While the incidence of gastric cancer has decreased worldwide in recent decades,the incidence of signetring cell carcinoma(SRCC) is rising. SRCC has a specific epidemiology and oncogenesis and has ...two forms: early gastric cancer,which can be resected endoscopically in some cases and which has a better outcome than non-SRCC,and advanced gastric cancer,which is generally thought to have a worse prognosis and lower chemosensitivity than non-SRCC. However,the prognosis of SRCC and its chemosensitivity with specific regimens are still controversial as SRCC is not specifically identified in most studies and its poor prognosis may be due to its more advanced stage. It therefore remains unclear if a specific therapeutic strategy is justified,as the benefit of perioperative chemotherapy and the value of taxanebased chemotherapy are unclear. In this review we analyze recent data on the epidemiology,oncogenesis,prognosis and specific therapeutic strategies in both early and advanced SRCC of the stomach and in hereditary diffuse gastric cancer.
The progressive conversion of normal cells into cancer cells is characterized by the acquisition of eight hallmarks. Among these criteria, the capability of the cancer cell to avoid the immune ...destruction has been noted. Thus, tumors develop mechanisms to become invisible to the immune system, such as the induction of immunosuppressive cells, which are able to inhibit the development of an efficient immune response. Molecules produced in the tumor microenvironment are involved in the occurrence of an immunosuppressive microenvironment. Recently, it has been shown that vascular endothelial growth factor A (VEGF-A) exhibits immunosuppressive properties in addition to its pro-angiogenic activities. VEGF-A can induce the accumulation of immature dendritic cells, myeloid-derived suppressor cells, regulatory T cells, and inhibit the migration of T lymphocytes to the tumor. Other pro-angiogenic factors such as placental growth factor (PlGF) could also participate in tumor-induced immunosuppression, but only few works have been performed on this point. Here, we review the impact of pro-angiogenic factors (especially VEGF-A) on immune cells. Anti-angiogenic molecules, which target VEGF-A/VEGFR axis, have been developed in the last decades and are commonly used to treat cancer patients. These drugs have anti-angiogenic properties but can also counteract the tumor-induced immunosuppression. Based on these immunomodulatory properties, anti-angiogenic molecules could be efficiently associated with immunotherapeutic strategies in preclinical models. These combinations are currently under investigation in cancer patients.
Strong evidence supports the concept of immunosurveillance and immunoediting in colorectal cancer.In particular,the density of T CD8+and CD45+lymphocyte infiltration was recently shown to have a ...better prognostic value than the classic tumor node metastasis classification factor.Other immune subsets,as macrophages,natural killer cells or unconventionnal lymphocytes,seem to play an important role.Induction of regulatory T cells(Tregs)or immunosuppressive molecules such as PD-1 or CTLA-4 and downregulation of antigen-presenting molecules are major escape mechanisms to antitumor immune response.The development of these mechanisms is a major obstacle to the establishment of an effective immune response,but also to the use of immunotherapy.Although im-munotherapy is not yet routinely used in colorectal cancer,we now know that most treatments used(chemotherapy and biotherapy)have immunomodulatory effects,such as induction of immunogenic cell death by chemotherapy,inhibition of immunosuppression by antiangiogenic agents,and antibody-dependent cytotoxicity induced by cetuximab.Finally,many immunotherapy strategies are being developed and tested in phaseⅠtoⅢclinical trials.The most promising strategies are boosting the immune system with cytokines,inhibition of immunoregulatory checkpoints,vaccination with vectorized antigens,and adoptive cell therapy.Comprehension of antitumor immune response and combination of the different approaches of immunotherapy may allow the use of effective immunotherapy for treatment of colorectal cancer in the near future.
A fundamental concern of the majority of cancer scientists is related to the identification of mechanisms involved in the evolution of neoplastic cells at the cellular and molecular level and how ...these processes are able to control cancer cells appearance and death. In addition to the genome contribution, such mechanisms involve reciprocal interactions between tumor cells and stromal cells within the tumor microenvironment (TME). Indeed, tumor cells survival and growth rely on dynamic properties controlling pro and anti-tumorigenic processes. The anti-tumorigenic function of the TME is mainly regulated by immune cells such as dendritic cells, natural killer cells, cytotoxic T cells and macrophages and normal fibroblasts. The pro-tumorigenic function is also mediated by other immune cells such as myeloid-derived suppressor cells, M2-tumor-associated macrophages (TAMs) and regulatory T (Treg) cells, as well as carcinoma-associated fibroblasts (CAFs), adipocytes (CAA) and endothelial cells. Several of these cells can show both, pro- and antitumorigenic activity. Here we highlight the importance of the reciprocal interactions between tumor cells and stromal cells in the self-centered behavior of cancer cells and how these complex cellular interactions control tumor progression and repression.
There is currently no standard second-line treatment for metastatic pancreatic adenocarcinoma (MPA), and progression-free survival is consistently <4 months in this setting. The aim of this study was ...to evaluate the efficacy and tolerability of Nab-paclitaxel plus gemcitabine (A+G) after Folfirinox failure in MPA.
From February 2013 to July 2014, all consecutive patients treated with A+G for histologically proven MPA after Folfirinox failure were prospectively enrolled in 12 French centres. A+G was delivered as described in the MPACT trial, until disease progression, patient refusal or unacceptable toxicity.
Fifty-seven patients were treated with Nab-paclitaxel plus gemcitabine, for a median of 4 cycles (range 1-12). The disease control rate was 58%, with a 17.5% objective response rate. Median overall survival (OS) was 8.8 months (95% CI: 6.2-9.7) and median progression-free survival was 5.1 months (95% CI: 3.2-6.2). Since the start of first-line chemotherapy, median OS was 18 months (95% CI: 16-21). No toxic deaths occurred. Grade 3-4 toxicities were reported in 40% of patients, consisting of neutropenia (12.5%), neurotoxicity (12.5%), asthenia (9%) and thrombocytopenia (6.5%).
A+G seems to be effective, with a manageable toxicity profile, after Folfirinox failure in patients with MPA.
In metastatic colorectal cancer (mCRC), circulating tumor DNA (ctDNA) monitoring can be used to genotype tumors and track clonal evolution. We investigated the clearance of RAS mutated clones under ...chemotherapy pressure by ctDNA analysis in patients with a RAS mutated mCRC. Patients with a RAS mutated tumor included in the prospective PLACOL study were monitored for ctDNA. Analyses were based on optimized targeted next‐generation sequencing and/or droplet‐based digital polymerase chain reaction (ddPCR). For plasma samples without detectable mutations at progression disease, we tested the methylation status of WIF1 and NPY genes using methylation‐ddPCR (met‐ddPCR) to validate the presence of ctDNA. Among the 36 patients with positive plasma samples for RAS mutations at inclusion, 28 (77.8%) remained RAS positive at disease progression and 8 (22.2%) became negative. Subsequent met‐ddPCR for methylated markers showed that only two out of the eight patients with RAS negative plasma had detectable ctDNA at progression. Therefore, only 2 samples among 36 were confirmed for clearance of RAS mutation in our series. In conclusion, this study suggests that the clearance of RAS mutations in patients treated by chemotherapy for a RAS mutated mCRC is a rare event. Monitoring tumor mutations in plasma samples should be combined with a strict control of the presence of ctDNA. The therapeutic impacts of RAS clearance need to be further explored.
What's new?
Evidence indicates that in about half of chemotherapy‐treated metastatic colorectal (mCRC) patients, RAS status switches from mutant to wild‐type, with possible therapeutic implications. Here, analyses of circulating tumor DNA (ctDNA) were used to monitor RAS mutation in mCRC patients treated with chemotherapy. More than three‐quarters of patients were found to be positive for RAS mutation at the time of disease progression, while remaining patients were RAS mutation‐negative. However, assessment of methylation status of WIF1 and NPY genes to validate ctDNA presence in RAS‐negative patients revealed that overall, out of 36 patients, just two experienced complete RAS mutation clearance by chemotherapy.
Triplet chemotherapy, with docetaxel-5FU-oxaliplatin (TEFOX), has yielded promising results in patients with advanced and operable gastric adenocarcinoma. This may prove useful in treating signet ...ring cell carcinoma (SRCC), which is known to be chemoresistant and has a poor prognosis. We therefore evaluated TEFOX in patients with untreated advanced SRCC.
Patients with metastatic or locally advanced non-resectable SRCC were treated with TEFOX. Chemotherapy was administered every 14 days, with combined docetaxel (50 mg/m
) and oxaliplatin (85 mg/m
) followed by 5FU (2400 mg/m
).
Among 65 patients enrolled, including 17 with linitis plastica, ORR and DCR were 66.1% and 87.6%, respectively. Median PFS and OS were 9.7 months (95% CI 6.9-11.4) and 14.3 months (95% CI 11.6-21.6) respectively. Twenty-six patients (40%) initially considered as unresectable had secondary resection (n = 24) or radiotherapy (n = 2) with curative intent, with median PFS and OS of 12.4 and 26.2 months, respectively.
TEFOX appears to be effective as first-line treatment in advanced gastric SRCC and has an acceptable safety profile. It allowed a curative intent approach in 40% of patients. Considering the low chemosensitivity of SRCC reported with other chemotherapy regimens and pending for randomised studies, TEFOX might be an option in advanced gastric SRCC.
Abstract only
4019
Background: Regorafenib (R) has been shown to modulate anti-tumor immunity by different mechanisms including reduction of tumor-associated macrophages (TAMs). Synergy between R and ...anti–PD-1/PD-L1 antibodies has been shown in pre-clinical models. Methods: This is a single-arm open-label multicentric phase II trial assessing the efficacy and safety of R (160 mg QD 3weeks/4) + Avelumab (A) (10 mg/kg every 2 weeks) combination in non MSI-H mCRC patients (pts). The primary endpoint was the confirmed objective response rate, based on central review according to RECIST 1.1. Secondary endpoints included: 1-year progression free survival (PFS), 1-year overall survival (OS), and Safety using NCI-CTCAE v5.0. Correlative studies were planned from pts tumor samples obtained at baseline and C2D1. Results: Between Nov. 2018 and Oct. 2019, 48 pts were enrolled in 4 centers. Median age was 61.8 (range: 26.3-78.7). Median follow-up was: 7.2 months. Median number of previous treatment lines was: 3 (range: 1-7). 41 (87.2%) pts experienced at least 1 dose modification or treatment interruption. The most common grade 3/4 adverse events were palmar-plantar erythro-dysesthesia syndrome (29.8%), hypertension (23.4%) and diarrhea (12.8%). No death was related to the treatment. Among 40 pts who had at least one imaging tumor assessment, 12 (30%) had reduction in tumor burden. Best response was stable disease for 23 pts (57.5%) and progressive disease for 17 pts (42.5%). The median PFS and OS were 3.6 months (CI
95%
: 1.8 – 5.4) and 10.8 months (CI
95%
: 5.9 – NA) respectively. Baseline tumor samples and paired biopsies were available for 24 and 15 pts respectively. High infiltration by TAMs at baseline was significantly associated with adverse outcome (PFS: 1.9 vs 3.7 months, p=0.045; OS: 4.8 months vs NR, p=0.027). Increased tumor infiltration by CD8+ at C2D1 compared to baseline was significantly associated with better PFS (p=0.011). Combining low TAMs infiltration and low tumor cells to CD8+ T cells distance enabled the identification of a subgroup of pts (n= 6/24, 25%) more likely to benefit from R+A combination: median PFS: 5.3 vs 1.9 months (p=0.037); median OS: NR vs 5.3 months (p=0.02). Conclusions: The R+A combination achieved PFS and OS that compared favourably with historical data of R alone in this clinical setting. High-resolution analysis of tumor samples identified a composite score based on TAMs infiltration and tumor cell to CD8+ T cells distance which could be used as a biomarker in further studies investigating this approach in mCRC pts. Clinical trial information: NCT03475953 .
The overexpression of the immunoinhibitory receptor programmed death-1 (PD1) on T-cells is involved in immune evasion in cancer. The use of anti-PD-1/PDL-1 strategy has deeply changed the therapies ...of cancers and patient survival. However, their efficacy diverges greatly along with tumor type and patient populations. Thereby, novel treatments are needed to interfere with the anti-tumoral immune responses and propose an adjunct therapy. In the current study, we found that the antifungal drug Sulconazole (SCZ) inhibits PD-1 expression on activated PBMCs and T cells at the RNA and protein levels. SCZ repressed NF-κB and calcium signaling, both, involved in the induction of PD-1. Further analysis revealed cancer cells treatment with SCZ inhibited their proliferation, and migration and ability to mediate tumor growth in zebrafish embryos. SCZ found also to inhibit calcium mobilization in cancer cells. These results suggest the SCZ therapeutic potential used alone or as adjunct strategy to prevent T-cell exhaustion and promotes cancer cell malignant phenotype repression in order to improve tumor eradication.
Archival tissue samples collected longitudinally from a patient who died from HPV16-induced high-grade anal intraepithelial squamous cell carcinoma with vertebral HPV16-positive metastasis were ...retrospectively analyzed by the Capture-HPV method (Capt-HPV) followed by Next-Generation Sequencing (NGS). Full length nucleotide sequences of the same HPV16 were identified from the initial and second anal biopsy samples, from plasma sample and from vertebral metastasis biopsy. Remarkably, HPV was episomal in each sample. The HPV genome sequence was closest to the HPV16 Qv18158E variant subtype (A1 lineage) exhibiting base substitutions and deletions in 7 and 2 HPV loci, respectively. In conclusion, the powerful Capt-HPV followed by NGS allows evidencing the detailed cartography of tumoral and circulating HPV DNA, giving rise to a unique and unexpected episomal virus molecular status in a context of aggressive carcinoma, underlying the importance of HPV status and its association with clinical features for further prospective studies.
PDF
