Methylation of ADAMTS1 was found to be positive in 87.5% (7/8) of stage I, 77.8% (7/9) of stage IIA, and 90% (18/20) of stage IIB disease. Similarly, BNC1 was positive in 62.5% (5/8) of stage I patients, 55.6% (5/9) of stage IIA, and 65% (13/20) of patients with stage IIB disease. The two-gene panel (ADAMTS1 and/or BNC1) was positive in 100% (8/8) of stage I, 88.9% (8/9) of stage IIA, and 100% (20/20) of stage IIB disease. The sensitivity and specificity of the two-gene panel for localized pancreatic cancer (stages I and II), where the cancer is eligible for surgical resection with curative potential, was 94.8% and 91.6% respectively. Additionally, the two-gene panel exhibited an AUC of 0.95 (95% CI 0.90–0.98) compared to 57.1% for CA 19-9 alone. The methylation status of ADAMTS1 and BNC1 in cfDNA shows promise for detecting pancreatic cancer during the early stages when curative resection of the tumor is still possible. This minimally invasive blood-based biomarker panel could be used as a promising tool for diagnosis and screening in a select subset of high-risk populations.

Sarcomas in the United States: Recent trends and a call for improved staging Sarcomas in the United States: Recent trends and a call for improved staging

Triple-negative breast cancer (TNBC) is considered one of the highest-risk subtypes of breast cancer and has dismal prognosis. Local recurrence rate after standard therapy in the early breast cancer setting can be upwards to 72% in 5 years, and in the metastatic setting, the 5-year overall survival is 12%. Due to the lack of receptor expression, there has been a paucity of targeted therapeutics available, with chemotherapy being the primary option for systemic treatment in both the neoadjuvant and metastatic setting. More recently, immunotherapy has revolutionized the landscape of cancer treatment, particularly immune checkpoint inhibitor (ICI) therapy, with FDA approval in over 20 types of cancer since 2011. Compared to other cancer types, breast cancer has been traditionally thought of as being immunologically cold; however, TNBC has demonstrated the most promise with immunotherapy use, a timely discovery due to its lack of targeted therapy options. In this review, we summarize the trials using checkpoint therapy in early and metastatic TNBC, as well as the development of biomarkers and the importance of immune related adverse events (IRAEs), in this disease process.

Metastatic colorectal cancer (CRC) is poorly immunogenic, with limited neoantigens that can be targeted by cancer vaccine. Previous approaches to upregulate neoantigen have had limited success. In this study, we investigated the role of a DNA methyltransferase inhibitor (DNMTi), 5-aza-2′-deoxycytidine (DAC), in inducing cancer testis antigen (CTA) expression and evaluated the antitumor efficacy of a combinatorial approach with an epigenetically regulated cancer vaccine EpiGVAX and DAC. A murine model of metastatic CRC treated with combination therapy with an irradiated whole-cell CRC vaccine (GVAX) and DAC was used to assess the antitumor efficacy. DAC significantly induced expression of CTAs in CRC, including a new CTA Tra-P1A with a known neoepitope, P1A. Epigenetically modified EpiGVAX with DAC improved survival outcomes of GVAX. Using the epigenetically regulated antigen Tra-P1A as an example, our study suggests that the improved efficacy of EpiGVAX with DAC may due in part to the enhanced antigen-specific antitumor immune responses. This study shows that epigenetic therapy with DNMTi can not only induce new CTA expression but may also sensitize tumor cells for immunotherapy. Neoantigen-based EpiGVAX combined with DAC can improve the antitumor efficacy of GVAX by inducing antigen-specific antitumor T cell responses to epigenetically regulated proteins.

Pancreatic cancer is an aggressive cancer with low survival rates. Genetic and epigenetic dysregulation has been associated with the initiation and progression of pancreatic tumors. Multiple studies have pointed to the involvement of aberrant chromatin modifications in driving tumor behavior. ATP-dependent chromatin remodeling complexes regulate chromatin structure and have critical roles in stem cell maintenance, development, and cancer. Frequent mutations and chromosomal aberrations in the genes associated with subunits of the ATP-dependent chromatin remodeling complexes have been detected in different cancer types. In this review, we summarize the current literature on the genomic alterations and mechanistic studies of the ATP-dependent chromatin remodeling complexes in pancreatic cancer. Our review is focused on the four main subfamilies: SWItch/sucrose non-fermentable (SWI/SNF), imitation SWI (ISWI), chromodomain-helicase DNA-binding protein (CHD), and INOsitol-requiring mutant 80 (INO80). Finally, we discuss potential novel treatment options that use small molecules to target these complexes.