Background
The purpose of this study was to determine whether neoadjuvant and/or perioperative chemotherapy (NAC) has an overall survival (OS) benefit for patients with T2N0 gastric adenocarcinoma.
...Study Design
We performed retrospective analyses using the National Cancer Data Base, 2004‐2013. Patients with T2N0 gastric adenocarcinoma were divided into two treatment groups: (1) NAC plus surgery (NA + S) and (2) surgery alone (S).
Results
Of 1,704 patients included, 277 (16.3%) received NAC, and 1,427 (83.7%) were treated with surgery alone. Patients in the NA + S group were more likely to be younger, have fewer comorbidities, and have larger tumors located in the proximal stomach. Although in an unadjusted analysis of OS, the NA + S group had improved survival compared to the S group (HR = 0.81, 95% CI 0.67‐0.99, P < 0.0001), this was not maintained in a propensity adjusted analysis (HR = 0.89, 95% CI 0.68‐1.18, P = 0.42). Similarly, propensity adjusted analyses accounting for potential bias from clinical misstaging or treatment effect from NAC did not show any OS benefit from NAC.
Conclusion
Based on the largest cohort of clinically staged T2N0 gastric adenocarcinoma, there was no OS benefit derived from NAC compared to surgery alone. For select patients with reliable preoperative staging, NAC may be omitted.
NSC319726 (ZMC1) is a small molecule that reactivates mutant p53 by restoration of WT structure/function to the most common p53 missense mutant (p53-R175H). We investigated the mechanism by which ...ZMC1 reactivates p53-R175H and provide evidence that ZMC1: 1) restores WT structure by functioning as a zinc-metallochaperone, providing an optimal concentration of zinc to facilitate proper folding; and 2) increases cellular reactive oxygen species that transactivate the newly conformed p53-R175H (via post-translational modifications), inducing an apoptotic program. We not only demonstrate that this zinc metallochaperone function is possessed by other zinc-binding small molecules, but that it can reactivate other p53 mutants with impaired zinc binding. This represents a novel mechanism for an anti-cancer drug and a new pathway to drug mutant p53.
We have elucidated a novel mechanism to restore wild-type structure/function to mutant p53 using small molecules functioning as zinc-metallochaperones. The pharmacologic delivery of a metal ion to restore proper folding of a mutant protein is unique to medicinal chemistry and represents a new pathway to drug mutant p53.
Abstract
Purpose: Although a recent genomic landscape study identified molecular and genetic signatures of immune cytolytic activity (CYT) related to immune-mediated cancer elimination, less is known ...about the clinical relevance of CYT in the tumors linked to immune microenvironment in breast cancer. The aim of our study was to assess whether intratumor CYT associates with genetic alterations and tumor immune microenvironment, which impacts survival in breast cancer patients.
Experimental Design: We utilized genomic data from primary samples of 1,090 breast cancer patients with clinicopathologic information from The Cancer Genome Atlas (TCGA). We developed an immunogenomics pipeline that correlates CYT with clinical outcome and intratumor immune microenvironment, including infiltrating immune cell composition.
Results: Breast cancer displays a range of intratumor CYT. Patients with high CYT showed significantly better prognostic outcome, independent of age, hormonal status, and stage. CYT also has a strongly positive association with the expression of immune checkpoint genes such as PD1, PD-L1, and CTLA4, as well as regulatory T-cell (Treg) markers such as FOXP3 and CCR4. Enrichment of immune-response gene sets was observed in the high-CYT tumors. CYT was associated with higher composition of immune-elimination cells such as CD8+ T-cell, CD4+ T-cell, gamma delta T-cell, and M1 macrophage, as opposed to negatively associated with immunosuppressive cells, such as Treg and M2 macrophage. High CYT was also associated with improved survival in tumor-infiltrating lymphocyte (TIL)-positive breast cancer.
Conclusions: Patients with high CYT breast cancers show improved survival, likely due to high intratumor immunogenicity. CYT could also be used as a potential biomarker for immunologic response within tumors.
Citation Format: Tstutomu Kawaguchi, Qianya Qi, Xuan Peng, Kerry-Ann McDonald, Sumana Narayanan, Jessica Young, Song Liu, Li Yan, Kazuaki Takabe. Local immune cytolytic activity stratifies clinical outcome and is linked to the immune microenvironment in breast cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 120.
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Background: Neoadjuvant chemotherapy is increasingly being utilized for locally advanced (LAPC)/borderline resectable pancreatic cancer (BRPC); however, long term follow up data is ...sparse. At our institution, we use FOLFIRINOX as the regimen of choice. Gemcitabine (Gem) and nab-Paclitaxel (Abraxane) is utilized in patients not suited for FOLFIRINOX or if they have poor radiographic response and/or develop significant toxicities to FOLFIRINOX. The aim of this study was to report our institutional experience with neoadjuvant therapy for patients with advanced pancreatic cancer. Methods: A retrospective review was performed of all patients with BRPC or LAPC who received FOLFIRINOX (or a modified regimen), Gem/nab-Paclitaxel, or both prior to surgical resection. FOLFIRINOX was typically given for 4 – 6 cycles while gem/nab-Paclitaxel was given for 2 cycles. Results: From January 2011 to December 2015, 39 patients were identified who met the study criteria. Eight patients received FOLFIRINOX alone (median age 62), 20 patients received FOLFIRINOX + Gem/nab-Paclitaxel, and 11 received only Gem/nab-Paclitaxel (median age 72). Eighteen patients (46%) completed the intended cycles of chemotherapy. Twenty two patients had a radiologic and/or biomarker response. Exploration was performed in 25 of 39 (64%) patients of whom 20 (51%) underwent curative resection. Of the 20 resected patients, there were no post-operative deaths. The median tumor size, median lymph node ratio, and R0 resection rates were 2.4 cm, 0, and 85% for the entire cohort. Median follow up was 20.7 months. The median overall survival for the resected cohort was not reached vs 13.5 months in the no resection group; two year overall survival for the resection vs. no resection groups was 87% vs 16% (p < .001). Conclusions: FOLFIRINOX and/or Gemcitabine/nab-Paclitaxel as neoadjuvant therapy for LAPC/BRPC is fairly well tolerated, leads to appreciable rates of margin negative surgical resection, and a significant overall survival advantage.
The purpose of this study was to characterize disparities among centers performing major surgery for esophageal or gastric cancer stratified by case volume.
The National Cancer Data Base (NCDB) was ...queried for cases of esophagectomy or total gastrectomy. Centers were compared based on number of cases during 2004-2013: low volume 1-99, middle 100-200, and high >200.
For esophagectomy, 17,547 patients were included; 73.5% were treated in low volume centers, 14.6% in middle, and 11.9% in high. For gastrectomy, 20,059 patients were included, with 87.5%, 8.3%, and 4.3%, respectively. Patients treated at low volume centers were more likely to be of racial/ethnic minorities, uninsured, and have lower socioeconomic status. Overall survival (OS) was superior for patients treated at high volume centers. On multivariable analysis for either procedure, a higher number of disparate factors was identified in the low and middle volume centers compared to the high volume centers, which were associated with poorer OS.
This study identified higher numbers of disparate patient factors associated with low/middle volume centers compared to high volume centers, which were associated with worse OS, and further makes the case for performance of esophagectomy and total gastrectomy at high volume centers.
Evaluation of the functional aspects if the tumor immune microenvironment (TIME), such as the recently introduced cytolytic activity score (CYT) index have been under the spotlight in cancer ...research; however, clinical relevance of immune cell killing activity in breast cancer has never been analyzed in large patient cohorts. We hypothesized that CYT reflects the immune activity of TIME and can predict patient survival. A total of 7533 breast cancer patients were analyzed as both discovery and validation cohorts. We found that high CYT was associated with advanced histological grade and triple-negative breast cancer (TNBC). High CYT in tumors was significantly associated with better survival in TNBC, but unexpectedly, not in other breast cancer subtypes. High CYT TNBC included both favorable immune-related, as well as unfavorable (suppressive) inflammation-related gene sets, and characterized by high infiltration with T cells and B cells. High CYT TNBC was associated with high homologous recombination deficiency and low somatic copy number alteration score and less mutant allele tumor heterogeneity, but not with tumor mutation burden (TMB). Although CYT was not associated with pathological complete response after neoadjuvant chemotherapy, it was significantly associated with high expression of multiple immune checkpoint molecules. In conclusion, CYT of TNBC is associated with enhanced anti-cancer immunity, less intra-tumoral heterogeneity, and with better survival.
Abstract
NSC319726 (ZMC1) is a small molecule that reactivates mutant p53 by restoration of WT structure/function to the most common p53 missense mutant (p53-R175H). We investigated the mechanism by ...which ZMC1 reactivates p53-R175H and provide evidence that ZMC1: 1) restores WT structure by functioning as a zinc-metallochaperone, providing an optimal concentration of zinc to facilitate proper folding; 2) increases cellular reactive oxygen species that transactivate the newly conformed p53-R175H (via post-translational modifications), inducing an apoptotic program. We not only demonstrate that this zinc metallochaperone function is possessed by other zinc-binding small molecules, but that it can reactivate other p53 mutants with impaired zinc binding. This represents a novel mechanism for an anti-cancer drug and a new pathway to drug mutant p53.
Citation Format: Xin Yu, Adam R. Blanden, Sumana Narayanan, Lalithapriya Jayakumar, David Lubin, David J. Augeri, S. David Kimball, Stewart N. Loh, Darren R. Carpizo. Small molecule restoration of wildtype structure and function of mutant p53 using a novel zinc metallochaperone based mechanism. abstract. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1761. doi:10.1158/1538-7445.AM2015-1761
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